There are some new kids on the block at the Old Man on His Back (OMB) Prairie and Heritage Conservation Area that will help to bring vitality and diversity to the bison herd.

The Nature Conservancy of Canada (NCC) is adding five young bison bulls to the herd as part of a revised management plan to grow the herd.

The bulls have already arrived at OMB and will be integrated with the herd during the annual roundup, when the herd is moved to their winter pasture.

It will definitely shake things up a little bit, because the existing bulls in the herd are all quite a bit older than these ones, NCC Program Director for Southwest Saskatchewan Michael Burak said. We don't anticipate that they'll consider them to be too much of a threat necessarily. There definitely will be a couple of squabbles here and there. It will really depend largely on the attitude of the five that we just brought in. If they're really trying to push boundaries and trying to test some of those older animals, they'll be put in their place pretty quickly.

The introduction of the young bulls during the annual roundup is done on purpose to make their arrival less noticeable, because there is a lot of movement and change during the herds shift from the summer to winter pasture.

Everybody is a little bit confused and there was a really big kind of change and a shift that happened, he said. They all go through a handling system. So they're all a little bit stressed out. It's kind of the perfect time to just push everybody out into their winter pasture at the same time and hopefully they will not notice that there's all of a sudden these extra individuals that weren't there previously.

The five bulls arrived about a month ago. They were released into a separate paddock to give them time to adjust to their new surroundings and their health can also be monitored before their introduction to the herd.

The date for the roundup will depend on when the herd decides to come into the corral, which usually only happens when there is already a good snow cover and they can be attracted with bales of hay.

All five bulls were born in 2017 and they are around two-and-a-half years old. They were born and raised in Canada, but their lineage can be traced back to the northern United States, including the bison herd at Theodore Roosevelt National Park in North Dakota.

They came from three different producers. Three are from different areas of Saskatchewan. Two are from a producer in the Prince Albert area and another one was obtained from a producer near Shaunavon. Two came from a producer in central Alberta.

The OMB herd is genetically pure plains bison and the new arrivals were evaluated to confirm they are also the same. Genetic samples were submitted to the University of California, Davis, where tests were done to determine the presence of any cattle genes in those animals. The Alberta producer has done regular genetic tests on his herd, and he picked bulls that he knew are genetically pure.

These bulls will have a lot more space to roam when they join the herd on the vast plains of the OMB conservation area.

I think it's definitely going to be a bit of a change for them, Burak said. They may not be used to having quite as much open space, but I don't think it would be too big a transition for them. Normally with bison, they tend to just want to stick socially close to each other.

The OMB conservation area covers 13,088 acres (5,297 hectares) and is located in the R.M. of Frontier, 15 kilometres west of Claydon and 210 kilometres southwest of Swift Current. NCC manages OMB as a working ranch, and the bison will graze on about 9,000 acres of land. The remaining 4,000 acres are used for annual grazing by about 200 cattle from around 11 neighbouring ranchers from early June to mid October.

We're really pleased with how the whole bison introduction and the bison program have been going, he said. We're definitely achieving the goals that we set for ourselves as far as keeping the property healthy and making sure the grass is nice and productive, and that it is being grazed in a sustainable way. We're really proud of the way that we are able to showcase the differences or the similarities as well between cattle and bison grazing.

The original introduction of a group of 50 two-year-old plains bison to the OMB conservation area took place in the winter of 2003. They came from Elk Island National Park in central Alberta. There were 25 males and 25 females, but over time the NCC staff realized this 50 per cent split between the two sexes did not work. There were too many male animals, and over time the composition of the herd was changed.

There are currently seven adult bulls (excluding the five new arrivals), 68 adult cow, and nine calves (six yearling heifers and three yearling bulls) that were kept back from the previous calving. The introduction of the five young bulls will help to diversify the genetics of the herd and the goal is to increase the size of the herd to about 100 breeding individuals.

We've been in the process of rewriting a management plan for that herd for probably the better part of a year now to shift towards managing them in a more natural kind of way, Burak said. That would involve the herd being larger for one, as well as we'll have more breadth within our age classes. Right now, the majority of our herd is about 10 years old and older, whereas in a natural herd you would probably have your largest age class from about four to eight years old and then you would have a continuum of younger animals and then some older.

The easiest and least expensive way to grow the herd will be to just keep their own calves back every year, but that will have a potentially negative effect on genetic diversity.

If we're keeping calves with only our current herd bulls left in there, then we have a pretty good chance that they'll actually end up bred back to their relatives or even their fathers, he explained. That's why we brought five more in so that we have a bit more variation and we can spread that out a bit more and dilute the effect of any inbreeding that we might see.

NCC staff still need to do more work to evaluate the carrying capacity of the conservation area as part of the implementation of the revised management plan. They will look at the kind of grass production on the property and that information will be compared with data on the forage needs of bison. They also have to take into account the needs of other foragers, and they will calculate the natural grazing rate of other wild ungulates such as deer.

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Five bulls joining bison herd at Old Man on His Back conservation area - Prairie Post

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Interferon Insight

Uncontrolled type I IFN activity has been linked to several human pathologies, but evidence implicating this cytokine response directly in disease has been limited. Here, Duncan et al. identified a homozygous missense mutation in STAT2 in siblings with severe early-onset autoinflammatory disease and elevated IFN activity. STAT2 is a transcription factor that functions downstream of IFN, and this STAT2R148W variant was associated with elevated responses to IFN/ and prolonged JAK-STAT signaling. Unlike wild-type STAT2, the STAT2R148W variant could not interact with ubiquitin-specific protease 18, which prevented STAT2-dependent negative regulation of IFN/ signaling. These findings provide insight into the role of STAT2 in regulating IFN/ signaling in humans.

Excessive type I interferon (IFN/) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN/, which manifest as prolonged Janus kinasesignal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN/ signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN/ signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN/ activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Type I interferons (including IFN/) are antiviral cytokines with pleiotropic functions in the regulation of cellular proliferation, death, and activation. Reflecting their medical importance, type I IFNs have been shown to be essential to antiviral immunity in humans (1), whereas their potent immunomodulatory effects have been exploited to treat both cancer and multiple sclerosis (2, 3).

IFN/ also demonstrates considerable potential for toxicity, which became apparent in initial studies in rodents (4) and subsequent clinical experience in patients (5, 6). Thus, the production of and response to type I IFNs must be tightly controlled (7). Transcriptional biomarker studies increasingly implicate dysregulated IFN/ activity in a diverse spectrum of pathologies ranging from autoimmune to neurological, infectious and vascular diseases (811).

The immunopathogenic potential of IFN/ is exemplified by a group of monogenic inborn errors of immunity termed type 1 interferonopathies, wherein enhanced IFN/ production is hypothesized to be directly causal (12). Neurological disease is typical of these disorders, which manifest as defects of neurodevelopment in association with intracranial calcification and white matter changes on neuroimaging, suggesting that the brain is particularly vulnerable to the effects of excessive type I IFN activity (9). A spectrum of clinical severity is recognized, from prenatal-onset neuroinflammatory disease that mimics in utero viral infectionAicardi-Goutires syndrome (13)to a clinically silent elevation of IFN activity (14).

However, the central tenet of the type I interferonopathy hypothesis, namely, the critical pathogenic role of type I IFNs (12), has yet to be formally established (15). Evidence for an IFN-independent component to disease includes (i) recognition that other proinflammatory cytokines are also induced by nucleic acid sensing, which might contribute to pathogenesis (16); (ii) imperfect correlations between IFN biomarker status and disease penetrance (14); (iii) the absence of neuropathology in mouse models of Aicardi-Goutires syndrome despite signatures of increased IFN activity (17); and (iv) the observation that crossing to a type I IFN receptor deficient background does not rescue the phenotype in certain genotypes (e.g., STING and ADAR1) (18, 19), although it does in others (e.g., TREX1 or USP18) (20, 21). Here, we provide concrete evidence of the pathogenicity of type I IFNs in humans, shedding new light on the critical importance of signal transducer and activator of transcription 2 (STAT2) in the negative regulation of this pathway.

We evaluated two male siblings, born in the United Kingdom to second cousin Pakistani parents. Briefly, patient II:3, born at 34 weeks + 6 days with transient neonatal thrombocytopenia, was investigated for neurodevelopmental delay at 6 months (which was attributed to compensated hypothyroidism). Aged 8 months, he presented with the first of three episodes of marked neuroinflammatory disease, associated with progressive intracranial calcification, white matter disease, and, by 18 months, intracranial hemorrhage (Fig. 1A). These episodes were associated with systemic inflammation and multiorgan dysfunction, including recurrent fever, hepatosplenomegaly, cytopenia with marked thrombocytopenia, raised ferritin, and elevated liver enzymes. Latterly, acute kidney injury with hypertension and nephrotic range proteinuria developed (see Table 1, Supplementary case summary, and table S1).

(A) Neuroimaging demonstrating calcifications [brainstem/hypothalamus (proband II:3, top), cerebral white matter/basal ganglia/midbrain/optic tract (sibling II:4, top and middle)], hemorrhages [occipital/subdural/subarachnoid (proband II:3, middle)], and cerebral white matter and cerebellar signal abnormality with parenchymal volume loss (both, bottom), accompanied by focal cystic change and cerebellar atrophy (sibling II:4). (B) Whole blood RNA-seq ISG profiles: controls (n = 5); proband II:3 (n = 4); and patients with mutations in: TREX1 (n = 6), RNASEH2A (n = 3), RNASEH2B (n = 7), RNASEH2C (n = 5), SAMHD1 (n = 5), ADAR1 (n = 4), IFIH1 (n = 2), ACP5 (n = 3), TMEM173 (n = 3), and DNASE2 (n = 3). (C) IFN scores (RT-PCR) of patients, parents, and n = 29 healthy controls. ****P < 0.001, ANOVA with Dunnetts posttest. (D) Renal histopathology in proband (400 magnification) showing TMA with extensive double contouring of capillary walls (silver stain, top left); endothelial swelling, mesangiolysis, and red cell fragmentation (top right); arteriolar fibrinoid necrosis (bottom left); and myxoid intimal thickening of an interlobular artery (bottom right, all hematoxylin and eosin). (E) Transcriptional response to JAK inhibitor (JAKi) ruxolitinib in both patients (RT-PCR).

HLH, hemophagocytic lymphohistiocytosis; EEG, electroencephalogram.

This clinical phenotype was reminiscent of a particularly severe form of type I interferonopathy. In keeping with this observation, IFN-stimulated gene (ISG) transcripts in whole blood, measured by RNA sequencing (RNA-seq) and reverse transcription polymerase chain reaction (RT-PCR), were substantially elevated over multiple time points at similar magnitudes to recognized type I interferonopathies (Fig. 1, B and C), notably without evidence of concomitant induction of IFN-independent inflammatory pathways (fig. S1). Disease in the proband, which not only met the diagnostic criteria for hemophagocytosis but also included features of a thrombotic microangiopathy (TMA) (Fig. 1D), was partially responsive to dexamethasone and stabilized with the addition of the Janus kinase (JAK) inhibitor ruxolitinib (Fig. 1E and fig. S2). Sadly, however, this child succumbed to overwhelming Gram-negative bacterial sepsis during hematopoietic stem cell transplantation.

Patient II:4, his infant brother, presented with abnormal neurodevelopment and neuroimaging in the neonatal period, characterized by apneic episodes from 3 weeks of age in conjunction with parenchymal calcifications and hemorrhage, abnormal cerebral white matter, and brainstem and cerebellar atrophy (Fig. 1A). Blood tests revealed an elevated ISG score (Fig. 1, B and C), anemia, elevation of D-dimers, and red cell fragmentation on blood film, together with proteinuria and borderline elevations of ferritin and lactate dehydrogenase; renal function was normal, and blood pressure was on the upper limit of the normal range for gestational age. Introduction of ruxolitinib led to prompt suppression of ISG expression in whole blood (Fig. 1E) and an initial reduction in apneic episodes, but neurological damage was irretrievable, and he succumbed to disease at 3 months of age. Mothers pregnancy with patient II:4 had been complicated by influenza B at 23 weeks gestation.

Whole-exome sequencing analysis of genomic DNA from the kindred, confirmed by Sanger sequencing (Fig. 2, A and B), identified an extremely rare variant in STAT2 (c.442C>T), which substituted tryptophan for arginine at position 148 in the coiled-coil domain (CCD) of STAT2 (p.Arg148Trp, Fig. 2C). The Arg148Trp variant was present in the homozygous state in both affected children and was heterozygous in each parent and one healthy sibling, consistent with segregation of an autosomal recessive trait (table S2). This variant was found in the heterozygous state at extremely low frequency in publicly available databases of genomic variation [frequency < 0.00001 in Genome Aggregation Database (22)], and no homozygotes were reported. A basic amino acid, particularly arginine, at position 148 is highly conserved (fig. S3). In silico tools predicted that this missense substitution was probably deleterious to protein function (table S2). STAT2 protein expression in patient cells was unaffected by the Arg148Trp variant, in contrast to the situation for pathogenic loss-of-expression STAT2 variants, which resulted in a distinct phenotype of heightened viral susceptibility (Fig. 2D) (23, 24). Filtering of exome data identified an additional recessive variant in CFH (c.2336A>G and p.Tyr779Cys; fig. S4) present in the homozygous state in II:3 but absent from II:4. We considered the possibility that this contributed to TMA in the proband, but functional studies of this variant showed negligible impact on factor H function (fig. S5).

(A) Pedigree, (B) capillary sequencing verification, (C) protein map, and (D) immunoblot (fibroblasts) showing normal expression of STAT2 protein. DBD, DNA binding domain; LD, linker domain; SH2, Src homology 2 domain; TAD, trans-activation domain.

The transcription factor STAT2 is essential for transcriptional activation downstream of the receptors for the innate IFN-/ (IFNAR) and IFN- and their associated JAK adaptor proteins. In the current paradigm (25), STAT2 is activated by tyrosine phosphorylation, associated with IFN regulatory factor 9 (IRF9) and phosphorylated STAT1 (pSTAT1) to form the IFN-stimulated gene factor 3 (ISGF3) to effect gene transcription by binding to IFN-stimulated response elements in the promoters of ISGs. Although loss-of-function variants in STAT2 increase susceptibility to viral disease (23, 24), evidence here suggested pathological activation. Germline gain-of-function variants have been reported in STAT1 (26, 27) and STAT3 (28, 29) but not hitherto STAT2. Consistent with the apparent gain of IFN activity associated with mutant STAT2R148W, we observed in patient fibroblasts (Fig. 3, A and B) and peripheral blood mononuclear cells (PBMCs; fig. S6) the enhanced expression of ISG protein products across a range of IFN concentrations. However, basal and induced production of IFNB mRNA by fibroblasts was indistinguishable from controls (Fig. 3C); nor was IFN protein substantially elevated in patient samples of cerebrospinal fluid (II:3) or plasma (II:4) as measured by a highly sensitive digital enzyme-linked immunosorbent assay (ELISA) assay (30), albeit samples were acquired during treatment (table S3). Thus, the response to type I IFNs, but not their synthesis, was exaggerated. This heightened IFN sensitivity was accompanied by enhancement of key effector functions, as revealed by assays of IFN-mediated viral protection (Fig. 3D) and cytotoxicity (Fig. 3E). Collectively, these data indicated that STAT2R148W was not constitutively active but rather resulted in an exaggerated response upon IFN exposure. To confirm that the Arg148Trp variant was responsible for this cellular phenotype, we transduced STAT2-null U6A cells (31) and STAT2-deficient primary fibroblasts (23) with lentiviruses encoding either wild type (WT) or STAT2R148W, recapitulating the heightened sensitivity of cells expressing the latter to IFN (Fig. 3, F and G, and fig. S7).

Unless stated, all data are from patient II:3 and control fibroblasts. (A) ISG expression (immunoblot, IFN for 24 hours) and (B) densitometry analysis (n = 3, t test). MX1, MX dynamin like GTPase 1; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; RSAD2, radical S-adenosyl methionine domain containing 2. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (C) IFNB mRNA (RT-PCR) external polyinosinic:polycytidylic acid (poly I:C) treatment (25 g/ml for 4 hours; n = 3, t test). US, unstimulated. (D) Antiviral protection assay (mCherry-PIV5). Twofold dilutions from IFN (16 IU/ml), IFN (160 IU/ml) n = 7 replicates, representative of n = 2 experiments (two-way ANOVA with Sidaks posttest). (E) Cytopathicity assay (IFN for 72 hours; n = 3, t test). (F) As in (A), ISG expression in STAT2/ U6A cells reconstituted with STAT2WT or STAT2R148W (immunoblot, IFN for 24 hours). (G) As in (B), n = 3 to 4, t test. Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., nonsignificant.

To explore the underlying mechanism for heightened type I IFN sensitivity, we first probed STAT2 activation in IFN-stimulated fibroblasts. In control lysates, levels of pSTAT2 had almost returned to baseline between 6 and 24 hours of treatment despite the continued presence of IFN (Fig. 4, A and B). In contrast, pSTAT2 persisted for up to 48 hours in patient cells. This abnormally prolonged pSTAT2 response to IFN was also observed in PBMCs of both patients (fig. S8). Consistent with immunoblot data, immunofluorescence analysis showed persistent ( 6 hours) nuclear localization of STAT2 in patient fibroblasts after IFN treatment, at times when STAT2 staining was predominantly cytoplasmic in control cells (Fig. 4, C and D, and fig. S9). This was accompanied by continued expression of ISG transcripts for 36 hours after the washout of IFN in patient cells as measured by RNA-seq and RT-PCR (Fig. 4, E and F). Thus, the type I IFN hypersensitivity of patient cells was linked to prolonged IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) pSTAT2 time course [immunoblot, IFN (1000 IU/ml)] and (B) densitometry analysis (n = 5 experiments, two-way ANOVA with Sidaks posttest). (C) Immunofluorescence analysis [IFN (1000 IU/ml); scale bar, 100 m; representative of n = 3 experiments] with (D) image analysis of STAT2 nuclear translocation (n = 100 cells per condition, ANOVA with Sidaks posttest). A.U., arbitrary units. (E) RNA-seq analysis of IFN-regulated genes (n = 3 controls) with (F) validation by RT-PCR (n = 3, two-way ANOVA with Sidaks posttest). CPM, read counts per million. (G) pSTAT2 decay (immunoblot). IFN (1000 IU/ml; 30 min) followed by extensive washing and treatment with 500 nM staurosporine (STAU). Times relative to STAU treatment. (H) No significant differences by densitometry analysis (n = 3, t test). Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

The IFNAR signaling pathway is subject to multiple layers of negative regulation that target STAT phosphorylation directlythrough the action of tyrosine phosphatasesor indirectly by disrupting upstream signal transduction (7). Prolonged tyrosine phosphorylation is reported with gain-of-function mutations in STAT1, in association with impaired sensitivity to phosphatase activity (27). By contrast, we observed no impairment of dephosphorylation of STAT2R148W in pulse-chase assays with the kinase inhibitor staurosporine (Fig. 4, G and H), implying instead a failure of negative feedback upon the proximal signaling events that generate pSTAT2.

To localize this defect, we analyzed by phosflow and immunoblot the successive activation steps downstream of IFNAR ligand binding in Epstein-Barr virus (EBV)transformed B cells from the proband (II:3) and a heterozygous parent (I:2). As was the case for STAT2 phosphorylation, we also observed prolonged phosphorylation of both JAK1 and STAT1 after IFN treatment (Fig. 5, A to D). This points to a defect in regulation of the most proximal IFNAR signaling events, upstream of STAT2 (7). We observed no evidence of this phenotype in cells bearing STAT2R148W in the heterozygous state, consistent with autosomal recessive inheritance and the lack of clinical disease or up-regulation of IFN activity in heterozygous carriers. This genetic architecture provides a notable contrast to gain-of-function mutations affecting other STAT proteins, all of which are manifest in the heterozygous state (2629).

Time course of IFN stimulation (1000 IU/ml) in EBV B cells from patient II:3 [homozygous (hom)], parent I:2 [heterozygous (het)], and n = 3 controls. (A) Immunoblot and (B) densitometry analyses. (C) Representative histograms (flow cytometry) and (D) mean fluorescence intensity (MFI). Data are means SEM of three repeat experiments (*P < 0.05, **P < 0.01, t test).

Known negative regulators of IFNAR signaling are suppressor of cytokine signaling (SOCS) 1 and SOCS3 (32) and the ubiquitin-specific protease 18 (USP18) (33). SOCS1 and SOCS3 participate in regulation of additional JAK-STAT signaling pathways, such as those activated by IFN and interleukin 6 (IL-6) (34, 35), whereas USP18 acts specifically upon IFNAR signaling (33). To better localize the molecular defect in patient cells, we examined the signaling responses to IFN (STAT1 phosphorylation) and IL-6 (STAT3 phosphorylation), based on the prediction that defects of SOCS1 or SOCS3 regulation would manifest under these conditions. These experiments revealed that regulation of STAT1 and STAT3 phosphorylation was normal in patient fibroblasts (fig. S10). Together with the absence of evidence of up-regulation of the IFN and IL-6 pathways in the analysis of whole blood RNA-seq data (fig. S1), these observations effectively ruled out the involvement of SOCS1 and SOCS3 in the clinical phenotype, leading us to suspect a defect of USP18 regulation.

To investigate this possibility, we primed patient and control cells with IFN for 12 hours, washed them extensively, and rested and restimulated them with IFN or IFN after 48 hours. In these experiments, IFN-induced pSTAT2 and pSTAT1 were strongly inhibited by priming in control cells, consistent with desensitization, a well-established phenomenon of type I IFN biology (Fig. 6, A and B) (36). In marked contrast, the response to IFN restimulation in patient cells was minimally suppressed, indicating a failure of desensitization. Desensitization has been shown to be exclusively mediated by USP18, an IFN-induced isopeptidase (37), through its displacement of JAK1 from the receptor subunit IFNAR2 (38, 39)a function that is independent of its isopeptidase activity toward the ubiquitin-like protein ISG15 (33). STAT2 plays a critical role as an adaptor protein by supporting binding of USP18 to IFNAR2 (Fig. 6C) (40). Both the clinical and cellular effects of STAT2R148W resemble homozygous USP18 deficiency, which was recently described as the molecular cause of a severe pseudo-TORCH syndrome associated with elevated type I IFN expression (table S4) (41). Although this STAT2:USP18 interaction has been shown to be essential for negative regulation of type I IFN signaling in vitro (40), its significance in vivo has not previously been examined. Furthermore, the precise residue(s) of STAT2 that bind USP18 were unresolved, although this interaction had been localized to a region including the CCD and/or DNA binding domain(s) of STAT2 (40).

(A) Desensitization assay (immunoblot, fibroblasts) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 4, ANOVA with Sidaks posttest). (C) Schematic of USP18 mechanism of action and proposed model of STAT2R148W pathomechanism. (D) Modeling of exposed WT (R148)/mutant (W148) residue, demonstrating charge-change (blue, positive; red, negative) and possible steric restriction. (E) Coimmunoprecipitation of USP18 by STAT2 in U6A cells expressing STAT2WT or STAT2R148W with (F) densitometry analysis (USP18/STAT2, ratio to WT; one-sample t test). Data are means SEM (**P < 0.01, ****P < 0.0001). IB, immunoblot.

Because USP18 was induced normally in patient cells (Fig. 6, A and B) and in vivo (Fig. 1B), our data implied that STAT2R148W impedes the proper interaction of STAT2 with USP18, compromising its regulatory function (Fig. 6C). Molecular modeling of STAT2R148W placed the substituted bulky aromatic tryptophan, and resulting charge change, at an exposed site within the CCD (Fig. 6D). Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, coimmunoprecipitation experiments in U6A cells stably expressing WT or STAT2R148W demonstrated a statistical significance reduction of USP18 pull down STAT2R148W compared with WT (Fig. 6, E and F), providing a molecular mechanism for the USP18 insensitivity of patient cells.

Although disruption to the STAT2R148W:USP18 interaction was the most plausible explanation for the clinical and molecular phenotype, we also considered the contribution of alternative regulatory functions of STAT2. Beyond the role of tyrosine phosphorylated STAT2 in innate IFN signal transduction, the unphosphorylated form of STAT2 (uSTAT2) has additional, recently described functions in the regulation of other cytokine signaling pathways. For example, uSTAT2 negatively regulates the activity of IFN (and other inflammatory cytokines that signal via STAT1 homodimers) by binding to uSTAT1 via its CCD (42). This interaction appears to limit the pool of STAT1 available for incorporation into transcriptionally active (tyrosine phosphorylated) STAT1 homodimers. Conversely, uSTAT2, induced by type I IFN signaling, has been reported to promote the transcriptional induction of IL6 through an interaction with the nuclear factor B subunit p65 (43). To investigate the potential relevance of these regulatory functions of STAT2, we first examined the induction of IL6 by RT-PCR analysis of RNA isolated from whole blood of patients, their heterozygous parents, and healthy controls. We found no evidence of increased expression of IL6 or its target gene SOCS3 (fig. S11, A and B), consistent with our previous pathway analysis of RNA-seq data (fig. S1) and implying that STAT2R148W does not influence IL-6 induction. Next, to explore any impact on STAT2s negative regulatory activity toward STAT1, we examined the transcriptional responses to IFN in patient fibroblasts and in U6A cells expressing STAT2R148W. Although we were able to reproduce the previously reported findings of heightened transcription of the IFN-regulated gene CXCL10 in U6A cells lacking STAT2, alongside a nonsignificant trend for IRF1 (fig. S12, A and B) (42), STAT2R148W did not enhance transcript levels of either CXCL10 or IRF1 above WT, in agreement with the data showing the preserved ability of STAT2R148W to bind STAT1 in a coimmunoprecipitation assay (fig. S12, C and D). Together, these studies effectively exclude a contribution of the USP18-independent regulatory functions of STAT2 to the disease phenotype.

To conclusively demonstrate the impairment of STAT2:USP18-mediated negative regulation in patient cells, we tested the impact of overexpression or knockdown of USP18. First, we probed IFNAR responses in fibroblasts stably expressing USP18. As predicted, USP18 was significantly impaired in its ability to suppress IFN signaling in patient cells, relative to controls, both in terms of STAT phosphorylation (Fig. 7, A and B) and STAT2 nuclear translocation (Fig. 7, C and D), recapitulating our prior observations with IFN priming (Fig. 6A). The reciprocal experiment, in which USP18 expression was stably knocked down using short hairpin RNA (shRNA), revealed significantly prolonged STAT2 phosphorylation in control cells at 24 hours, recapitulating the phenotype of patient cells (Fig. 7, E and F). In contrast, there was no effect of USP18 knockdown in patient cells, demonstrating that they are USP18 insensitive. Incidentally, we noted that the early peak (1 hour) of STAT2 phosphorylation in USP18-knockdown control fibroblasts was marginally reduced (Fig. 7E). This subtle reduction was also apparent in STAT2R148W patient fibroblasts (Fig. 4B), although not in EBV B cells (Fig. 5). We speculate that the cell typespecific induction of other negative regulator(s) of IFNAR signaling at early times after IFN treatment, such as SOCS1, might be responsible for this observation. RT-PCR analysis confirmed the increased expression of SOCS1 mRNA in whole blood of patients (fig. S11C), whereas examination of RNA-seq data from IFN-treated fibroblasts revealed an eightfold enhancement of SOCS1 expression at 6 hours in patient cells as compared with controls (Padj = 0.0001; Fig 4E). Together, these data provide preliminary support for the hypothesis that alternative negative regulator(s) of IFNAR signaling may be up-regulated in patient cells. Nevertheless, such attempts at compensation are clearly insufficient to restrain IFNAR responses in the context of STAT2R148W, reflecting the nonredundant role of STAT2/USP18 in this process (39). Collectively, these data support a model in which the homozygous presence of the Arg148Trp STAT2 variant compromises an essential adaptor function of STAT2 toward USP18, rendering cells USP18 insensitive and culminating in unrestrained, immunopathogenic IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) STAT phosphorylation in USP18 and vector expressing fibroblasts (immunoblot) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 3, ANOVA with Sidaks posttest). (C) Immunofluorescence analysis of STAT2 nuclear translocation [IFN (1000 IU/ml 30 min); representative of n = 3 experiments] with (D) image analysis (n = 100 cells per condition, ANOVA with Sidaks posttest). (E) Time course of STAT phosphorylation upon IFN stimulation (1000 IU/ml for 0, 1, 6, and 24 hours) of cells transduced with USP18 shRNA or nontargeting (NT) shRNA with (F) densitometry analysis of pSTAT2 (n = 3, t test). Data are means SEM (**P < 0.01, ***P < 0.001, ****P < 0.0001).

We report a type I interferonopathy, caused by a homozygous missense mutation in STAT2, and provide detailed studies to delineate the underlying molecular mechanism. Our data indicate the failure of mutant STAT2R148W to support proper negative regulation of IFNAR signaling by USP18revealing an essential regulatory function of human STAT2. This defect in STAT2 regulation results in (i) an inability to properly restrain the response to type I IFNs and (ii) the genesis of a life-threating early-onset inflammatory disease. This situation presents a marked contrast with monogenic STAT2 deficiency, which results in heightened susceptibility to viral infection due to the loss of the transcription factor complex ISGF3 (23, 24). Thus, just as allelic variants of STAT1 and STAT3 are recognized that either impair or enhance activity of the cytokine signaling pathways in which they participate (44), we can now add to this list STAT2. Our findings also highlight an apparently unique property of human STAT2: That it participates directly in both the positive and negative regulation of its own cellular signaling pathway. Whether this is true of STAT2 in other species remains to be determined. Our findings also localize the interaction with USP18 to the CCD of STAT2, indicating a specific residue critical for this interaction. This structural insight may be relevant to efforts to therapeutically interfere with the STAT2:USP18 interaction to promote the antiviral action of IFNs.

This monogenic disease of STAT2 regulation provides incontrovertible evidence of the pathogenic effects of failure to properly restrain IFNAR signaling in humans. The conspicuous phenotypic overlap with existing defects of IFN/ overproduction, particularly with regard to the neurological manifestations, provides compelling support for the type I interferonopathy hypothesis, strengthening the clinical rationale for therapeutic blockade of IFNAR signaling (15). JAK1/2 inhibition with ruxolitinib was highly effective in controlling disease in the proband; however, the damage that already accrued at birth in his younger brother was irreparable, emphasizing the importance of timely IFNAR blockade in prevention of neurological sequelae. A notable aspect of the clinical phenotype in patient II:3 was the occurrence of severe TMA. Our studies did not support a pathogenic contribution of the coinherited complement factor H variant in patient II:3. This evidence, together with clinical hematological and biochemical results suggestive of incipient vasculopathy in patient II:4who did not carry the CFH variantsuggests that type I IFN may have directly contributed to the development of TMA. Although it is not classically associated with type I interferonopathies, TMA is an increasingly recognized complication of both genetic (41, 42) and iatrogenic states of IFN excess (43), consistent with the involvement of vasculopathy in the pathomechanism of IFN-mediated disease. The fact that STAT2R148W is silent in the heterozygous state at first sight offers a confusing contrast with gain-of-function mutations of its sister molecules STAT1 and STAT3, both of which produce autosomal dominant disease with high penetrance (2629). However, the net gain of IFNAR signaling activity results from the isolated loss of STAT2s regulatory function, which evidently behaves as a recessive trait. There are other examples of autosomal recessive loss-of-function disorders of negative regulators, including USP18 itself (41, 45); the unique aspect in the case of STAT2R148W is that the affected molecule is itself a key positive mediator within the regulated pathway.

In light of the intimate relationship between STAT2 and USP18 revealed by these and other recent data (40), it is reasonable to conclude that the clinical manifestations of human USP18 deficiency are dominated by the loss of its negative feedback toward IFNAR rather than the STAT2-independent functions of USP18 including its enzymatic activity (40, 46, 47). In mouse, white matter pathology associated with microglia-specific USP18 deficiency is prevented in the absence of IFNAR (21). There are now three human autosomal recessive disorders that directly compromise the proper negative regulation of IFNAR signaling and thus produce a net gain of signaling function: USP18 deficiency, which leads to embryonic or neonatal lethality with severe multisystem inflammation (41); STAT2R148W, which largely phenocopies USP18 deficiency; and ISG15 deficiency, in which there is a much milder phenotype of neurological disease without systemic inflammation (45). ISG15 stabilizes USP18, and human ISG15 deficiency leads to a partial loss of USP18 protein (41). Thus, a correlation is clearly evident between the extent of USP18 dysfunction and the clinical severity of these disorders, with STAT2R148W closer to USP18 deficiency and ISG15 on the milder end of the spectrum (table S4). Those molecular defects that result in a failure of negative regulation of IFNAR signaling (i.e., STAT2R148W and USP18/) lead to more serious and extensive systemic inflammatory disease than do defects of excessive IFN/ production (41), suggesting that the STAT2:USP18 axis acts to limit an immunopathogenic response toward both physiological (48) and pathological (41) levels of IFN/. Thus, variability in the efficiency of this process of negative regulation might be predicted to influence the clinical expressivity of interferonopathies. Determining the cellular source(s) of physiological type I IFNs and the molecular pathways that regulate their production are important areas for future investigation.

Some limitations of our results should be acknowledged. Although strenuous efforts were made, we were only able to identify a single kindred, which probably reflects the rarity of this variant. As more cases are identified, our understanding of the clinical phenotypic spectrum will inevitably expand. Furthermore, for practical and cultural/ethical reasons, limited amounts of cellular material and tissues were available for analysis. As a result, we were unable to formally evaluate the relevance of STAT2 regulation toward type III IFN signaling; however, existing data suggest that USP18 plays a negligible role in this context (38). Together, our findings confirm an essential regulatory role of STAT2, supporting the hypothesis that type I IFNs play a causal role in a diverse spectrum of human disease, with immediate therapeutic implications.

We investigated a kindred with a severe, early-onset, presumed genetic disease, seeking to determine the underlying pathomechanism by ex vivo and in vitro studies. Written informed consent for these studies was provided, and ethical/institutional approval was granted by the NRES Committee North East-Newcastle and North Tyneside 1 (ref: 16/NE/0002), South Central-Hampshire A (ref: 17/SC/0026), and Leeds (East) (ref: 07/Q1206/7).

Dermal fibroblasts from patient II:3 and healthy controls were obtained by standard methods and cultured in Dulbeccos modified Eagles medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (DMEM-10), as were human embryonic kidney 293 T cells and the STAT2-deficient human sarcoma cell line U6A (31). PBMCs and EBV-transformed B cells were cultured in RPMI medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (RPMI-10). Unless otherwise stated, cytokines/inhibitors were used at the following concentrations: human recombinant IFN-2b (1000 IU/ml; Intron A, Schering-Plough, USA); IFN- (1000 IU/ml; Immunikin, Boehringer Ingelheim, Germany); IL-6 (25 ng/ml; PeproTech, USA); and 500 nM staurosporine (ALX-380-014-C250, Enzo Life Sciences, NY, USA). Diagnostic histopathology, immunology, and virology studies were conducted in accredited regional diagnostic laboratories to standard protocols.

Whole-exome sequencing analysis was performed on DNA isolated from whole blood from patients I:1, I:2, II:3, and II:4. Capture and library preparation was undertaken using the BGI V4 exome kit (BGI, Beijing, China) according to manufacturers instructions, and sequencing was performed on a BGISEQ (BGI). Bioinformatics analysis and variant confirmation by Sanger sequencing are described in the Supplementary Materials.

RNA was extracted by lysing fibroblasts in TRIzol reagent (Thermo Fisher Scientific) or from whole blood samples collected in PAXgene tubes (PreAnalytix), as described previously (49). Further details, including primer/probe information, are summarized in the Supplementary Materials and table S5.

Whole-blood transcriptome expression analysis was performed using nine whole blood samples, from the proband taken before and during treatment, and five controls. In addition, the four patient II:3 samples taken before treatment and samples from six patients with mutations in TREX1, three with mutations in RNASEH2A, seven with mutations in RNASEH2B, five with mutations in RNASEH2C, five with mutations in SAMHD1, four with mutations in ADAR1, two with mutations in IFIH1, three with mutations in ACP5, three with mutations in TMEM173, and three with mutations in DNASE2 were analyzed, as described in the Supplementary Materials. RNA integrity was analyzed with Agilent 2100 Bioanalyzer (Agilent Technologies). mRNA purification and fragmentation, complementary DNA (cDNA) synthesis, and target amplification were performed using the Illumina TruSeq RNA Sample Preparation Kit (Illumina). Pooled cDNA libraries were sequenced using the HiSeq 4000 Illumina platform (Illumina). Fibroblasts grown in six-well plates were mock-treated or treated with IFN for 6 or 12 hours, followed by extensive washing and 36-hour rest, before RNA extraction. The experiment was performed with patient II:3 and control cells (n = 3) in triplicate per time point. RNA was extracted using the ReliaPrep RNA Miniprep kit (Promega) according to manufacturers instructions and processed as described above, before sequencing on an Illumina NextSeq500 platform. Bioinformatic analysis is described in the Supplementary Materials. PMBC and fibroblast STAT2 patient and control data have been deposited in ArrayExpress (E-MTAB-7275) and Gene Expression Omnibus (GSE119709), respectively.

Details of lentiviral constructs, mutagenesis, and preparation are included in the Supplementary Materials. Cells were spinoculated in six-well plates for 1.5 hours at 2000 rpm, with target or null control viral particles, at various dilutions in a total volume of 0.5 ml of DMEM-10 containing hexadimethrine bromide [polybrene (8 g/ml); Sigma-Aldrich]. Cells were rested in virus-containing medium for 8 hours and then incubated in fresh DMEM-10 until 48 hours, when they were subjected to selection with puromycin (2.0 g/ml) or blastocidin (2.5 g/ml) (Sigma-Aldrich). Antibiotic-containing medium was refreshed every 72 hours.

EBV B cells were seeded at a density of 8 105 cells/ml in serum-free X-VIVO 15 medium (Lonza, Basel, Switzerland) and stimulated with IFN (1000 IU/ml) for the indicated times. After staining with Zombie UV (BioLegend, San Diego, CA, USA), cells were fixed using Cytofix buffer (BD Biosciences, Franklin Lakes, NJ, USA). Permeabilization was achieved by adding ice-cold PermIII buffer (BD Biosciences, Franklin Lakes, NJ, USA), and cells were incubated on ice for 20 min. After repeated washing steps with phosphate-buffered saline (PBS)/2% fetal bovine serum (FBS), cells were stained for 60 min at room temperature with directly conjugated antibodies (table S6). Samples were acquired on a Symphony A5 flow cytometer (BD Biosciences) and analyzed using FlowJo (FlowJo LLC, Ashland, OR, USA). The gating strategy is shown in fig. S13.

Immunoblotting was carried out as previously described (1) and analyzed using either a G:BOX Chemi (Syngene, Hyarana, India) charge-coupled device camera with GeneSnap software (Syngene) or a LI-COR Odyssey Fc (LI-COR, NE, USA). Densitometry analysis was undertaken using ImageStudio software (version 5.2.5, Li-COR). For complement studies, sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis (PAGE) under nonreducing conditions was performed on patient/parental serum [diluted 1:125 in nonreducing buffer (PBS)] or affinity-purified factor H (diluted to 200 ng in nonreducing buffer), separated by electrophoresis on a 6% SDS-PAGE gel, and transferred to nitrocellulose membranes for immunoblotting (antibodies in table S6). Blots were developed with Pierce ECL Western blotting substrate (Thermo Fisher Scientific) and imaged on a LI-COR Odyssey Fc (LI-COR).

U6A cells were lysed in immunoprecipitation buffer [25 mM Tris (pH 7.4), 1 mM EDTA, 150 mM NaCl, 1% Nonidet P-40, 1 mM sodium orthovanadate, and 10 mM sodium fluoride, with complete protease inhibitor (Roche, Basel, Switzerland)]. Lysates were centrifuged at 13,000 rpm at 4C for 10 min. Soluble fractions were precleared for 1 hour at 4C with Protein G Sepharose 4 (Fast Flow, GE Healthcare, Chicago, USA) that had been previously blocked with 1% bovine serum albumin (BSA) IP buffer for 1 hour. Precleared cell lysates were immunoprecipitated overnight with blocked beads that were incubated with anti-STAT2 antibody (A-7) for 1 hour and then washed three times in IP buffer before boiling with 4 lithium dodecyl sulfate buffer at 95C for 10 min to elute the absorbed immunocomplexes. Immunoblot was carried out as described above.

Fibroblasts grown on eight-well chamber slides (Ibidi, Martinsried, Germany) were fixed with 4% paraformaldehyde in PBS for 15 min at room temperature before blocking/permeabilization with 3% BSA/0.1% Triton X-100 (Sigma-Aldrich) in PBS. Cells were incubated overnight with anti-STAT2 primary antibody (10 g/ml; C20, Santa Cruz Biotechnology, Dallas, USA) at 4C, and cells were washed three times with PBS. Secondary antibody [goat anti-rabbit Alexa Fluor 488 (1 g/ml), Thermo Fisher Scientific] incubation was performed for 1 hour at room temperature, followed by nuclear staining with 4,6-diamidino-2-phenylindole (DAPI; 0.2 g/ml; Thermo Fisher Scientific). Cells were imaged with an EVOS FL fluorescence microscope with a 10 objective (Thermo Fisher Scientific). The use of STAT2-deficient cells (23) demonstrated the specificity and lack of nonspecific background of the staining approach. Image analysis was performed in ImageJ. The DAPI (nuclear) image was converted to binary, and each nucleus (object) was counted. This mask was overlaid onto the STAT2 image, and the mean fluorescence intensity of STAT2 within each nucleus was calculated (see also fig. S9). About n = 100 cells were analyzed per image.

The structure of human STAT2 has not been experimentally determined. We therefore used comparative modeling to predict the structure. The sequences of both the WT and mutant were aligned to mouse STAT2 (Protein Data Bank code 5OEN, chain B). For each sequence, 20 models were built using MODELLER (50), and the one with the lowest discrete optimized protein energy score was chosen. Protein structures and electrostatic surfaces were visualized with PyMOL (Schrodinger, USA).

Fibroblasts grown on 96-well plates were treated with IFN (1000 or 10,000 IU/ml) or DMEM-10 alone for 72 hours. Cells were fixed in PBS containing 5% formaldehyde for 15 min at room temperature and then incubated with crystal violet stain. Plates were washed extensively then allowed to air dry. The remaining cell membrane-bound stain was solubilized with methanol and absorbance at 595 nm measured on a TECAN Sunrise plate reader (Tecan, Switzerland). Background absorbance was subtracted from all samples, and the results were expressed as a percentage of the absorbance values of untreated cells.

Fibroblasts grown on 96-well plates were pretreated in septuplicate for 18 hours with twofold serial dilutions of IFN and IFN, followed by infection with mCherry-expressing parainfluenza virus 5 (PIV5) in DMEM/2% FBS for 24 hours. Monolayers were fixed with PBS containing 5% formaldehyde, and infection was quantified by measuring mean fluorescence intensity of mCherry (excitation, 580/9; emission, 610/20) using a TECAN Infinite M200 Pro plate reader (Tecan, Switzerland). Background fluorescence was subtracted from all samples, and the results were expressed as a percentage of the fluorescence values of untreated, virus-infected cells.

Unless otherwise stated, all experiments were repeated a minimum of three times. Data were normalized/log10-transformed before parametric tests of significance in view of the limitations of ascertaining distribution in small sample sizes and the high type II error rates of nonparametric tests in this context. Comparison of two groups used t test or one-sample t test if data were normalized to control values. Comparisons of more than one group used one-way analysis of variance (ANOVA) or two-way ANOVA as appropriate, with posttest correction for multiple comparisons. Statistical testing was undertaken in GraphPad Prism (v7.0). All tests were two-tailed with 0.05.

immunology.sciencemag.org/cgi/content/full/4/42/eaav7501/DC1

Materials and Methods

Supplementary case summary

Fig. S1. Ingenuity pathway analysis of whole blood RNA-seq data.

Fig. S2. Longitudinal series of laboratory parameters.

Fig. S3. Multiple sequence alignment of STAT2.

Fig. S4. Factor H genotyping and mutant factor H purification strategy.

Fig. S5. Functional analysis of factor H Tyr779Cys variant.

Fig. S6. Immunoblot analysis of MX1 expression in PBMCs.

Fig. S7. Transduction of STAT2-deficient primary fibroblasts.

Fig. S8. Prolonged STAT2 phosphorylation in PBMCs.

Fig. S9. STAT2 immunofluorescence image analysis.

Fig. S10. STAT phosphorylation is not prolonged in patient cells in response to IFN or IL-6.

Fig. S11. RT-PCR analysis of gene expression in whole blood.

Fig. S12. STAT2R148W does not impair regulation of STAT1 signaling.

Fig. S13. Phosflow gating strategy.

Table S1. Laboratory parameters, patients II:3 and II:4.

Table S2. Rare variants segregating with disease.

Table S3. Digital ELISA detection of IFN protein concentration.

Table S4. Phenotypes of monogenic defects of USP18 expression and/or function.

Table S5. RT-PCR primers and probes.

Table S6. Antibodies.

Data file S1. Raw data (Excel).

References (5159)

Acknowledgments: We are grateful to the patients and our thoughts are with their family. Funding: British Infection Association (to C.J.A.D.), Wellcome Trust [211153/Z/18/Z (to C.J.A.D.), 207556/Z/17/Z (S.H.), and 101788/Z/13/Z (to D.F.Y. and R.E.R.)], Sir Jules Thorn Trust [12/JTA (to S.H.)], UK National Institute of Health Research [TRF-2016-09-002 (to T.A.B.)], NIHR Manchester Biomedical Resource Centre (to T.A.B.), Medical Research Foundation (to T.A.B.), Medical Research Council [MRC, MR/N013840/1 (to B.J.T.)], MRC/Kidney Research UK [MR/R000913/1 (to Vicky Brocklebank)], Deutsche Forschungsgemeinschaft [GO 2955/1-1 (to F.G.)], Agence Nationale de la Recherche [ANR-10-IAHU-01 (to Y.J.C.) and CE17001002 (to Y.J.C. and D.D.)], European Research Council [GA 309449 (Y.J.C.); 786142-E-T1IFNs], Newcastle University (to C.J.A.D.), and ImmunoQure for provision of antibodies (Y.J.C. and D.D.). C.L.H. and R.S. were funded by start-up funding from Newcastle University. D.K. has received funding from the Medical Research Council, Wellcome Trust, Kidney Research UK, Macular Society, NCKRF, AMD Society, and Complement UK; honoraria for consultancy work from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Novartis, and Idorsia; and is a director of and scientific advisor to Gyroscope Therapeutics. Author contributions: Conceptualization: C.J.A.D., S.H., and T.A.B. Data curation: C.F., G.I.R., A.J.S., J.C., A.M., R.H., Ronnie Wright, and L.A.H.Z. Statistical analysis: C.J.A.D., B.J.T., R.C., G.I.R., F.G., D.F.Y., S.C.L., V.G.S., A.J.S., L.A.H.Z., C.L.H., D.K., and T.A.B. Funding acquisition: C.J.A.D., D.D., Y.J.C., R.E.R., D.K., S.H., and T.A.B. Investigation: C.J.A.D., B.J.T., R.C., F.G., G.I.R., D.F.Y., Vicky Brocklebank, V.G.S., B.C., Vincent Bondet, D.D., S.C.L., A.G., M.A., B.A.I., R.S., Ronnie Wright, C.L.H., and T.A.B. Methodology: C.J.A.D., B.J.T., R.C., F.G., D.F.Y., A.J.S., D.D., K.R.E., Y.J.C., R.E.R., C.L.H., and D.K. Project administration: C.J.A.D., K.R.E., S.H., and T.A.B. Resources: S.M.H., Robert Wynn, T.A.B., J.H.L., J.P., E.C., S.B., K.W., and D.K. Software: C.F., A.J.S., M.Z., L.A.H.Z., and Ronnie Wright. Supervision: C.J.A.D., K.R.E., Y.J.C., D.D., C.L.H., R.E.R., D.K., S.H., and T.A.B. Validation: B.J.T., R.C., A.J.S., V.G.S., and C.L.H. Visualization: C.J.A.D., B.J.T., R.C., and S.C.L. Writing (original draft): C.J.A.D., with B.J.T., R.C., S.H., and T.A.B. Writing (review and editing): C.J.A.D., G.I.R., A.J.S., S.C.L., M.Z., S.M.H., K.R.E., R.E.R., D.K., S.H., and T.A.B. Competing interests: The authors declare that they have no competing interests. Data and materials availability: GEO accession: GSE119709. ArrayExpress accession: E MTAB-7275. Materials/reagents are available on request from the corresponding author(s). MBI6 is available from Claire Harris under a material agreement with Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 - Science

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Cultivators of any background can find information or help on tissue culture through the Cannadabis homepage. They are posting helpful videos and literature on cannabis tissue culture and hope to share the benefits with every grower. All horticulturalists, cannabis or not, can benefit from having their cloning area be 100x more efficient, through stackable containers. Furthermore, their mother plants can easily be maintained with minimal care. 100-1000 mother cultures can be stored within a refrigerator for 4-8 months, no adding nutrient or water. For larger cultivators, Cannadabis provides PGR matrices to more easily troubleshoot difficult cultivars. They also will custom blend and sterilise mediums to customer preference.

Cannadabis has begun developing an automated cell culture process for mass propagation of cultivars. The economies of scale of which are expected to change the supply chain of the entire cannabis industry. Automated cell culturing will provide starting materials to the industry at a fraction of the cost of inhouse cloning. Clones produced through cell culturing will also have the benefit of being totally sterile and free from disease.

Cannadabis has been offered an NRC-IRAP grant for initial developments of the process and are in early negotiations with a Canadian cannabis company to commercialise. The founders are expecting to file patents, mid 2020, and begin construction of a commercial scale process by mid-2021. Cannadabis anticipates that a 5000 sq ft facility will produce 5+ million clones annually, with minimal labour.

The project is looking to possibly incorporate the production of artificial seeds, which would simplify transportation and ease of storage for cultivators. They will also be developing cryogenic preservation methods. Cultivators around the world are encouraged to reach out to Cannadabis if they are looking to simplify their process, access cell culture benefits, and maximise growing space.

Working with Cannadabis cultured clones will be the most affordable, safe, and efficient way of acquiring starting material. Their services would include meristem culturing to remove systemic disease, and long-term storage of genetic inventory. Partners who end up with a pest could rest easy knowing their mother cultures will be perfectly preserved in tissue culture, and fifty thousand clones for the next crop are still on the way.

Cannadabis Medical and Delta 9 Cannabis have teamed up to provide an affordable, turnkey, tissue culture laboratory, complete with operating procedures, equipment, and cannabis medium recipes.

The two companies have co developed this system for their own commercial use and have recently made the system available for other cultivators. Both companies have recognised that the cannabis industry is still reliant on black market methods of propagation, and as a result, there have been countless incidents of crop and genetic loss in the legal industry; many of the stories circulating are understandably refuted by the companies experiencing such loss.

Rather than ignore the inevitable pest problems, the two companies are going toe to toe with mother nature, developing half century old technology and making it specifically for cannabis. Hopefully delivering the same modicum of control to the rest of the industry; cultivators slow to develop tissue culture science may soon find their genetics and crop totally destroyed by a single, often microscopic pest. On a commercial scale, these pests become essentially impossible to remove without the use of tissue culture.

With feet rooted in genuine care, Cannadabis and Delta 9 are prepared and excited to deliver a tissue culturing system to the global cannabis industry. They recognise the value and utility available to growers, and they also recognise that learning tissue culturing can feel out of reach for cultivators with no prior knowledge, or excess funding to hire an inhouse specialist.

Instead of missing out or paying specialists, cultivators can rely on Cannadabis and Delta 9 to deliver a ready to use laboratory, the development of which was based on maximising value for the growers.

The laboratory comes with only bare essentials and extensive, yet simple, operating procedures. Training materials will detail cannabis specific mediums, sanitation protocols, along with troubleshooting methods for finicky cultivars; an inexperienced grower will be comfortably blending and using mediums on the same day of commissioning. The whole system, equipment and all, will be much more affordable than hiring a tissue culture specialist.

Over the next three years, Cannadabis will be working to establish an expanded cultivation with the hope of supplying medical, organic, indoor grown cannabis to domestic and international markets.

They will also pioneer an original cell culture process that expects to be the most affordable source for starting materials in the world; Cannadabis is especially excited to deliver their polyploid cultivars as starting materials to industry members.

Cannadabis would like to offer an open invitation to all scientists, entrepreneurs, and industry professionals for collaboration. We are actively seeking partners who share a similar vision for the cannabis industry. Any professionals who are driven by a sense of genuine care and have a passion for cannabis medicine are encouraged to reach out.

References

1 hempindustrydaily.com/hemp-cultivators-tissue-culture-increase-propagation-preserve-genetics/2 Meyers, L. A., and Levin, D. A. (2006). On the abundance of polyploids in flowering plants. Evolution 60, 11981206. doi: 10.1111/j.0014 3820.2006.tb01198.x3 http://www.slideshare.net/ranganihennayaka/plant-polyploids4 http://www.frontiersin.org/articles/10.3389/fpls.2019.00476/full5 plantbreeding.coe.uga.edu/index.php?title=5._Polyploidy

Alexander CalkinsCEOCANNADABIS Medical INC+1 306 552 4242alexander@cannadabismedical.caTweet @cannadabiscannadabismedical.ca

This article will appear in the first issue ofMedical Cannabis Networkwhich will be out in January.Clickhereto subscribe.

Continued here:
Cannadabis: tissue culture and the future of cannabis cultivation - Health Europa

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Female cyclists are at a lower risk of suffering Sudden Cardiac Death than male athletes, but women should still learn about ways to screen for heart problems before engaging in endurance sports.

Dr. Mehreen Quhreshi is a cardiologist with advanced training in stress testing and cardiac imaging from Columbia University Medical Center in New York. She practices in Harrisburg, Pennsylvania and serves as the director of the Preventative Cardiology Program and the Nuclear Stress Lab at UPMC Pinnacle Heart and Vascular Institute. Dr. Bill Apollo, an amateur bike racer, runner, and duathlete is a Harrisburg, Pennsylvania-based cardiologist, who directs the UPMC Pinnacle Sports and Exercise Cardiology Clinic.

At the Paris Olympics in 1900, endurance sports were exclusively dominated by men; a mere 22 women participated, competing in the five gentrified events of croquet, equestrian, golf, tennis, and sailing. It took until the latter half of the twentieth century for the world to witness women competing in major Olympic endurance sports such as cycling (Los Angeles, 1984) and triathlon (Sydney, 2000).

Wider womens participation in the Olympics roughly coincided with the establishment of Title IX of the United States Educational Amendments of 1972, which mandated equal access for women in any program that received Federal funding including sports in public schools and universities. These two major developments fueled an explosion of female participation in a variety of events at all skill levels. The percentage of women finishers in marathons in the U.S. rose from only 10% in 1980 to a robust 45% by 2015. Women set a new record for Olympic participation at the 2016 Rio Olympics, with nearly equal numbers (5,176 athletes, or 45% of total), and with representation in all events included in the games.

Paradoxically, women have generally been under-represented in medical research studies looking at cardiac health, adaptation to endurance training and its potential consequences. Despite this surge of female athletic participation, we still havent achieved gender equality when it comes to understanding and caring for the female athletes heart. And recent small-scale studies suggest that there are in fact important cardiac differences between the sexes.

Some of the key questions are: to what extent do underlying genetic and hormonal factors impact normal changes in a womans heart related to exercise? How do these influences alter her risk for developing chronic heart problems or sudden cardiac death during competition? Are women better equipped to handle endurance training by design? Some recent research suggests that pregnancy subjects the female body to cardiac stresses similar to those that male athletes experience in even the most competitive events, including events like the Tour de France.

Below we examine the current understanding of cardiac development and risks in women endurance athletes, how and why women may differ from men in this regard, and recommended precautions that should be taken in training and competition by elite female endurance athletes.

Sudden cardiac death (SCD) during athletic competition is fortunately a rare occurrence, and it tends to affect men more commonly than women. In fact, a womans risk of SCD during endurance sports is estimated to be some 10 times lower than for her male colleagues. Professional cycling, during the past 3 seasons, has seen a total of 6 elite men tragically die directly from heart problems during races (5 in road racing, 1 on the track), with the most recent being Robbert de Greef in March 2019. During the same time period, there were zero incidents involving women, and indeed there are no known reports of SCD during elite womens cycling events for the past 20 years. Professional female cyclists are far more likely to die from training accidents (usually involving automobile collisions) than from heart problems.

Interestingly, these observations regarding SCD in cycling seem not to be true for other endurance sports. Marathon running has a huge participant base much larger than the womens pro peloton with nearly a half million participants in 2019 alone. This huge statistical sampling clarifies the measure of SCD risk: 1 incident per 150,000 participants overall, but more commonly occurring in men (1/ 100,000), and much less likely to occur in women (1/243,000).

Despite this fairly low risk of SCD in women, the sheer volume of running participants makes it easier to find reports of SCD. For example, Taylor Ceepo, age 22, died in May 2019 less than 1 mile from the finish line at the Rite-Aid Cleveland Marathon. The medical examiners report indicated that Ceepo experienced sudden cardiac death in association with physical exertion, pseudoephedrine use (a fairly benign over-the-counter decongestant) and cardiomyopathy. Her tragedy should remind us that even in very young and apparently healthy women, undiagnosed heart disease is still a common killer (3rd behind unintentional injuries and cancer in her age group), and her autopsy findings highlight the importance of screening women for underlying heart problems.

The most common causes of SCD are generally driven by age rather than sex. Athletes under age 35 both men and women alike are susceptible to genetically inherited structural heart problems including hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as potentially lethal heart rhythm problems called channelopathies. Above age 35, coronary artery disease predominates, with women being preferentially protected by their higher estrogen levels, until they reach menopause. Initially, the ten-fold higher incidence of SCD in men was thought to be simply due to the much larger numbers of men participating in endurance sports. But now that participation rates are becoming nearly equal, womens risk of SCD is still not as high as that experienced in the male population.

Several theories exist that might explain why women appear to be more protected from SCD during intense competition. One explanation may lie in the sympathetic nervous system, which is responsible for the bodys fight or flight response. Male physiology is observed to be wound more tightly, meaning that their arteries and blood vessels tend to constrict more during intense activity than women. The increased blood pressure adds resistance to blood the heart is pumping out. When this increased pressure load is coupled with an outpouring of adrenaline during competition, the strains placed on the heart may trigger lethal rhythm problems in susceptible individuals generally those with underlying inherited cardiac problems or acquired fibrosis (scarring) from long-term training. For unclear reasons, even in the context of equal training volumes, men more commonly develop potentially lethal fibrosis substrate, placing them at higher risk of SCD than women.

Another possible explanation relates to obvious hormonal differences between men and women. In some animal models, testosterone has been shown to affect the way the heart conducts impulses making men, at least in theory more susceptible than women to developing electrical instability resulting in malignant heart arrhythmias. Clinically, testosterone promotes thickening of the heart muscle, which may explain why men are more susceptible than women in developing complications from diseases like HCM and ARVC. Estrogens, on the other hand, are protective in this regard, and delay that same process of heart muscle thickening. Despite equal patterns of genetic transmission of HCM and ARVC between both sexes, hormonal differences may explain why these maladies tend to remain latent for a longer period of time in women, presumably translating to a survival advantage and lower risk of SCD.

Sports medicine screening programs are designed to identify potential cardiac risks in individuals who exhibit no outward symptoms of heart problems. Such programs aim to increase participation but to do so with a reasonable level of caution, to ensure the safety of the athlete. Despite the lower risk of SCD in women, screening is still important.

Pre-participation screening typically involves a comprehensive medical history review, focused physical examination, and in some cases an electrocardiogram (EKG). EKG tests are proven to be more sensitive than history and physical examination alone in detecting pathology, especially regarding heart rhythm issues. EKG interpretation should always be completed by a skilled reader able to distinguish the fine line between normal adaptation to exercise and pathology. Guidelines like the International Recommendations for EKG Interpretation in Athletes will increase reading accuracy and reduce the number of false findings, which often lead to expensive and unnecessary longitudinal testing. Men exhibit changes in their EKG patterns more often than women, and these variations in many instances are considered normal purely as the result of physiologic adaptation to training. On the other hand, women are less likely to stray from normal parameters, so most EKG changes are concerning and more likely represent a real problem.

Consistent endurance training induces physiologic remodeling, or normal adaptations to the heart resulting in improved efficiency of an athletes engine. Cyclists are unique because they typically perform the most prolonged exercise pattern more hours per day and more days per year than nearly any other athletes. Cyclists often sustain markedly elevated heart rates for extended periods of time during two distinct types of high cardiac output workouts. First, high intensity aerobic workouts at near peak efficiency, coupled with sustained elevations in heart rate, create a dynamic stress, or a volume load on the heart. And second, long tempo efforts punctuated by intense anaerobic dashes create static stress, exposing the heart to a pressure load because of sustained increases in blood pressure.

Cyclists therefore typically exhibit prominent changes in heart structure due to a combination of dynamic stress (volume overload) and static stress (pressure overload) resulting in generally increased cardiac mass, with mildly enlarged hearts and mildly increased heart wall thickness at least in men. Statistically, women are generally smaller than men with lower lean body mass. Due to their higher estrogen levels, women tend to adapt to exercise in a qualitatively similar manner, but quantitatively different than men showing only minimal heart enlargement and virtually no heart wall thickening. In fact, only about 7% of healthy women show any significant increase in their heart size due to habitual exercise, whereas 47% of men show cardiac enlargement.

Symptoms of heart problems in women are often different to those reported by men. For example, women are less likely to experience classic chest pain due to a heart problem, but may report more subtle symptoms like indigestion, heartburn, fatigue, or poor exercise performance. Misinterpretation of these sometimes confusing symptoms often leads to a delay in diagnosis and poorer long-term outcomes for women. An unexplained decline in athletic performance is obviously concerning to any elite athlete whether male or female because this may be the only clue to a serious underlying heart problem.

However, in young women, such nonspecific symptoms are often incorrectly blamed on things like menstrual problems, eating disorders, iron deficiency anemia, pregnancy, or thyroid disease. In many cases it is the womans primary care provider who must be savvy enough to exclude these other diagnoses, realizing there is a potential heart problem and then making an appropriate referral to a cardiologist.

Estrogen generally protects women from developing CAD at young ages, but the risk rises as they reach menopause. And paradoxically, some young women may actually be at increased risk for CAD because of a syndrome called Relative Energy Deficiency in Sports (RED-S). Sports which favor lean body mass are often associated with heavy training loads and dieting to achieve optimal body weight. In some women this results in the Female Athlete Triad of menstrual dysfunction, unexplained decline in performance (with or without an eating disorder), and decreased bone density, leading to increased probability of fractures.

Prolonged endurance training in young women can lead to menstrual irregularities resulting in the same kind of reduced estrogen levels typically seen in older postmenopausal women. These athletes should be evaluated for the more traditional cardiac risk factors such as high blood pressure, cholesterol problems, and diabetes, with appropriate intervention to modify their risk. Treatment of the Female Athlete Triad is challenging and may require a multidisciplinary approach to improve an athletes overall energy balance. Strategies include decreasing training volume, modifying dietary habits, medically replacing estrogen levels, promoting bone health with dietary supplements, and seeking appropriate professional help to correct eating disorders if present. Due to the focused and highly competitive nature of many endurance athletes, this is often a tall order to fill since they may resist decreasing their training volume.

Regular exercise is the cornerstone of prevention and treatment of many cardiac and non-cardiac diseases. But some researchers suggest that the benefits of exercise are like a drug the benefits of moderate training reach a plateau and exceeding that plateau, or overdosing, may be detrimental to the athletes health. Several studies have reported unexpected abnormalities in endurance athletes primarily in men suggesting either transient or permanent heart damage which puts them at risk for chronic heart issues. Findings have included a five-fold increased risk of atrial fibrillation (AFIB), increased coronary artery calcium deposits (which indicate clinically silent CAD), and scarring of the heart muscle. However, there are several general guidelines that all athletes should be aware of:

The biological adaptation to handle the stress of pregnancy may be a key reason for the apparently better female adaptation to endurance training. Recent research has highlighted that during pregnancy, the body functions at a basal metabolic rate of 2.2 times the normal burning up to 4000 calories a day. Extended over a period of 40 weeks, pregnancy can essentially be considered the ultimate endurance event a true test on the limits of human performance. Under typical circumstances, a body functioning above 2.5 times the normal metabolic rate over a prolonged period will begin to break down. But most women emerge from pregnancy and go on to live healthy lives, having tolerated a level of metabolic strain considered by some to be similar to that experienced by athletes participating in some of the most competitive endurance events.

There are also massive changes in the amount of fluid in a womans body during pregnancy, creating cardiac stresses similar to endurance training. In order to support the developing fetus, she must increase her blood volume by a massive 50%, and her cardiac output by 40-50% constituting the ultimate dynamic stress on the heart. The female body appears to require less adaptation by the heart muscle and chambers to accommodate these changes.

More overlap in research examining the similarities between the effects of endurance training in women and the cardiac demands placed on them during pregnancy may help to explain these gender-based differences in adaptation to exercise and related cardiac risk. Additional research specifically devoted to women is critical to a better understanding of how gender influences normal cardiac adaptation to exercise, as well as to more accurately identify pathologic conditions which sometimes seem to overlap with normal physiology.

Despite the substantially lower risk of SCD in women, cardiac risk screening of female endurance athletes and at-risk pregnant women is still important, and should be carried out by clinicians familiar with the differences in adaptive physiology between men and women. Women often experience challenging and atypical cardiac symptoms, requiring a high index of suspicion on the part of their doctors often at the primary care level to identify these underlying problems. As the current generation of elite female athletes matures into tomorrows Masters champions, we will undoubtedly learn a great deal more about the long-term cardiac implications of endurance training in women.

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The Outer Line: The impact of endurance training on the cardiac health of women - VeloNews

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The results of rodent studies by a Stanford University School of Medicine-led research team have shown that the abuse potential of the illicit street drug, ecstasy()3,4-methylenedioxymethamphetamine (MDMA)involves a different neuronal signaling pathway to that which mediates the potentially therapeutic, prosocial effects of the drug. If the findings can be confirmed in humans, they could lead to the development of novel treatments for psychiatric disorders that are associated with social awkwardness and withdrawal.

Weve figured out how MDMA promotes social interaction and showed thats distinct from how it generates abuse potential among its users, said research lead Robert Malenka, MD, PhD, the Nancy Friend Pritzker professor in psychiatry and behavioral sciences. Malenka and colleagues reported their findings in Science Translational Medicine, in a paper titled, Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.

MDMA is a mind-altering drug that is used by an estimated three million people in the United States every year. It gives users a sense of wellbeing, making them extremely sociable, and can even generate feelings of unguarded empathy for strangers, which makes MDMA a natural fit for raves and dance parties.

These features of MDMA use may also have applications in psychiatry, and the drug is in late-stage, multicenter clinical trials as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD). The goal is to harness MDMAs prosocial effects to strengthen the bond between patient and therapist. Its hoped that people who have experienced trauma may be able to feel comfortable reliving it through guided therapy.

About 25 million people in the United States who suffer from PTSD could benefit from a drug that helps to establish, with a single dose in a therapists office, a trust level that would otherwise typically take months or years to achieve, said Boris Heifets, MD, PhD, assistant professor of anesthesiology, perioperative and pain medicine, who is the newly reported studys lead author.

The flip side is that MDMA can be addictive. Taken in the wrong settings or in repeated or oversized doses, it can have life-threatening consequences. MDMAs abuse potential stems from its capacity to stimulate the brains reward circuitry, Malenka said. The brains reward circuitry tells us something is good for our survival and propagation. It evolved to tell us food is good when were hungry, water is good when were thirsty, and warmth is good when were cold. For most of us, hanging out with friends is fun, because over the course of our evolution its promoted our survival.

This reward circuitry involves neural connections projecting from one midbrain structure, the ventral tegmental area, to another, the nucleus accumbens (NAc), which is a conserved brain region that regulates appetitive behavior, the authors noted. When those neurons release a chemical called dopamine, the nucleus accumbens forwards signals throughout the brain that induce a sense of reward. Malenka further commented, Drugs of abuse trick our brains by causing an unnatural dopamine surge in the nucleus accumbens. This massive increase is much higher and more rapid than the one you get from eating ice cream or having sex.

MDMA also releases serotonin, but the role of this neurotransmitter is less clear. MDMA is a substituted amphetamine with high affinity for the serotonin [5-hydroxytryptamine (5-HT)] and dopamine (DA) transporters (SERT and DAT, respectively), through which it stimulates release of these neurotransmitters, the team explained. MDMAs acute reinforcing effects, which strongly predict addictive liability, have been linked to its DA-releasing properties, whereas the role of SERT in this action is uncertain.

There have been some pointers, however. Serotonin-releasing neurons in the dorsal raphe nucleus of the brain send projections to the same part of the nucleus accumbens that is connected by the dopamine-releasing neurons. And neuroscientists had previously shown that MDMA triggers the release of far more serotonin than dopamine. We, therefore, hypothesized that MDMAs interaction with SERT specifically in the NAc could fully account for MDMAs prosocial effect but not its rewarding effect, the authors commented. To investigate this they carried out a suite of behavioral, and complementary genetic and brain region-specific pharmacological manipulations in mice, together with in vivo calcium imaging, to demonstrate that MDMA acts at SERT-containing 5-HT terminals in the NAc.

The researchers tested whether an explorer mouse given a relatively low dose of MDMA or, control mice given saline, preferred to spend time in a chamber holding another mouse under an upside-down mesh cup (to keep that mouse from moving about) or in an otherwise identical chamber with a cup but no mouse. They found, consistently, that the saline-treated explorer mice get bored after 10 minutes with another mouse. But an explorer mouse given MDMA sustained its social curiosity for at least 30 minutes.

You cant ask mice how theyre feeling about other mice, Malenka said. But you can infer it from their behavior. Its also likely that the same effects would be seen in humans because the midbrain areas have been remarkably conserved among mammalian species over evolutionary time, Malenka said.

The test results also clearly implicated serotonin as the signaling substance responsible for promoting social behavior in both male, and in female mice. Heifets added, Giving MDMA to both mice enhanced the effect even further. It makes you wonder if maybe the therapist should also be taking MDMA.

Like humans, mice will return to places where theyve had a good time. This can also be linked to the brains reward circuitry. To determine MDMAs addictive potential, the researchers gave mice an MDMA dose equal to the one in the first, social experiment, but only when the mice were in a particular room of a two-room structure. The next day, the mice showed no preference for either room. This provided evidence that at the dose used, MDMA hadnt noticeably triggered the reward circuitry.

However, mice given a higher MDMA dose exhibited both its social and abuse-potential effects. Further tests determined that the secretion of dopamine triggered by MDMA is not necessary for promoting sociability. Serotonin release, triggered by the low MDMA dose, was all it took. And in a subsequent set of experiments, the scientists were able to induce sociability in mice by infusing the drug only into the animals nucleus accumbens, providing further evidence that this is where the serotonin, released as a result of MDMA administration, exerts its sociability-inducing effect.

Where, exactly, in the brain thats happening hadnt been proven, Heifets said. If you dont know where somethings happening, youre going to have a hell of a time figuring out how its happening.

The researchers made this discovery when they showed that blocking a specific subtype of serotonin receptor in the nucleus accumbens fully inhibited MDMAs prosocial effect. And giving the mice a different serotonin-releasing drug, fenfluramine, (FEN), which does not cause dopamine release, was enough to mimic the prosocial effects of MDMA, without causing any addictive, or rewarding, effects. Consistent with the enhancement of sociability by FEN in our experiments, early clinical data suggest that higher doses of FEN have subjective effects reminiscent of MDMA, team pointed out. FEN has been reported to improve social deficits in children with autism.

Fenfluramine, is also the fen part of the once-popular diet pill called fen/phen, a two-drug combination developed in the 1960s. Fen/phen was pulled off the market in the 1990s after 30% of patients taking it were found to be showing signs of heart disease, including pulmonary hypertension. And as the authors pointed out, like MDMA, long-term and/or heavy use of FEN is associated with cardiovascular and neurological toxicity Furthermore, tolerance to MDMAs acute effects may develop with frequent use. They suggested that it would seem prudent to use these drugs sparingly and infrequently, consistent with recent clinical trial designs for MDMA.

Although the long-term cardiovascular and neurotoxic effects of MDMA and FEN mean that neither drug would be suitable for any indications requiring daily use, Heifets pointed out that the damaging effects of chronic use would be highly unlikely to occur in the one or two sessions that would be required for patient-therapist bonding in a psychiatric setting. Even so, the authors concluded, Given MDMAs long history of abuse and potential toxicity, it would be prudent to develop drugs or other therapies that mimic its prosocial effects with reduced associated morbidities. We propose that future therapeutic strategies, including drug design and brain stimulation approaches, may be more successfully developed by targeting relevant brain circuits rather than by modifying existing drugs based on putative structure/activity relationships.

Link:
Rave Drug Ecstasy's Therapeutic, Addictive Qualities Teased Apart - Genetic Engineering & Biotechnology News

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Gene editing using the CRISPR system has been established as the most powerful tool in the search for new drugs and is now being exploited for therapeutic purposes. Here, Pushpanathan Muthuirulan discusses the promises and wider opportunities of using CRISPR technology to open up the possibility of large-scale screening of drug targets. He also highlights the importance of implementing CRISPR technology into clinical practice for development of next-generation therapeutics and patient-tailored medicine.

THE DRUG discovery process, in which new drug candidates are discovered and evaluated for therapeutic use, has resulted in both promising and life-saving therapies for numerous diseases including inherited genetic disorders and pathogenic infections.1 However, the discovery and testing of a new drug candidate typically takes more than a decade and the total cost associated with drug discovery processes can exceed $1 billion.2 In the United States, the drug discovery process takes an average of 12 years and in excess of $1 billion to develop a new drug.3 Furthermore, only a few drug candidates actually make it to market; the chance of a new drug actually reaching market is only one in 5,000. The high cost and lengthy effort of getting new drugs to market make the drug development process a risky endeavour for pharmaceutical companies, which consequently hinders discovery and development of new therapies. The recent emergence of genome editing technologies and advances in our understanding of human genome sequences have raised hope that direct manipulation of the genome could potentially revolutionise the process of drug discovery and therapeutics.4 In particular, new technologies like CRISPR-Cas9 are key to unlocking potential drug targets and could have a profound impact on modern drug discovery and development.1,5

Originally posted here:
CRISPR: kick-starting the revolution in drug discovery - Drug Target Review

Recommendation and review posted by Bethany Smith

An artist's illustration of a DNA double helix. New technology makes it easy to edit the human genome, even the germline which can affect all of human evolution. (Image:. U.S. National Human Genome Research Institute/Reuters

By making genetic research so much easier, the recent technology known as CRISPR has allowed scientists an enormous advantage in research into so many areas.

Unfortunately theres a downside which raises serious ethical questions.

Franoise Baylis (CM, ONS, PhD, FRSC, FCAHS), is a research professor at Dalhousie University Halifax who has written on the subject.

The concern with gene-editing is with experiments into modification of human DNA, which could lead in theory to changing of the human genome forever. It could in theory enable creating designer babies. Indeed its been just over a year since the first genome edited babies were created by a Chinese scientist. A Russian researcher has since announced plans to carry out similar human gene editing experiments. Other Chinese experiments involve putting human genes into monkeys. All of these, and other potential experiments, have raised the concern of the scientific world that some of its members are going beyond ethical concerns of science.

Research professor Francoise Baylis at Dalhousie University, Halifax

While some experts have expressed concern about state manipulation to create specific charachteristics, Professor Bayliss suggests that designer babies could result in greater class divide. This would be due to the expense making such technology accessible to the upper echelons and entrenching elite advantage, and thus privilege, in their DNA.

However she says these experiments have resulted in governments and the scientific community coming out with regulations and recommendations to slow down or halt such research until such time as serious ethical discussions take place to establish limits on what should be done and how.

F Baylis on the ethical questions involving CRISPR technology and gene editing of the human genome , Harvard University Press

She says the human genome belongs to all of us and any single or small group of scientists shouldnt be altering it on their own.

As a direct consequence of increasingly audacious moves by some scientists to engineer future generations, important decisions must now be made decisions that will set a new course for science, society, and humanity. May these decisions be inclusive and consensual. May they be characterized by wisdom and benevolence. And, may we never lose sight of our responsibilities to us all. F Bayliss: Altered Inheritance: CRISPR and the Ethics of Human Genome Editing F Bayliss: Altered Inheritance: CRISPR and the Ethics of Human Genome Editing

Fortunately some action has been taken. The WHO has convened a multi-disciplinary Expert Advisory Committee on Human Genome Editing to examine the scientific, ethical, social and legal challenges associated with human genome editing (both somatic and germ cell). Professor Bayliss is a member of the group which met for the first time this spring.

She lauds those countries that have established regulations regarding such research but notes there is always the chance of rogue scientists.

She also notes that scientists are usually very concerned about recognition by their peers and being shunned for having crossed established ethical lines is something they would very likely avoid

Additional information

The Conversation: F Bayliss: Dec 10/19: A year after the first CRISPR babies, stricter regulations are now in place

Excerpt from:
CRISPR: Ethics and the gene editing of humans - Radio Canada International (en)

Recommendation and review posted by Bethany Smith

We can already edit genes in human embryos. We can even do it in a way to pass the edits down generations, fundamentally changing a familys genetic makeup.

Doing it well, however, is far more difficult.

Its impossible to talk about human germline genome editing without bringing up the CRISPR baby fiasco. Over a year ago, a rogue Chinese scientist performed an edit on fertilized human embryos that, in theory, makes them resistant to HIV infection. Two twin girls were born, and both had multiple unplanned edits in their genome with unknown health consequencesconsequences that may be passed on to their offspring.

The brash attempt at making scientific history clearly shows that, ethics and morality issues aside, when it comes to germline editingthat is, performing gene edits in egg, sperm, or the embryowere simply technologically not there. Make no mistake: CRISPR may one day wipe out devastating genetic diseases throughout entire family lines, or even the human race. But to harness its power responsibly, there are plenty of technical challenges we need to master first.

This week, Rebecca Lea and Dr. Kathy Niakan at the Human Embryo and Stem Cell Laboratory at the Francis Crick Institute in London, UK, laid out those challenges in a sweeping articlein Nature. CRISPR as a gene editor is getting more specific and efficient by the day, they explained. However, for it to gradually move into germline editing, we also need to understand how the tool tangos with cells during early human development.

The data, they argue, will not only let us zoom into the creation of human life. It will also help inform the debate about potential safe and effective clinical uses of this technology, and truly unlock the doors to the human genome for good.

Correcting dangerous genetic mutations is one reason to pursue germline editing, but CRISPRing human embryos can also unveil insights into the very first stages of human embryo development. Research shows that trying to understand how human embryos form by studying mice might not be the best route, especially when it comes to using those results to tackle infertility and other medical problems. With CRISPR, we have insight into these early stages that were previously completely unattainable. We might only solve infertility issues, but perhaps also allow same-sex couples to have genetic children in the future.

Another argument is that couples already screen for life-threatening mutations during IVF, and using CRISPR on top of that is unnecessary. Not true, the authors argued. When both parents carry a similar mutation that robs them of the ability to have a healthy child, CRISPRnot selection during IVFis the answer. Ultimately, providing more options for patients empowers them to make the choice that is best for their family and circumstances, they said.

This is where it gets complicated.

The big one: were still trying to tease out how CRISPR works in cells that form the embryo, in hopes that we can cut down on potential mistakes.

Let me explain: all cells in the body have a cell cycle, somewhat analogous to a persons life cycle. Many checkpoint life events happen along the way. The cell could decide to divide and have kids, so to speak, or temporarily halt its cycle and stop its own aging. During a cycle, the cells DNA dramatically changes in number and packaging in preparation for its next stage in life.

The problem? The way CRISPR works heavily depends on the cell cycle. Although dubbed an editor, CRISPR actually vandalizes the genome, creating breaks in the DNA strands. What we call gene editing is the cells DNA repair system kicking into high gear, trying to patch up the mess CRISPR left behind. Adult cells that cant be repaired stop their own life cycle at a checkpoint for the greater good. In embryos, however, cells arent nearly as altruistic. Their checkpoints arent fully developed, so they might continue to develop even with severe mutations. Zooming back to the full picture, it means that the resulting early-stage embryo may keep accumulating damage, until it fails in the mothers womb.

To get around this, scientists have tried other ways to push an embryo into accepting a healthy DNA template after a CRISPR snip, which in theory would cut down on unwanted mutations. One idea is injecting the CRISPR machinery at a specific time into fertilized eggs, so it catches the early-stage embryo at just the right time to reduce DNA breaks in both strands. While theoretically possible, the process is kind of like a person trying to jump from a high-speed train into a specific cabin on a rapidly rotating Ferris wheel while blindfolded.

But science is making progress. Although we dont have a detailed movie of cell cycles in human embryos yet, multiple labs are beginning to piece one together, with hopes itll eventually help take off the blindfold when injecting CRISPR. Others are looking into adding CRISPR to sperm before fertilization as an alternative.

At the same time, scientists are also trying to characterize the entire scope of mutations caused by CRISPR. Its not just adding, swapping, or deleting specific letters in genes. Rather, the range of mutations is more complex, including large swaths of genetic rearrangements, unintended cuts relatively far from targeted spots, and other dramatic DNA lesions following CRISPR action. Its perhaps not surprising that the edits in CRISPR babies didnt work as intended.

Base editors, which swap one genetic letter for another, might be a better approach compared to the classic hack-and-paste, the authors said. So far, however, the tools havent yet been validated in embryosnot even those from mice.

Finally, for the edit to make a difference to the child, the embryo has to develop normally inside a womb into a baby. But success rates for assisted reproductive technologies are already fairly low. Add in a dose of genetic editing tool that cuts into an already-sensitive genomic landscape, and it becomes incredibly hard to maintain the health of the edited embryo.

Putting it all together, there is simply not enough data at present to understand the capability of early[embryos] to repair DNA, the authors said.

Far from it. Although theres much we dont yet understand, we do have an impressive range of tools to predict and evaluate mutations in human embryos. Exactly how to determine whether a gene-edited embryo is healthy remains up for debatefor example, is five unexpected mutations considered ok? What about 500 or 5,000?

That said, just having tools to diagnose the genetic health of an embryo from a tiny bit of DNA is already extremely useful, especially if we as a society decide to move into germline editing as a treatment.

With machine learning making an ever-larger splash in computational biology, these predictive tools will only become more accurate. Add to that ever-more-effective CRISPR variations, and were on the right trackas long as any potential applications of embryo editing only come after in-depth public and policy discussions and fit a number of strict ethical and safety criteria, the authors said.

In response to the CRISPR baby scandal, multiple governments and the World Health Organization have all drafted new guidelines or legislation to tap on the brakes. The technology isnt mature enough for clinical use, the authors said, and much more work is needednot just to further improve CRISPR tools, but especially for understanding how it works in human embryos.

Ultimately, were talking about potentially engineering the future of the human race. Tiptoeing, rather than stumbling ahead, is the least we can do. One must ensure that the outcome will be the birth of healthy, disease-free children, without any potential long-term complications, the authors concluded.

Image Credit: Image by marian anbu juwan from Pixabay

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How Far Are We from (Accurately and Safely) Editing Human Embryos? - Singularity Hub

Recommendation and review posted by Bethany Smith

Increase in applications of CRISPR and Cas gene editing technology in bacteria and usage of gene editing technology for prevention of various diseases are the major factors anticipated to drive the market from 2018 to 2026. Rise in need of alternative medicine for chronic diseases and increase in investments by key players in Asia Pacific are projected to propel the market during the forecast period.

The report also provides profiles of leading players operating in the global CRISPR and Cas market such as Synthego, Thermo Fisher Scientific, Inc., GenScript, Addgene, Merck KGaA (Sigma-Aldrich), Integrated DNA Technologies, Inc., Transposagen Biopharmaceuticals, Inc., OriGene Technologies, Inc., New England Biolabs, Dharmacon, Cellecta, Inc., Agilent Technologies, and Applied StemCell, Inc.

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Increase in Usage of DNA-free Cas

DNA-free Cas9 is most commonly used with synthetic crRNA tracrRNA and chosen by researchers who strive to avoid unwanted vector DNA integration into their genomic DNA. CRISPR-Cas9 utilizing mRNA or protein is ideal for applications such as knocking of a fluorescent reporter using HDR or knockout cell line generation. Advantages such as gene editing with DNA-free CRISPR-Cas9 components to reduce potential off-targets and potential usage of CRISPR-Cas9 gene editing to find correlations with human diseases in model systems drive the segment.

Rise in Incidence of Genetic Disorders and Increase in Applications of CRISPR and Cas Genes to Propel Market

Genetic diseases are generally termed as rare diseases. According to NCBI, prevalence of these rare diseases is approximately 5 in 10,000. There are 6,000 to 8,000 rare diseases, with 250 to 280 new diseases diagnosed every year. Hence, 6% to 8% of the global population is projected to be affected by rare diseases i.e., genetic diseases in the near future. Researchers are developing treatments for these diseases with applications of new technologies such as CRISPR. The applications of CRISPR technology are expanding in other industrial sectors. This is expected to drive the market during the forecast period.

Usage of CRISPR/Cas9 technology in plant research has enabled the investigation of plant biology in detail which has helped to create innovative applications in crop breeding. Site-directed mutagenesis and site-specific integration of a gene, which is also called knock-in, are important in precision crop breeding. Cas9/gRNA-mediated site-directed mutagenesis and knock-in is widely used in rice and Arabidopsis protoplasts. CRISPR/Cas9 provides a simple method to generate a DSB at a target site to trigger HDR repair.

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Asia Pacific Market to Witness Exponential Growth

In terms of revenue, the CRISPR and Cas genes market in Asia Pacific is expected to expand at a CAGR of 22.0% during the forecast period. Growth of the market in the region can be attributed to increase in incidence of chronic diseases such as cancer and the need of development of genetic engineered treatment options. According to the report, Call for Action: Expanding Cancer Care for Women in India, 2017, an estimated 0.7 million women in India are suffering from cancer. China dominated the CRISPR and Cas genes market in Asia Pacific. In 2016, scientists based in China launched the first known human trials of CRISPR, the genomic tech that involves slicing and dicing the bodys very source code to fight cancer. Japan was the second largest market for CRISPR and Cas genes in Asia Pacific.

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CRISPR and Cas Genes Market will Likely Rise to US$ 7,234.5 Mn by the End of 2026 - Montana Ledger

Recommendation and review posted by Bethany Smith

In the wake of the Conservative Partys crushing victory in the election in the United Kingdom, Prime Minister Boris Johnson is poised to navigate Britains exit from the European Union. Once out of the EU, the UK could regain full control over its laws and regulations. And that might open the door to a reversal on what scientists consider its backward-looking policies on GMOs and CRISPR gene editing in agriculture.

Though the election debate has centered around immigration, security and healthcare, the question of what direction the UK should take in terms of science policy persists. Will the UK manage to unleash the potential of its biotechnological sector and become a global advocate for innovation and consumer choice, or will it retain the EUs antiquated approach?

In a manifesto released in November, the Conservatives pledged to take the path of science-led, evidence-based policy to improve the quality of food, agriculture and land management. Previously, Johnson hadpromised to liberate the UKs biotech sector from the EUs anti-genetic modification rules.

The laws that concern genetically modified organisms in the UK are primarily based on European Union regulations. For years, the EU has backpedaled on agricultural innovation, preventing European consumers from accessing biologically enhanced food. This can be seen in the very limited number of genetically modified crops authorized for cultivation in the EU, and a very cumbersome and expensive process of importing genetically modified crops from other countries. In July 2018, the European Court of Justice (ECJ) decided that gene-edited plants should be regulated the same way that genetically modified organisms are regulated, rendering them practically illegal and hindering innovation even further.

If the UK chooses to move away from these EU-based regulations as a consequence of Brexit, it could become a forward-looking global biotech powerhouse.

The first step would be to replace fear-based skepticism of genetic modification with an evidence-based, pro-innovation approach. Despite popular rhetoric, there is no substantial scientific evidence behind the alleged health and environmental risks ascribed to GM products. Abandoning these baseless assertions and creating and sustaining the conditions under which UK farmers could innovate, lower their production costs, and use fewer chemicals would be an enterprising move on the part of the UK government.

Approving GM pest-resistant crops, for instance, could save about 60 million ($79 million) a year in pesticide use in the UK. Moreover, 60 million in savings would mean more leeway for competitive food pricing in a country where prices at the grocery store are rising 2 percent annually.

Once restrictive genetic modification laws are relaxed, it would be necessary to enable easy market access for GM foods. Under current EU legislation, products containing GMOs need to be labeled as such, and the requirements also apply to non-prepacked foods. It is legally established that such products (soy, for example) not only require written documentation but also should have an easily readable notice about their origin. No such rule exists with regards to foods that are 100% GMO-free, meaning there is explicit discrimination in place giving GMO-free food an unfair advantage on the market.

The EUs strict regulations on the use of GM technology have been, first and foremost, harmful to consumers, depriving them access to innovative options such as Impossible Foods plant-based burger, which so closely mimics meat thanks to an ingredient produced with the help of genetically engineered yeast. Vastly popular in the US and now expanding to Asia, vegan burgers using plant-based substitutes for meat and dairy products, are absent from the European market due to backwards-looking anti-GM rules.

The United Kingdom should strive for the smartest regulation in the field of approval and market access to GMOs. Relaxed regulations on gene-editing methods like CRISPR-Cas9 could also attract massive investment and lead to wide-reaching biotech innovation in the UK.

Enabling gene-editing is an essential part of unleashing scientific innovation in the United Kingdom after Brexit. Skepticism of gene-editing centers around the potential but largely exaggerated adverse effects of the technology and ignores the astonishing benefits that could accrue to both farmers and consumers.

If the UK manages to replace the EUs overly cautious biotech rules with a pro-innovation and prosperity-fostering regulatory scheme, it could become a true global biotech powerhouse. This is an ambitious, exciting, and above all, achievable future.

Maria Chaplia is a European Affairs Associate at the Consumer Choice Center. Visit her website and follow her on Twitter @mchapliaa

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Viewpoint: With Conservative sweep of the 'Brexit election', Boris Johnson poised to steer the UK out of 'outdated' EU GMO, CRISPR regulations -...

Recommendation and review posted by Bethany Smith

MELVILLE, N.Y., Dec. 12, 2019 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (BioRestorative or the Company) (BRTX), a life sciences company focused on stem cell-based therapies, today announced that the Israeli Patent Office has issued BioRestorative a Notice of Allowance on its patent application for a method of generating brown fat stem cells. This is the eighth patent issued, in the United States and other countries, for the Companys brown fat technology related to BioRestoratives metabolic program (ThermoStem Program).

Once issued in Israel, the final patent will allow for a method of isolating and differentiating a non-embryonic human brown adipose-derived stem cell into functional human brown adipocytes and a method of identifying compounds that modifies metabolic activity of human brown adipocytes. The technology is applicable for potential therapeutic uses for treating a wide range of degenerative and metabolic disorders, including but not limited to diabetes, obesity, hypertension and cardiac deficiency.

We continue to drive innovative and novel technology focusing on transformative therapies for our brown fat program, said Mark Weinreb, CEO of BioRestorative Therapies. We are pleased to add to our intellectual property library this recently issued patent by the Israeli Patent Office for our metabolic program to help power disruptive ways to treat metabolic disorders.

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, whether the Company will be able to consummate the private placement and the satisfaction of closing conditions related to the private placement and those set forth in the Company's Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:Email: ir@biorestorative.com

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BioRestorative Therapies Receives Patent in Israel For Its Metabolic Program - Yahoo Finance

Recommendation and review posted by Bethany Smith

A synopsis of the global canine stem cell therapy market with reference to the global healthcare pharmaceutical industry

Despite the economic and political uncertainty in the recent past, the global healthcare industry has been receiving positive nudges from reformative and technological disruptions in medical devices, pharmaceuticals and biotech, in-vitro diagnostics, and medical imaging. Key markets across the world are facing a massive rise in demand for critical care services that are pushing global healthcare spending levels to unimaginable limits.

A rapidly multiplying geriatric population; increasing prevalence of chronic ailments such as cancer and cardiac disease; growing awareness among patients; and heavy investments in clinical innovation are just some of the factors that are impacting the performance of the global healthcare industry. Proactive measures such as healthcare cost containment, primary care delivery, innovation in medical procedures (3-D printing, blockchain, and robotic surgery to name a few), safe and effective drug delivery, and well-defined healthcare regulatory compliance models are targeted at placing the sector on a high growth trajectory across key regional markets.

Parent Indicators Healthcare Current expenditure on health, % of gross domestic product Current expenditure on health, per capita, US$ purchasing power parities (current prices, current PPPs) Annual growth rate of current expenditure on health, per capita, in real terms Out-of-pocket expenditure, % of current expenditure on health Out-of-pocket expenditure, per capita, US$ purchasing power parity (current prices, current PPPs) Physicians, Density per 1000 population (head counts) Nurses, Density per 1000 population (head counts) Total hospital beds, per 1000 population Curative (acute) care beds, per 1000 population Medical technology, Magnetic Resonance Imaging units, total, per million population Medical technology, Computed Tomography scanners, total, per million population

Research Methodology

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XploreMR utilizes a triangulation methodology that is primarily based on experimental techniques such as patient-level data, to obtain precise market estimations and insights on Molecule and Drug Classes, API Formulations and preferred modes of administration. Bottom-up approach is always used to obtain insightful data for the specific country/regions. The country specific data is again analysed to derive data at a global level. This methodology ensures high quality and accuracy of information.

Secondary research is used at the initial phase to identify the age specific disease epidemiology, diagnosis rate and treatment pattern, as per disease indications. Each piece of information is eventually analysed during the entire research project which builds a strong base for the primary research information.

Primary research participants include demand-side users such as key opinion leaders, physicians, surgeons, nursing managers, clinical specialists who provide valuable insights on trends and clinical application of the drugs, key treatment patterns, adoption rate, and compliance rate.

Quantitative and qualitative assessment of basic factors driving demand, economic factors/cycles and growth rates and strategies utilized by key players in the market is analysed in detail while forecasting, in order to project Year-on-Year growth rates. These Y-o-Y growth projections are checked and aligned as per industry/product lifecycle and further utilized to develop market numbers at a holistic level.

On the other hand, we also analyse various companies annual reports, investor presentations, SEC filings, 10k reports and press release operating in this market segment to fetch substantial information about the market size, trends, opportunity, drivers, restraints and to analyse key players and their market shares. Key companies are segmented at Tier level based on their revenues, product portfolio and presence.

Please note that these are the partial steps that are being followed while developing the market size. Besides this, forecasting will be done based on our internal proprietary model which also uses different macro-economic factors such as per capita healthcare expenditure, disposable income, industry based demand driving factors impacting the market and its forecast trends apart from disease related factors.

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Standard Report Structure Executive Summary Market Definition Macro-economic analysis Parent Market Analysis Market Overview Forecast Factors Segmental Analysis and Forecast Regional Analysis Competition Analysis

Target Audience Production Companies Suppliers Channel Partners Marketing Authorities Subject Matter Experts Research Institutions Financial Institutions Market Consultants Government Authorities

Market Taxonomy

The global canine stem cell therapy market has been segmented into:

Product Type: Allogeneic Stem Cells Autologous Stem cells

Application: Arthritis Dysplasia Tendonitis Lameness Others

End User: Veterinary Hospitals Veterinary Clinics Veterinary Research Institutes

Region: North America Latin America Europe Asia Pacific Japan Middle East & Africa

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Read the rest here:
Canine Stem Cell Therapy Market Industry Outlook, Size, Share, Growth Prospects, Key Opportunities, Trends and Forecast - Downey Magazine

Recommendation and review posted by Bethany Smith

KRAS mutations occur in approximately 20% of people with non-small cell lung cancer, and some previous studies have suggested that these mutations are associated with a poorer response to treatment, said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. It was therefore encouraging to see in this exploratory analysis that KEYTRUDA monotherapy was associated with a survival benefit in certain patients with metastatic nonsquamous non-small cell lung cancer, regardless of KRAS mutational status.

The objective of the exploratory analysis was to assess the prevalence of KRAS mutations and their association with efficacy in the KEYNOTE-042 trial. Of the 1,274 untreated patients with metastatic nonsquamous NSCLC whose tumors expressed PD-L1 (TPS 1%) enrolled in KEYNOTE-042, 301 patients had KRAS evaluable data (n=232 without any KRAS mutation; n=69 with any KRAS mutation, including n=29 with the KRAS G12C mutation). Tissue tumor mutational burden (tTMB) and KRAS mutational status were determined by whole-exome sequencing (WES) of tumor tissue and matched normal DNA (blood). Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks (Q3W) (n=637) or investigators choice of chemotherapy (pemetrexed or paclitaxel) (n=637). Treatment continued until progression of disease or unacceptable toxicity. The primary endpoint was OS with a TPS of 50%, 20% and 1%, which were assessed sequentially. The secondary endpoints were PFS and ORR.

Findings from this exploratory analysis showed that KEYTRUDA monotherapy was associated with improved clinical outcomes, regardless of KRAS mutational status, in patients with metastatic nonsquamous NSCLC versus chemotherapy. In this analysis, KEYTRUDA reduced the risk of death by 58% (HR=0.42 [95% CI, 0.22-0.81]) in patients with any KRAS mutation and by 72% (HR=0.28 [95% CI, 0.09-0.86]) in patients with the KRAS G12C mutation compared to chemotherapy. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with metastatic NSCLC.

Additional efficacy results from this exploratory analysis showed:

With Any KRAS Mutation

With KRAS G12CMutation

Without Any KRAS Mutation

KEYTRUDA Mono-therapy

(N = 30)

Chemo-therapy

(N = 39)

KEYTRUDA Mono-therapy(N = 12)

Chemo-therapy(N = 17)

KEYTRUDA Mono-therapy

(N = 127)

Chemo-therapy(N = 105)

OS, median, mo(95% CI)

28 (23-NR)

11 (7-25)

NR (23-NR)

8 (5-NR)

15 (12-24)

12 (11-18)

OS, HR(95% CI)

0.42 (0.22-0.81)

0.28 (0.09-0.86)

0.86 (0.63-1.18)

ORR, %(95% CI)

56.7

18.0

66.7

23.5

29.1

21.0

PFS, median, mo(95% CI)

12 (8-NR)

6 (4-9)

15 (10-NR)

6 (4-8)

6 (4-7)

6 (6-8)

PFS, HR(95% CI)

0.51 (0.29-0.87)

0.27 (0.10-0.71)

1.00 (0.75-1.34)

Data from an exploratory analysis of KEYNOTE-189 (Abstract #LBA5), which evaluated KRAS mutations and their association with efficacy outcomes for KEYTRUDA in combination with pemetrexed and platinum chemotherapy, were also presented in a mini-oral session today at the ESMO Immuno-Oncology Congress 2019. KEYNOTE-189 was conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. Lung cancer can also be characterized by the presence of different biomarkers, including PD-L1, KRAS, ALK, EGFR and ROS1. KRAS mutations occur in about 20% of NSCLC cases. Between 2008 and 2014, the five-year survival rate for patients diagnosed in the U.S. with advanced NSCLC was only 5%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [CPS 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

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Data from Exploratory Analysis Show Merck's KEYTRUDA (pembrolizumab) Improved Overall Survival as Monotherapy for the First-Line Treatment of...

Recommendation and review posted by Bethany Smith

Transparency Market Research (TMR)has published a new report on the globalcell separation technology marketfor the forecast period of 20192027. According to the report, the global cell separation technology market was valued at ~US$ 5 Bnin 2018, and is projected to expand at a double-digit CAGR during the forecast period.

Overview

Cell separation, also known as cell sorting or cell isolation, is the process of removing cells from biological samples such as tissue or whole blood. Cell separation is a powerful technology that assists biological research. Rising incidences of chronic illnesses across the globe are likely to boost the development of regenerative medicines or tissue engineering, which further boosts the adoption of cell separation technologies researchers.

Expansion of the global cell separation technology market is attributed to an increase in technological advancements and surge in investments in research & development, such asstem cellresearch and cancer research. The rising geriatric population is another factor boosting the need for cell separation technologies Moreover, the geriatric population, globally, is more prone to long-term neurological and other chronic illnesses, which, in turn, is driving research to develop treatment for chronic illnesses. Furthermore, increase in the awareness about innovative technologies, such as microfluidics, fluorescent-activated cells sorting, and magnetic activated cells sorting is expected to propel the global cell separation technology market.

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North America dominated the global cell separation technology market in 2018, and the trend is anticipated to continue during the forecast period. This is attributed to technological advancements in offering cell separation solutions, presence of key players, and increased initiatives governments for advancing the cell separation process. However, insufficient funding for the development of cell separation technologies is likely to hamper the global cell separation technology market during the forecast period. Asia Pacific is expected to be a highly lucrative market for cell separation technology during the forecast period, owing to improving healthcare infrastructure along with rising investments in research & development in the region.

Rising Incidences of Chronic Diseases, Worldwide, Boosting the Demand for Cell Therapy

Incidences of chronic diseases such as diabetes, obesity, arthritis, cardiac diseases, and cancer are increasing due to sedentary lifestyles, aging population, and increased alcohol consumption and cigarette smoking. According to the World Health Organization (WHO), 2020, the mortality rate from chronic diseases is expected to reach73%, and in developing counties,70%deaths are estimated to be caused chronic diseases. Southeast Asia, Eastern Mediterranean, and Africa are expected to be greatly affected chronic diseases. Thus, the increasing burden of chronic diseases around the world is fuelling the demand for cellular therapies to treat chronic diseases. This, in turn, is driving focus and investments on research to develop effective treatments. Thus, increase in cellular research activities is boosting the global cell separation technology market.

To Obtain All-Inclusive Information On Forecast Analysis Of Global Market, Request A PDF Brochure Here.

Increase in Geriatric Population Boosting the Demand for Surgeries

The geriatric population is likely to suffer from chronic diseases such as cancer and neurological disorders more than the younger population. Moreover, the geriatric population is increasing at a rapid pace as compared to that of the younger population. Increase in the geriatric population aged above 65 years is projected to drive the incidences of Alzheimers, dementia, cancer, and immune diseases, which, in turn, is anticipated to boost the need for corrective treatment of these disorders. This is estimated to further drive the demand for clinical trials and research that require cell separation products. These factors are likely to boost the global cell separation technology market.

According to the United Nations, the geriatric population aged above 60 is expected to double 2050 and triple 2100, an increase from962 millionin 2017 to2.1 billionin 2050 and3.1 billion2100.

Productive Partnerships in Microfluidics Likely to Boost the Cell Separation Technology Market

Technological advancements are prompting companies to innovate in microfluidics cell separation technology. Strategic partnerships and collaborations is an ongoing trend, which is boosting the innovation and development of microfluidics-based products. Governments and stakeholders look upon the potential in single cell separation technology and its analysis, which drives them to invest in the development ofmicrofluidics. Companies are striving to build a platform utilizing their expertise and experience to further offer enhanced solutions to end users.

Stem Cell Research to Account for a Prominent Share

Stem cell is a prominent cell therapy utilized in the development of regenerative medicine, which is employed in the replacement of tissues or organs, rather than treating them. Thus, stem cell accounted for a prominent share of the global market. The geriatric population is likely to increase at a rapid pace as compared to the adult population, 2030, which is likely to attract the use of stem cell therapy for treatment. Stem cells require considerably higher number of clinical trials, which is likely to drive the demand for cell separation technology, globally. Rising stem cell research is likely to attract government and private funding, which, in turn, is estimated to offer significant opportunity for stem cell therapies.

Biotechnology & Pharmaceuticals Companies to Dominate the Market

The number of biotechnology companies operating across the globe is rising, especially in developing countries. Pharmaceutical companies are likely to use cells separation techniques to develop drugs and continue contributing through innovation. Growing research in stem cell has prompted companies to own large separate units to boost the same. Thus, advancements in developing drugs and treatments, such as CAR-T through cell separation technologies, are likely to drive the segment.

As per research, 449 public biotech companies operate in the U.S., which is expected to boost the biotechnology & pharmaceutical companies segment. In developing countries such as China, China Food and Drug Administration(CFDA) reforms pave the way for innovation to further boost biotechnology & pharmaceutical companies in the country.

Global Cell Separation Technology Market: Prominent Regions

North America to Dominate Global Market, While Asia Pacific to Offer Significant Opportunity

In terms of region, the global cell separation technology market has been segmented into five major regions: North America, Europe, Asia Pacific, Latin America, and the Middle East & Africa. North America dominated the global market in 2018, followed Europe. North America accounted for a major share of the global cell separation technology market in 2018, owing to the development of cell separation advanced technologies, well-defined regulatory framework, and initiatives governments in the region to further encourage the research industry. The U.S. is a major investor in stem cell research, which accelerates the development of regenerative medicines for the treatment of various long-term illnesses.

The cell separation technology market in Asia Pacific is projected to expand at a high CAGR from 2019 to 2027. This can be attributed to an increase in healthcare expenditure and large patient population, especially in countries such as India and China. Rising medical tourism in the region and technological advancements are likely to drive the cell separation technology market in the region.

Launching Innovative Products, and Acquisitions & Collaborations Key Players Driving Global Cell Separation Technology Market

The global cell separation technology market is highly competitive in terms of number of players. Key players operating in the global cell separation technology market include Akadeum Life Sciences, STEMCELL Technologies, Inc., BD, Bio-Rad Laboratories, Inc., Miltenyi Biotech, 10X Genomics, Thermo Fisher Scientific, Inc., Zeiss, GE Healthcare Life Sciences, PerkinElmer, Inc., and QIAGEN.

These players have adopted various strategies such as expanding their product portfolios launching new cell separation kits and devices, and participation in acquisitions, establishing strong distribution networks. Companies are expanding their geographic presence in order sustain in the global cell separation technology market. For instance, in May 2019, Akadeum Life Sciences launched seven new microbubble-based products at a conference. In July 2017, BD received the U.S. FDAs clearance for its BD FACS Lyric flow cytometer system, which is used in the diagnosis of immunological disorders.

More:
Cell Separation Technology Market Overview, Growth Forecast, Demand and Development Research Report to 2027 - VaporBlash

Recommendation and review posted by Bethany Smith

Dmitry Kaminskiy speaks as though he were trying to unload everything he knows about the science and economics of longevityfrom senolytics research that seeks to stop aging cells from spewing inflammatory proteins and other molecules to the trillion-dollar life extension industry that he and his colleagues are trying to fosterin one sitting.

At the heart of the discussion with Singularity Hub is the idea that artificial intelligence will be the engine that drives breakthroughs in how we approach healthcare and healthy aginga concept with little traction even just five years ago.

At that time, it was considered too futuristic that artificial intelligence and data science might be more accurate compared to any hypothesis of human doctors, said Kaminskiy, co-founder and managing partner at Deep Knowledge Ventures, an investment firm that is betting big on AI and longevity.

How times have changed. Artificial intelligence in healthcare is attracting more investments and deals than just about any sector of the economy, according to data research firm CB Insights. In the most recent third quarter, AI healthcare startups raised nearly $1.6 billion, buoyed by a $550 million mega-round from London-based Babylon Health, which uses AI to collect data from patients, analyze the information, find comparable matches, then make recommendations.

Even without the big bump from Babylon Health, AI healthcare startups raised more than $1 billion last quarter, including two companies focused on longevity therapeutics: Juvenescence and Insilico Medicine.

The latter has risen to prominence for its novel use of reinforcement learning and general adversarial networks (GANs) to accelerate the drug discovery process. Insilico Medicine recently published a seminal paper that demonstrated how such an AI system could generate a drug candidate in just 46 days. Co-founder and CEO Alex Zhavoronkov said he believes there is no greater goal in healthcare todayor, really, any venturethan extending the healthy years of the human lifespan.

I dont think that there is anything more important than that, he told Singularity Hub, explaining that an unhealthy society is detrimental to a healthy economy. I think that its very, very important to extend healthy, productive lifespan just to fix the economy.

The surge of interest in longevity is coming at a time when life expectancy in the US is actually dropping, despite the fact that we spend more money on healthcare than any other nation.

A new paper in the Journal of the American Medical Association found that after six decades of gains, life expectancy for Americans has decreased since 2014, particularly among young and middle-aged adults. While some of the causes are societal, such as drug overdoses and suicide, others are health-related.

While average life expectancy in the US is 78, Kaminskiy noted that healthy life expectancy is about ten years less.

To Zhavoronkovs point about the economy (a topic of great interest to Kaminskiy as well), the US spent $1.1 trillion on chronic diseases in 2016, according to a report from the Milken Institute, with diabetes, cardiovascular conditions, and Alzheimers among the most costly expenses to the healthcare system. When the indirect costs of lost economic productivity are included, the total price tag of chronic diseases in the US is $3.7 trillion, nearly 20 percent of GDP.

So this is the major negative feedback on the national economy and creating a lot of negative social [and] financial issues, Kaminskiy said.

That has convinced Kaminskiy that an economy focused on extending healthy human lifespansincluding the financial instruments and institutions required to support a long-lived populationis the best way forward.

He has co-authored a book on the topic with Margaretta Colangelo, another managing partner at Deep Knowledge Ventures, which has launched a specialized investment fund, Longevity.Capital, focused on the longevity industry. Kaminskiy estimates that there are now about 20 such investment funds dedicated to funding life extension companies.

In November at the inaugural AI for Longevity Summit in London, he and his collaborators also introduced the Longevity AI Consortium, an academic-industry initiative at Kings College London. Eventually, the research center will include an AI Longevity Accelerator program to serve as a bridge between startups and UK investors.

Deep Knowledge Ventures has committed about 7 million ($9 million) over the next three years to the accelerator program, as well as establishing similar consortiums in other regions of the world, according to Franco Cortese, a partner at Longevity.Capital and director of the Aging Analytics Agency, which has produced a series of reports on longevity.

One of the most recent is an overview of Biomarkers for Longevity. A biomarker, in the case of longevity, is a measurable component of health that can indicate a disease state or a more general decline in health associated with aging. Examples range from something as simple as BMI as an indicator of obesity, which is associated with a number of chronic diseases, to sophisticated measurements of telomeres, the protective ends of chromosomes that shorten as we age.

While some researchers are working on moonshot therapies to reverse or slow agingwith a few even arguing we could expand human life on the order of centuriesKaminskiy said he believes understanding biomarkers of aging could make more radical interventions unnecessary.

In this vision of healthcare, people would be able to monitor their health 24-7, with sensors attuned to various biomarkers that could indicate the onset of everything from the flu to diabetes. AI would be instrumental in not just ingesting the billions of data points required to develop such a system, but also what therapies, treatments, or micro-doses of a drug or supplement would be required to maintain homeostasis.

Consider it like Tesla with many, many detectors, analyzing the behavior of the car in real time, and a cloud computing system monitoring those signals in real time with high frequency, Kaminskiy explained. So the same shall be applied for humans.

And only sophisticated algorithms, Kaminskiy argued, can make longevity healthcare work on a mass scale but at the individual level. Precision medicine becomes preventive medicine. Healthcare truly becomes a system to support health rather than a way to fight disease.

Image Credit: Photo byh heyerleinonUnsplash

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Why AI Will Be the Best Tool for Extending Our Longevity - Singularity Hub

Recommendation and review posted by Bethany Smith

Global Soy Isoflavones Market report is the new addition announced by CMFE Insights, which offers qualitative insights into factors that impact the growth of the global market. It offers a wide-ranging study of the competitive landscape of the market and also considers the share of the market key players in each region as well as the overall market by estimating their revenue and sales.

The demand for the global Soy Isoflavones market is rising significantly as it proves to give a better quality of experience and due to this, the market is displaying high growth in its size. The upsurge in its technological progression is anticipated to propel substantially in the coming years.

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Chapter 3:Soy Isoflavones Market Competition by Manufacturers

Chapter 4: Global Production, Revenue (Value) by Region

Chapter 5: Global Supply (Production), Consumption, Export, Import by Regions

Chapter 6: Global Production, Revenue (Value), Price Trend by Type

Chapter 7: Global Market Analysis by Application

Chapter 8: Manufacturing Cost Analysis

Chapter 9: Industrial Chain, Sourcing Strategy and Downstream Buyers

Chapter 10: Marketing Strategy Analysis, Distributors/Traders

Chapter 11: Soy Isoflavones Market Effect Factors Analysis

Chapter 12: GlobalSoy Isoflavones Market Forecast

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Best Informative Report on Soy Isoflavones Market 2019 to 2025 | Leading Companies- NOW Foods, InVite Health, ADM, DHC, GNC and Life Extension -...

Recommendation and review posted by Bethany Smith

Heathrow Airport is a massive employer in London.

Not only do you have four terminals each requiring their own teams of security, cleaning and ground crew staff, but you've also got the many shops, bars and restaurants.

It's always busy at the West London airport, meaning it's all hands on deck.

Have you ever fancied a behind the scenes look at Heathrow? Well, now might be your chance.

Heathrow Airport is currently hiring a total of 21 positiions.

Here is everything you need to know.

Closing date: December 19, 2019

The role involves being responsible for implementing a quality assurance function at the airport.

Basically - you need to make sure everything runs smoothly and well. From reviewing activities in the supply chain and dealing with members of the public, you will be first on hand.

For more information, click here.

Closing date: January 5, 2020

The control room operative works in the engineering maintenance department.

You will be monitoring the system and ensuring trains and planes are running smoothly and making sure any delays are dealt with appropriately.

It's also important to work safely at all times and follow procedures as well as spot any hazards.

Click here for more information.

Closing date: December 19, 2019

In this role, you will act as Data Steward for the Property Team under the General Data Protection Regulations and ensure the airport complies with all Heathrow standards associated with GDPR and Data Protection.

To apply, click here.

Closing date: December 13, 2019

You'll be participating in all movements of trolleys across Heathrow, clearing all areas of trolleys, pushing them back into the areas where our passengers need them and making sure passengers do not use any broken trolleys.

What's more, the job would pay you more than 21,000 a year.

Click here for more information.

Closing date: December 24, 2019

One responsibility for this role is acting as the airport contact with the statutory authorities, Highways Agency and Local borough councils for engineering works associated with airport-based utilities.

Click here to apply.

Closing date: December 24, 2019

You will be managing the development and upkeep of asset plans and asset standards that reflect asset systems strategies.

To apply, click here.

Closing date: December 24, 2019

For this role, you will be providing technical knowledge and support to operational teams within the function and wider organisation to ensure a robust asset management strategy.

For more information, click here.

Closing date: December 18, 2019

This role is all about developing asset plans and asset standards that reflect the asset system strategies, with detailed maintenance strategies, renewal plans, refurbishment and life extension plans.

You can apply here.

Closing date: December 13, 2019

This is the role for you if you are able to drive revenue and merchandise and trading for our key service products including Car parking, VIP lounges, Meet and Assist, Fast track and porters.

Click here for more information.

Closing date: December 24, 2019

You'll be responsible for content managing product information for non-automated retailers as well as managing key retail partner online relationships in conjunction with existing offline account management team.

You can apply for the role here.

Closing date: January 5, 2020

You'll undertake planned and reactive maintenance tasks on assets in accordance with allocated target dates to maximise availability and service levels.

As well as this, you'll complete working orders and accurately capturing maintenance history.

For more information, click here.

Closing date: January 5, 2020

As a rail systems engineer you'll be designing and delivering solutions to system and component obsolescence for HAL Rail assets and designing and delivering system upgrades to improve system safety and reliability.

Click here for more information.

Closing date: January 5, 2020

Developing performance improvement plans for rail assets, to deliver continuous improvements and meet stakeholders requirements is what you'll be doing in this role.

More information can be found here.

Closing date: December 19, 2019

For this role, you'll be part of the Heathrow expansion team ensuring the successful delivery and implementation of the services.

Click here to apply.

Closing date: December 20, 2019

In this role, you'll be making sure everyone sticks to the health and safety procedures, as well as updating them.

You can apply for the role here.

Closing date: December 13, 2019

You'll be leading and driving a data driven strategy on omnichannel personalisation across the customer journey and driving optimisation ROI within digital estates across Heathrow.

Click here for more information.

Closing date: January 5, 2020

The job involves ensuring systems, assets and components perform at optimum levels against design standards, making sure any changes are effectively communicated.

Apply here.

Closing date: January 21, 2020

You will provide support to the IT Supplier Relationship Manager in managing the relationship and governance across all IT suppliers.

Click here for more information.

Closing date: January 21, 2020

Your role will be to champion GDPR compliance within IT on behalf of CIO, providing assurance to ITLT, Deputy General Counsel and Data Protection Officer.

If you'd like to apply for this role, click here.

Closing date: December 24, 2019

You'll be providing technical steering to asset systems strategies including the asset management plan.

Another responsibility is developing asset intervention plans including method statements to support the achievement of the long-term business plans.

Click here to apply.

To keep up to date with all the latest breaking news, stories and events happening across West London, give the My West London Facebook page a like.

We will provide you with the latest traffic and travel updates, including updates on train and London Underground services, in areas including Brent, Ealing, Hammersmith, Fulham, Harrow, Hillingdon, Hounslow, Uxbridge and Richmond upon Thames.

The latest breaking news will be brought straight to your news feed including updates from the police, ambulance and fire brigade. We will also bring you updates from our courts and councils, as well as more lighthearted long reads.

We also publish your pictures and videos, so do message us with your stories.

Like the My West London Facebook page here.

You can also follow us on Twitter here.

Closing date: December 11, 2019

Your role will be to provide leadership and line management to a team of technicians, ensuring they are offering great quality and reliable service for Heathrow whilst also adhering to company policies.

Click here for more information.

Originally posted here:
21 Heathrow Airport jobs that are currently on offer - MyLondon

Recommendation and review posted by Bethany Smith

Investors gravitate towards Canadian banks, and with good reason. As few of the most stable banks in the world and generous dividend providers, they make for excellent long-term stocks stocks you can bank on. And, of course, the first stock that draws the eyes of the investors is the king itself: Royal Bank of Canada a bank that possesses every significant attribute that makes the countrys banking sector stand out.

But if you want to explore more investment options, there are other stable and attractive ones in the market Dividend Aristocrats with juicier yields than Royal Banks 3.86%. TC Energy, Emera (TSX:EMA), and Exchange Incomeare three stocks to consider for higher yields.

TC Energy owns and operates one of the largest natural gas pipeline networks in North America, spanning 92,600 kilometres. The company has a 4,900-kilometre liquid pipelines and electricity production capacity of 6,000 MW. TC Energy has steady cash flows, and its banking on its ongoing projects for better future profitability projects like Keystone XL, NGTL, and Bruce Power Life extension.

The company is stable, relative to the market, with a beta of 1.04. TC Energys operating margin of 45% is better compared to the overall sector. This year has been especially fruitful for the companys growth, with the market value up by 38%. Currently, the company is trading at $67.2 per share. The yield of 4.43% is also an attractive attribute to consider TC Energy as a potential investment.

Emera is an energy company with a focus on clean electricity production. It focuses on zero-emission renewables like wind, hydro, and solar, as well as low-emission sources like natural gas. With its eye on a cleaner and sustainable future, the companys growth potential seems high. Emera operates in Canada, the U.S., and four Caribbean countries.

The company has well earned its title of a Dividend Aristocrat by increasing dividends for 12 consecutive years. The current yield of 4.45% is also a significant scale up from Royal Bank. But the dividend yield isnt the only factor that makes Emera an attractive investment. Its impressive history of growth is also worth considering. In the past five years, the company has grown its market value by 40%, including this years sizeable increase of 22%.

But even at a conservative estimate, the company stands at a chance 8% growth a year, all the while handing out increasingly generous payouts.

If you are thinking about diversifying your portfolio, the adequately diversified company, Exchange Income, might prove to be a fantastic stock. Exchange income focuses on acquiring aerospace and aviation-based businesses, and it has created a well-balanced portfolio of many such companies. This acquisition policy has played out very well for the company and investors.

The companys five-year growth is a whopping 92%. Even if the company underperforms a bit, it stands at a chance of doubling its investors money in the next seven years. And the cherry on top is the yield of 5.15%, with a prestigious payout history of increasing dividends for nine consecutive years.

Stability, growth, and dividends payouts three common attributes that almost every long investor should consider before choosing stocks. The stocks mentioned above provide the right mix of all three traits, maybe even an edge better than the Royal Bank.

Fool contributor Adam Othman has no position in any of the stocks mentioned.

View post:
3 Stocks That Will Pay You More Dividends Than RBC (TSX:RY) - The Motley Fool Canada

Recommendation and review posted by Bethany Smith

The value of a bull is a variable equation to variable producers. But much like a piece of machinery or a tract of land, it is relatable to return on investment. A basic requirement of the cow-calf business is to make sure each female has a healthy calf that weighs to its full potential every calendar year.

But before that can happen, a calculated investment in a well-managed virile bull and the infrastructure and management to maintain him properly and safely through the offseason is necessary. This is nothing new or earth shattering, but if the bull is defective, becomes damaged goods or is otherwise mishandled, there can be large financial consequences.

Related: We must account hidden losses from subfertile bulls

Winter can be a stressful time for cattle. In colder areas of the country, it is essential to provide protection from extreme and volatile weather as the opportunity for frost-bitten testicles is always high. Brett Andrews of Burwell Nebraska Veterinary Hospital encourages producers to keep bulls where shelter, trees or man-made windbreaks are available to block the north winds that can cause frost or freeze damaged scrotums.

Provide bedding during the severest cold or blizzard conditions so the scrotums wont be on the bare, cold ground. The producers who do this have very few permanent testicular injuries due to extreme cold. However, I have seen bulls that were left out with no or minimal shelter and they suffered permanent testicular injury.

Related: So many bulls, so little time

Hypothetically, consider that a single herd bull sires 120 calves in his working life over the course of four years, improving the weight yield of calves sold at weaning by a 15-pound average at $1.50 per pound. This scenario will increase the bottom line by $2,700 over the bulls productive lifetime. On top of this is the value of any females kept as replacements during the four years.

If a third of the approximately 60 heifers are kept from a 100-head female herd, the derivative economic effect of the bull buying ability is 20% of the annual profit and loss statement. Not to be forgotten, of course, an average salvage value for a mature bull should yield in the $2,000 range.

On the negative side, if the bull is the cause of one cow going un-bred through her first cycle and becoming pregnant during her next estrus cycle, on an average year, it can cost the producer close to $100 on lost weaning weight of that calf alone. Factored over numerous cows, the losses become exponentially large. When running the numbers, it is undeniable that the management of this bull is a vital component of the operations overall health.

With bulls that are held over, it is extremely important to complete the normal procedures of the breeding soundness exam (BSE), vaccination, feet trimming and a trichomoniasis test. Pencil out the bull power needed per cow and beyond that, the focus should be on body conditioning.

Tom Troxel Ph.D., at the University of Arkansas, states it is important to divide bulls into management groups in order to more effectively meet dietary needs. Separating younger and older bulls may be particularly important in preventing injuries and meeting nutritional requirements.

Younger bulls are growing rapidly and will need a different diet to compensate their growth rate and to replace the condition they lost during a previous breeding season. He suggests that herd bulls be kept in a separate location away from cows, heifers and younger bulls, with plenty of exercise room, clean water and mineral supplements.

A body conditioning score of 5 or slightly higher is optimal before bulls are turned out, as during the breeding season, bulls can lose up to 3 pounds per day. Thus it is essential for all ages to enter this period in peak physical condition.

As winter retreats and spring approaches, the smell of females in the air can once again destroy the tentative peace and confrontations may begin. The readiness to rearrange existing bulls by ages, size or personalities, along with the facilities to accommodate this, are vital.

Bulls that will later be combined in multi-sire breeding pastures should be penned together for several weeks before the season begins to allow the inevitable re-establishment of the social pecking order. This will create a large enough cushion of time should injuries occur and a replacement bull be required. Bulls WILL establish and re-establish social order, but a producer can manipulate the process to avoid a damaged goods situation.

Unfortunately, no system is perfect, so it is important to have a Plan B, but it should never be the unknown hold-over bull dumped at the local auction barn. The negatives of this mystery bull could be very costly.

If possible, having an extra suitable bull is wise, or pencil in a potential quality replacement that might be available at short notice. These days there is no reason to purchase inferior and unknown bulls.

For all involved, it is the goal to have fit and healthy bulls ensuring pregnant females as early in the breeding season as possible, plus have these bulls in optimal condition throughout the off season, ensuring their readiness when called upon in the upcoming year.

Derksen is a freelance writer and feedyard pen rider in Lacombe, Alberta, Canada.

Originally posted here:
Maintaining the value of bulls through the off-season - Beef Magazine

Recommendation and review posted by Bethany Smith

A Campus meeting in November reviewed the arguments for and against donor conception, and the sometimes difficult ethical arguments raised by the prospect of a donor-conceived child. About the latter, opinion now seems universally in favour of early disclosure of biological origins.

Defining 'success' as a single healthy birth delivered at term, ESHRE's senior research specialist Nathalie Vermeulen presented indisputable evidence (from SART and ESHRE registries) that success rates decline terminally with age; by contrast, LBR with donor eggs at 35 years and over is almost 30%, and continues at this steady rate to age 40 and beyond, while the rate with non-donor eggs declines to below 5%. Although this considerably improved outcome in women over 35 should be balanced by an added risk of maternal hypertension during pregnancy, such risk rates do little to explain the continuing attraction of autologous cycles.

Is it simply that patients are not adequately informed? Consultant Meena Choudhary from Newcastle, UK, was quite categorical about what patients should be told: that the risk of birth defects increases with rising female age; IVF treatment cannot reverse the effect of ageing; the chance of having a healthy baby becomes much lower as mothers age; and PGTA will not increase the chance of live birth. Moreover, de novo mutations are more common with paternal than maternal ageing (although paternal age on its own does not affect the chance of success), and, as with PGT-A, there is no robust evidence to suggest that DNA fragmentation testing will improve results. And echoing Nathalie Vermeulen, Choudhary reaffirmed that egg donation 'surpasses' the effect of female age in live birth rate (while sperm donors up to age 45 have not been shown to reduce that chance in older women).

This Campus meeting was jointly organised by the SIGs Andrology and Psychology & Counselling and it was clear from many presentations that psychological factors - what Mariana Martins of the latter SIG described as 'concerns' - explain the value of genetic parenthood for many couples, especially those faced with the option of third-party donation. However, said Martins, many of the concerns associated with third-party donation, or more accurately the wish for a fully genetically related child, are the result of misconceptions about the importance of genetics. For example, disposition to a range of psychological traits cited by Martins - from depression to hyperactivity - can be clearly attributed to experience and the environment. There is also strong evidence that, while heritability of personality traits decreases over the life-span, environmental influence increases. Martins also suggested, particularly with reference to poor prognosis patients, that, in assuming option one is always IVF with your own genes and gametes, years may actually pass by before option two (donor gametes) is even considered. 'We may unintentionally be delaying a live birth, or even promoting dropout,' said Martins, 'so leaving patients with an unfulfilled child wish.'

However, Kirkman-Brown named disclosure to the future child about their origin of conception as 'probably the most studied and controversial subject' governing decisions about donor treatment. Despite the 'harms' associated with secrecy and non-disclosure, fewer than half the parents of 10-year and older children reported disclosure to them in one 2016 study. Petra Thorn, a former co-ordinator of the SIG Psychology & Counselling, listed several commonly cited reservations about third-party donation, including 'abnormal' family composition, the possibility of stigmatisation, the contrast between 'social' and biological parenthood, and of course disclosure and access to information. These, said Thorn, were important concerns for many couples, which makes counselling at the earliest stage - and certainly before any treatment begins - imperative. 'We must ensure that both partners fully support the type of treatment,' she insisted, 'and avoid any risk of ambivalences during pregnancy.' This might be achieved through exploring the new family boundaries implied by donation, disclosure, the role of the donor, and legal implications. Moreover, said Thorn, all the evidence suggests that, if children are informed of their conception early with the opportunity to access their biological origins, if parents feel comfortable with the idea of third-party conception and if donors are well informed and prepared for offspring to contact them, the children, parents and donors will do well.

Direct-to-consumer DNA testingNear the surface of this presentation was a view shared by all speakers at this meeting, that donor children should be informed of their origins at an early stage. 'No-one should go into treatment with a view that they will not tell their children,' said Marilyn Crawshaw from the University of York, UK, after describing the implications of direct-to-consumer DNA testing. As Focus on Reproduction has already reported, the huge DNA databanks now assembled by genealogy discovery companies have already rendered donor anonymity an unsustainably impossible concept. Our reporta few months ago noted DNA samples in storage of around 30 million people, with traceability going back three or four generations. However, this burgeoning increase, said Crawshaw, is likely to reach 100 million samples by 2021, with countless internet-based forums and support groups for donor-conceived individuals, their donors and their parents. 'Everything will change,' said Crawshaw. Or has changed already? Indeed, 37% of donor-conceived children in one recent study said they found out about their origins from results of a commercial DNA test (against 51% from their parents when a child or adult).

The shift in attitude towards donor anonymity - and reflected in more relaxed attitudes to fertility treatment in single and lesbian women with donor sperm - was already evident in so many jurisdictions switching their policies from anonymity to formal information release mechanisms. Even France, which has long protected the anonymity of sperm donors in its CECOS system, will with new legislation switch to an identity release system.

Of course, for those discovering unexpected information about their biological origins, the consequences can be devastating. Citing one parent quoted in BioNews, Crawshaw reported: 'More support is needed, urgently, as the tidal wave of unanticipated disclosure is only beginning. The future for social justice in donor conception leads towards openness and support, not bans and anonymity. And where will that 'support' come from? From the fertility clinics, the ancestry industry, the state?

The vulnerability of donor-conceived people to such surprises has prompted calls for greater openness and inclusivity, argued Eric Blyth, a veteran researcher in gamete donation and families. He too saw a shift in the narrative - from an exclusively medical perspective (treatment for infertility/childlessness) to a broader familybuilding paradigm, reflected in more widespread disclosure legislation, greater use of sperm donation treating singles and lesbians, in increasing number of jurisdictions, and in direct-to-consumer genetic testing. And he too looked to the 'family-building' approach to donor conception as the way forward in accommodating a child's genetic heritage and integrating donor relationships within existing family ties.

1. Much of the content of this Campus meeting has now been summarised. See when published: Kirkman-Brown J, Martins MV. 'Genes versus children': If the goal is parenthood, are we using the optimal approach? Hum Reprod 2019; doi:10.1093/humrep/dez256.

See more here:
CAMPUS: EGG DONATION - Biological or donor parenthood in the treatment of infertility - ESHRE

Recommendation and review posted by Bethany Smith

Commercial surrogacy, the practice of paying a woman to carry and birth a child whom she will not parent, is largely unregulated in America. Its illegal, with rare exceptions, in three states: New York, Louisiana, and Michigan. But, most states have no surrogacy laws at all. Though the technology was invented in 1986, the concept still seems, for many, a bit sci-fi, and support for it does not follow obvious political fault lines. It is typically championed by the gay-rights community, who see it as the only reproductive technology that allows gay men to have biological children, and condemned by some feminists, who see it as yet another business that exploits the female body. In June, when the New York State Assembly considered a bill that would legalize paid surrogacy, Gloria Steinem vigorously opposed it. Under this bill, women in economic need become commercialized vessels for rent, and the fetuses they carry become the property of others, Steinem wrote in a statement.

In a new book, Full Surrogacy Now: Feminism Against the Family, the author Sophie Lewis makes a forceful argument for legalization. Lewis takes little interest in the parents. Its the surrogates who concern her. Regulation, she says, is the only way for them to avoid exploitation. Lewis frequently, if reluctantly, compares surrogacy to sex work, another industry that persists despite being illegal. Banning these jobs is pointless, Lewis says, aside from giving privileged feminists something to do, and making the work more dangerous. Surrogacy bans uproot, isolate, and criminalize gestational workers, driving them underground and often into foreign lands, where they risk prosecution, she writes. As with sex work, the question of being for or against surrogacy is largely irrelevant. The question is, why is it assumed that one should be more against surrogacy than other risky jobs.

Lewis does not offer straightforward policy suggestions. Her approach to the material is theoretical, devious, a mix of manifesto and memoir. Early in the book, she struggles to understand why anyone would want to get pregnant in the first place, and later she questions whether continuing the human race is a good idea. But she is solemn and unsparing in her assessment of the status quo. A portion of the book studies the Akanksha Fertility Clinic, in India, a surrogacy center that, according to Lewis, severely underpays and mistreats its workers. (Nayana Patel, who runs the clinic, has argued that Akanksha pays surrogates more than they would make at other jobs.) All of the Akanksha surrogates are required to have children of their own already, ostensibly because they know how difficult it is to raise a child and are therefore less likely to want to keep the ones theyre carrying.

According to Lewis, Akanksha surrogates have to live at the clinic and leave their children in the care of family. Its unclear how much money the surrogates take home afterwardespecially once the scouts take their cut. What especially frustrates Lewis is that, despite the obvious sacrifices of pregnancy and of being away from family, the Akanksha clinicians and clients are still skittish about referring to surrogacy as work. Akanksha offers surrogates classes in embroidery and candle-making, and its promotional literature assures prospective parents that surrogacy is more than a jobits a ladder to a new life. According to Lewis, the surrogates usually deliver via C-section when they are thirty-six weeks pregnant, shaving five weeks or so off production time, delivering the baby just-in-time for collection. These clinics are factories, Lewis writeswhy pretend otherwise?

Lewiss occasionally blithe humor belies a surprisingly earnest argument. She wants to legitimate surrogacy in order to legitimate a more communal way of raising children. One could say that shes ready to cancel the family unit. Unabashedly interested in family abolition, I want us to look to waged gestational assistance specifically insofar as it illuminates the possibilities of its imminent destruction by something completely different, she writes. Gestational surrogacy makes it more difficult to name the biological mother with complete certainty, and this sort of murkiness strikes Lewis as the best possible world in which to raise children. The polymaternal ideal, Lewis argues, already exists for rich children, whose parents are able to purchase full surrogacy by hiring wet nurses, nannies, ayahs, and mammies. Lewis thinks that such a childhood should be available to all.

Lewis fantasizes about replacing the modern family with a classless commune, where children dont belong to anyonea commune that would eventually render commercial surrogacy obsolete. Another surrogacy is possible, she writes. India recently banned commercial surrogacy; now all surrogacy in the country must be unpaid, or altruistic. Volunteer surrogacy may sound like a perfect way to encourage communal child-rearing, but Lewis says that, in practice, altruistic surrogacy usually has the same dynamic as commercial surrogacy, insofar as a woman still gets pregnant with a wealthier womans baby. (She writes that unpaid surrogacy should concern those who understand how Indian class society works.) And, for Lewis, even in the most open-minded arrangement, where the surrogate remains in the childs life, the basic family structure remains the same. The surrogate is an appendage of the nuclear family, relegated to the fringe.

Lewis wants something else, something far more sweeping. Lets prefigure a way of manufacturing one another noncompetitively. Lets hold one another hospitably, explode notion of hereditary parentage, and multiply real, loving solidarities. Let us build a care commune based on comradeship, a world sustained by kith and kind more than by kin, she writes. In other words, if it takes a village to raise a child, then why dont we will such a village into existence? Why are we so committed to the traditional biological family when so many children feel stymied and exhausted by their parents, and so many parents feel stymied and exhausted by their children? Lewis blames capitalism, a system in which, she argues, everyone needs a home teampeople to root for, and to fall back on when things go south. She implores her reader not just to redraw the teams but to reinvent the game entirely: We are the makers of one another. And we could learn collectively to act like it. It is those truths that I wish to call real surrogacy, full surrogacy. Nowhere in her book does she mention maternity leave or affordable child care. These are merely concessions to a systema system that she hopes to uproot.

Lewis rigorously argues for the world she wants to create, but her book is too polemical to rigorously imagine it. That task is handled, in part, by Joanne Ramoss dbut novel, The Farm. The Farm is a largely naturalistic book set in a modern-day New York, where the immigrants live in Flushing and the rich live on Park Avenue. But theres one speculative twist: surrogacy is legal, and the Hosts, as Ramos calls them, have no regulatory protections. The books premise appears to be loosely based on Gloria Steinems nightmares.

Most of the story takes place at Golden Oaks, an upscale surrogacy clinic in upstate New York where the Hosts, most of them black or Filipina, live in seclusion while they attend to the fetuses growing inside them. Gestation is considered a full-time job; the days at Golden Oaks have the same intense orderliness of a factory floor. Many of the women are former domestic workers or nannies or health aides, and have found that caring for a fetus is more lucrative than caring for a person. They have little, if any, interaction with the clients. A client may be a war lord or a Nobel Prize winner; she may be perfectly capable of getting pregnant but would rather have someone else do it. The Hosts are not allowed to care. They must deliver a healthy baby if they want to receive their bonusthe big money, as the women call it.

Like the surrogates at Akanksha, most Hosts at Golden Oaks have only signed on because they need that money to support families of their own, whom they are not allowed to see for the duration of their contract. The Farm is an ensemble book, told from the perspective of four different characters, but its hero is Jane, a Filipina-American woman in her early twenties, who turns to Golden Oaks after shes fired from her baby-nurse job and can find no better way to support her infant daughter.

For a novel about the ruthlessness of capitalism, Ramos demonstrates remarkable tenderness for her characters. In another writers hands, Mae, the director of Golden Oaks, would be wholly diabolical, but in Ramoss depiction she is only moderately soa perky middle manager obsessed with earning the trust of her bosses and the respect of the rich white kids she met at Harvard Business School, where she was among the minority of students who paid their own tuition. Mae is biracial (her father is Chinese), and she sees the Hosts as co-travellers on her journey of upward mobility. When she describes a job at Golden Oaks as a gateway to a better life, she appears to mostly believe what shes saying. She sees surrogacy as work, but, unlike Lewis, who believes that work is inherently oppressive, Mae thinks that work can set you free. Its isnt like we force our Hosts to be Hosts, she tells a prospective surrogate in an early scene. They choose to work for us freelyId argue: happily.

The prospect, Reagan, is something of a special case. In Golden Oaks parlance, Reagan is a Premium Hostcollege-educated and white. But it doesnt take much to get her onboard. She could use the moneyher father is too conventional to pay for an M.F.A. in photographyand shes a restless spirit, desperate for moral clarity and the knowledge that she is doing something inarguably worthwhile. Shes drawn to the purity of being a Host. Life, the very act of it, is blindingly, stupendously courageous, Reagan thinks. Lewis, of course, would disagree with the idea that creating new life is inherently valuable. The fact that gestation makes an economic contribution or makes the world go round is nothing much to be proud of, given the state of the world, she writes. Im more impressed by contributions gestating might make to this worlds destruction.

Reagan is the only character in the book who insists on the sanctity of her job. We never meet her clientor, indeed, any of the clients. We get only their rsums: fashion tycoon, tech giant, the richest woman in China. They could be decent people, and even remarkable parents. Ramoss richly ambivalent novel leaves the possibility open, even as she details how the Hosts at Golden Oaks are denied basic rights. At one point, a Catholic surrogate is forced to have an abortion after a doctor discovers that the fetus has a possible birth defect. (The reader does not witness the procedure; Ramos is almost too devoted to her characters to linger on their pain, and the novel skips over any childbirth scenes.) Whats apparent at the novels end is that, while a life-altering thinga baby!has entered the clients lives, their surrogates, even after earning the big money, are in similar circumstances to those they were in at the storys beginning. The Farm does not take a clear stance on the ethics of surrogacy itself, but, like Lewiss book, it makes a mockery of Maes claim that such a job is a gateway to a better life. For the Hosts at Golden Oaks, surrogacy is merely a new way to tread water.

In her 2002 memoir, Love Works Like This, the writer and psychologist Lauren Slater discovers that she is pregnant and decides to list the pros and cons of parenthood. Under cons, she writes: Less time for friends, less time for work, less money, famous women writers who had children? The list goes on. Under pros, she has just one item: Learning a new kind of love. She ends up keeping the baby.

The pull of this mysterious variety of love is not something Lewis contends with in her book. For the sake of her argument, she focusses on the system, rather than the people who compose it. Parental love is many things: devotional, magnificent, demented, myopic. Its a love that motivates terrific sacrifice and heroism, as well as terrible acts of greed. It drives otherwise prudent people to discard caution, whether by emigrating to another country or by bribing a childs way into college.

While Lewis would like to replace this inherited love with a more logical kind of affection, one based on earned affinity or kith and kind, Ramoss novel explores the warped devotion of parents. One character in The Farm, Ate, tirelessly works as a cook, a maid, and a baby nurse to support her disabled adult son in the Philippines, whom she hasnt seen for more than twenty years. Everything Ate did was for him, Jane observes. Jane is quarantined at Golden Oaks when her one-year-old, Mali, takes her first steps and speaks her first words. She, too, would do anything for Mali. And the clients, of course, are willing to do anything for their unborn childrenthats why theyve come to Golden Oaks in the first place.

But the question, for both Ramos and Lewis, isnt about what wed do for our children. Its about what wed do for other peoples children. At one point in Full Surrogacy Now, Lewis recalls a memory from her own childhood. One afternoon, driving in the car with her father, she insouciantly asked how he would feel if it turned out that she wasnt histhat they werent biologically related after all. There was a stony, awkward silence that made clear to me I was not going to get the answer I needed, Lewis writes. I felt so devastated that, for the rest of the drive, I could not speak. Her fathers love, she realized, was contingent on their shared genetics. This was a profound betrayal. Her book, like Ramoss, tries to depict a new conception of lovea love freed from structures of biology or circumstance, a love that recognizes that children belong to everyone.

Originally posted here:
Can Surrogacy Remake the World? - The New Yorker

Recommendation and review posted by Bethany Smith

Editor's note: Among this week's top stories were four powerful female Houston innovators, a generous donation to the University of Houston, and more. Scroll through to see what Houston innovation stories trended this week.

This week's set of who's who include a startup founder trying to change the world, a passionate PhD with a story of failure to tell, and a biomedical engineer enhancing health tech in Houston. Courtesy photos

Another set of female innovation leaders are making headlines as we move into another week of innovators to know.

This week's set of who's who include a startup founder trying to change the world, a passionate PhD with a story of failure to tell, and a biomedical engineer enhancing health tech in Houston. Continue reading.

UH has maintained its spot on the top 100 global universities for number of patents issued. Photo courtesy of University of Houston

University of Houston's C.T. Bauer College of Business has received its second largest donation to benefit its entrepreneurship program.

The Cyvia and Melvyn Wolff Center for Entrepreneurship, which was recently ranked the top undergraduate entrepreneurship program in the country, received the $13 million gift from its namesake foundation The Cyvia and Melvyn Wolff Family Foundation and the state of Texas is expected to match an additional $2 million, bringing the total impact to $15 million.

"Our family is deeply committed to the ideals of entrepreneurship," says Cyvia Wolff in a news release. "Our business personified everything that it means to be an entrepreneur. The skills, the thinking, the mindset are fundamental to success for business leaders today and in the future. On behalf of my late husband, we are truly honored to ensure the entrepreneurial legacy not only endures but remains accessible for students. We are truly honored to be part of this program and university." Continue reading.

Houston-based Roovy Technologies has created a mobile app where people can control their dining experience completely from their phones. Photo via roovy.io

Imagine going into a popular restaurant, sitting down at an open table and controlling the entire dining experience from a smartphone. That's food, drinks, and even dessert all ordered and paid for on a phone.

Prolific Houston-area restaurateur Ken Bridge had the vision to converge dining with technology by creating a digital solution to combat chronic wait times in restaurants. That vision became the Roovy Technologies mobile app, a platform designed to create the ultimate convenience for gastronauts everywhere. Continue reading.

Houston, home to the largest medical center in the world, was ranked the second in the nation for emerging life science clusters. Photo by Dwight C. Andrews/Greater Houston Convention and Visitors Bureau

Editor's note: As 2019 comes to a close, InnovationMap is looking back at the year's top stories in Houston innovation. Within the health category, top stories included new details from the Texas Medical Center's ongoing TMC3 project, health tech and medical device startups in Houston, and more. Continue reading.

Roberta Schwartz is leading the innovation initiative at Houston Methodist. Courtesy of Houston Methodist

It may come as no surprise to anyone who's met Roberta Schwartz that she's a self starter. Schwartz, who is the executive vice president and chief innovation officer for Houston Methodist, was among the group that organized to create what is now the Center for Innovation within the hospital system.

But one of her earlier moments of innovation leadership came when she was diagnosed with cancer at a young age. She co-founded the Young Survival Coalition to help connect young breast cancer patients like herself.

"I was 27 when I was unexpectedly diagnosed with breast cancer I have no family history, no cancer in the family. It certainly was a shock to my system," Schwartz says on this week's episode of the Houston Innovators Podcast. "Once I was diagnosed, and through some of the original surgery and care I had to do, I knew that I wanted to reach out and find a larger community of young women." Continue reading.

More:
5 most popular innovation stories in Houston this week - InnovationMap

Recommendation and review posted by Bethany Smith

We are still in an overall bull market and many stocks that smart money investors were piling into surged through the end of November. Among them, Facebook and Microsoft ranked among the top 3 picks and these stocks gained 54% and 51% respectively. Hedge funds' top 3 stock picks returned 41.7% this year and beat the S&P 500 ETFs by 14 percentage points. Investing in index funds guarantees you average returns, not superior returns. We are looking to generate superior returns for our readers. That's why we believe it isn't a waste of time to check out hedge fund sentiment before you invest in a stock likeCRISPR Therapeutics AG (NASDAQ:CRSP).

CRISPR Therapeutics AG (NASDAQ:CRSP) was in 16 hedge funds' portfolios at the end of September. CRSP investors should be aware of an increase in enthusiasm from smart money recently. There were 13 hedge funds in our database with CRSP positions at the end of the previous quarter. Our calculations also showed that CRSP isn't among the 30 most popular stocks among hedge funds (click for Q3 rankings and see the video below for Q2 rankings). Video: Click the image to watch our video about the top 5 most popular hedge fund stocks.

5 Most Popular Stocks Among Hedge Funds

So, why do we pay attention to hedge fund sentiment before making any investment decisions? Our research has shown that hedge funds' small-cap stock picks managed to beat the market by double digits annually between 1999 and 2016, but the margin of outperformance has been declining in recent years. Nevertheless, we were still able to identify in advance a select group of hedge fund holdings that outperformed the Russell 2000 ETFs by 40 percentage points since May 2014 (see the details here). We were also able to identify in advance a select group of hedge fund holdings that underperformed the market by 10 percentage points annually between 2006 and 2017. Interestingly the margin of underperformance of these stocks has been increasing in recent years. Investors who are long the market and short these stocks would have returned more than 27% annually between 2015 and 2017. We have been tracking and sharing the list of these stocks since February 2017 in our quarterly newsletter. Even if you aren't comfortable with shorting stocks, you should at least avoid initiating long positions in stocks that are in our short portfolio.

We leave no stone unturned when looking for the next great investment idea. For example Europe is set to become the world's largest cannabis market, so we check out this European marijuana stock pitch. One of the most bullish analysts in America just put his money where his mouth is. He says, "I'm investing more today than I did back in early 2009." So we check out his pitch. We read hedge fund investor letters and listen to stock pitches at hedge fund conferences. We also rely on the best performing hedge funds' buy/sell signals. We're going to take a glance at the fresh hedge fund action surrounding CRISPR Therapeutics AG (NASDAQ:CRSP).

At Q3's end, a total of 16 of the hedge funds tracked by Insider Monkey were long this stock, a change of 23% from one quarter earlier. On the other hand, there were a total of 16 hedge funds with a bullish position in CRSP a year ago. So, let's examine which hedge funds were among the top holders of the stock and which hedge funds were making big moves.

Story continues

Is CRSP A Good Stock To Buy?

More specifically, Cormorant Asset Management was the largest shareholder of CRISPR Therapeutics AG (NASDAQ:CRSP), with a stake worth $44.4 million reported as of the end of September. Trailing Cormorant Asset Management was Farallon Capital, which amassed a stake valued at $23 million. OrbiMed Advisors, Clough Capital Partners, and Valiant Capital were also very fond of the stock, becoming one of the largest hedge fund holders of the company. In terms of the portfolio weights assigned to each position Cormorant Asset Management allocated the biggest weight to CRISPR Therapeutics AG (NASDAQ:CRSP), around 2.71% of its 13F portfolio. Clough Capital Partners is also relatively very bullish on the stock, dishing out 1.63 percent of its 13F equity portfolio to CRSP.

Now, key hedge funds were leading the bulls' herd. OrbiMed Advisors, managed by Samuel Isaly, assembled the largest position in CRISPR Therapeutics AG (NASDAQ:CRSP). OrbiMed Advisors had $21.2 million invested in the company at the end of the quarter. Steven Boyd's Armistice Capital also made a $10.8 million investment in the stock during the quarter. The other funds with new positions in the stock are William Harnisch's Peconic Partners, Israel Englander's Millennium Management, and Sculptor Capital.

Let's check out hedge fund activity in other stocks similar to CRISPR Therapeutics AG (NASDAQ:CRSP). We will take a look at Fastly, Inc. (NYSE:FSLY), The Hain Celestial Group, Inc. (NASDAQ:HAIN), TeleTech Holdings, Inc. (NASDAQ:TTEC), and Chart Industries, Inc. (NASDAQ:GTLS). This group of stocks' market caps match CRSP's market cap.

[table] Ticker, No of HFs with positions, Total Value of HF Positions (x1000), Change in HF Position FSLY,16,126686,3 HAIN,19,545805,2 TTEC,14,41238,-3 GTLS,19,261236,-5 Average,17,243741,-0.75 [/table]

View table hereif you experience formatting issues.

As you can see these stocks had an average of 17 hedge funds with bullish positions and the average amount invested in these stocks was $244 million. That figure was $150 million in CRSP's case. The Hain Celestial Group, Inc. (NASDAQ:HAIN) is the most popular stock in this table. On the other hand TeleTech Holdings, Inc. (NASDAQ:TTEC) is the least popular one with only 14 bullish hedge fund positions. CRISPR Therapeutics AG (NASDAQ:CRSP) is not the least popular stock in this group but hedge fund interest is still below average. Our calculations showed that top 20 most popular stocks among hedge funds returned 37.4% in 2019 through the end of November and outperformed the S&P 500 ETF (SPY) by 9.9 percentage points. A small number of hedge funds were also right about betting on CRSP as the stock returned 74.8% during the first two months of Q4 and outperformed the market by an even larger margin.

Disclosure: None. This article was originally published at Insider Monkey.

Related Content

Continue reading here:
Did Hedge Funds Drop The Ball On CRISPR Therapeutics AG (CRSP) ? - Yahoo Finance

Recommendation and review posted by Bethany Smith

by Tyler English | published Dec. 11th, 2019

illustration by Darius Serebrova

Ever wonder where those neon yellow, green, blue and pink fish came from? You know, the ones that have all the matching accessories: tanks, decorations, rocks and their own special ultraviolet light? Well, as it turns out, a team ofscientists in Singapore were the first ones to genetically modify fish to glow in such a way.

Genetic editing in small animals and plants has been aroundsince the 1970s, according to Synthego, a company that providesgeneticallyedited stem cells. Starting with plants and bacteria, scientists began to explore the realm of DNA and genetics. As their understanding of the proteins grew, so did their curiosity.

When scientists learned how to modify the genes of small, simple organisms, they began to wonder, "How could this be applied to humans?"

The scientific community is stirring with the emergence of CRISPR DNA,more specifically known as the CRISPR-Cas9 protein.CRISPR stands forClustered Regularly Interspaced Short Palindromic Repeats.CRISPR is a faster, cheaper and more accurate way of editing the genome, according to theNational Institute of Health.By sending in two different pieces of CRISPR DNA,scientists are able to modify genes. To do so, theycutout areas of genes that aren'tperforming how they should be or as they're expected to.

Dr. Sandi Connelly, a principallecturer in the Thomas H. Gosnell School of Life Sciences, explained how DNA works and what the CRISPRCas-9 protein actually does. Connelly compared DNA to a street of houses each person has different foundations that sprout out different and unique homes.

CRISPR is a piece of DNA, and we [scientists] attach to it an enzyme ...it cuts the DNA at a very specific place like a pair of scissors, Connelly said. When we look at CRISPR, typically we look at CRISPR Cas-9."

Whereas CRISPR is the DNA itself, Cas-9 is the enzyme, a specialized protein that splits the DNA.Connelly said that this allows for both the CRISPR DNA and the original DNA to stick together like magnets. However, due to the specificity of this technique, scientists need to know where in the DNA they'relooking.

Using those same enzymes, we can cut [and] place back inthe good gene, Connelly said.

Now, this technique would not be doneby injecting the CRISPR DNA directlyinto a fully grown adult. Instead,scientists would take a sample of a persons bone marrow and alter the genes of those cells. Since bone marrow is responsible for producing red blood cells, the new altered bone marrow will produce cells with the new DNA.

Connelly saidthechangeswouldnot be instantaneous.The human body replaces a majority of its cells within 13 days, soit would take around two weeks for the newly edited gene to be present in the human body.

The ability to now alter genes of morecomplexorganisms brings with it a variety of applications. Plants can be changed to increase nutritional value and pesticidal properties,whereas bacteria can be used to generate hormones and medicines.

Dr. David Holtzman,an adjunct professor in the College of Science, understands how gene editing is used and what it could be used for.

Most people are familiar with it [gene editing] for things like modifying plants ...[but] there is a lot of misunderstanding about gene editing, Holtzman said.

There is a lot of misunderstanding about gene editing.

CRISPR has begun to work its way into at-home kits, where those with some scientificexpertise can genetically modify their own plants to glow or be a different color. This is fairly simple in the world of gene editing as it is changing a simple expressed trait one that isbiologically shown.

Genes decide what traits a person has, but that persons environment and what happens to their body determines how those traits are expressed. As gene editing becomes more and more innovative, Holtzman said that there are limitations to what gene editing can and cannot do.

It turns out most traits are more than one gene, Holtzman said.

Holtzman used hair color as an example. Numerous genes and sections of DNA code for what an individual's hair colorwill be. Itcan behard and time-consuming to find the right area of the DNA to target for modification.

Connelly talked about the idea of changing hair coloras well,but took it a few steps further. Shesuggestedthat we may start wanting to create offspring that all have blonde hair and blue eyes, which realistically we could accomplish. This then opens parents up to the ideas of having all male children or all female children.

In recent years, science has progressed faster than we could have thought.What appeared to be science fiction in the past is inching ever closer to our scientific reality.

The ability to do [new]things happens a lot faster than our understanding of what we are doing, Holtzman said.

Regardless of the potential scientific progress that could be made, Holtzman, Connelly and other members of the scientific community are having conversations about what should be done with this technology. Where should the limits lie, and how far should humans gowith genetic technology?

"Where should the limits lie, and how far should humansgowith genetic technology?"

If our parents changed our genes, they would also be changing the genes of all of our descendants by extension. Did they consent to something like that?

Some might argue, whether we gene edit or not, we dont really have control over what our parents did, Holtzman said. There is the possibility that if we changed [certain genes]then we can change them back.

Reversal isn't a guarantee, though.

Holtzman mentioned ways in which gene editing could greatly improve the quality of life for all humankind, such as curing Alzheimers disease. Connelly brought up how easy it would be to reduce the effects of aging using genetic modification.

The consequences of the choices made nowmay not affect the generation making them. As the movement to improve the genetic composition of the human race pushes forward,plots in sci-finovelsmay no longer be abstract, distant futures. Rather, for better or worse, they could bethe reality we are setting up for generations to come.

Read more:
Science Fiction Becoming Reality - Reporter Magazine

Recommendation and review posted by Bethany Smith

On the 12th of December, the United Kingdom will hold a general election. With the UKs exit from the European Union (Brexit) remaining unresolved, tensions are as high as ever. Once out of the EU, though, the UK could regain full control over its laws and regulations.

Though the election debate has centered around immigration, security and healthcare, the question of what direction the UK should take in terms of science policy persists. Will the UK manage to unleash the potential of its biotechnological sector and become a global advocate for innovation and consumer choice, or will it retain the EUs antiquated approach?

In a manifesto released in November, the Conservatives pledged to take the path of science-led, evidence-based policy to improve the quality of food, agriculture and land management. Previously, Prime Minister Boris Johnson promised to liberate the UKs biotech sector from the EUs anti-genetic modification rules.

The laws that concern genetically modified organisms in the UK are primarily based on European Union regulations. For years, the EU has backpedaled on agricultural innovation, preventing European consumers from accessing biologically enhanced food. This can be seen in the very limited number of genetically modified crops authorized for cultivation in the EU, and a very cumbersome and expensive process of importing genetically modified crops from other countries. In July 2018, the European Court of Justice (ECJ) decided that gene-edited plants should be regulated the same way that genetically modified organisms are regulated, rendering them practically illegal and hindering innovation even further.

If the UK chooses to move away from these EU-based regulations as a consequence of Brexit, it could become a forward-looking global biotech powerhouse.

The first step would be to replace fear-based skepticism of genetic modification with an evidence-based, pro-innovation approach. Despite popular rhetoric, there is no substantial scientific evidence behind the alleged health and environmental risks ascribed to GM products. Abandoning these baseless assertions and creating and sustaining the conditions under which UK farmers could innovate, lower their production costs, and use fewer chemicals would be an enterprising move on the part of the UK government.

Approving GM pest-resistant crops, for instance, could save about 60 million ($79 million) a year in pesticide use in the UK. Moreover, 60 million in savings would mean more leeway for competitive food pricing in a country where prices at the grocery store are rising 2 percent annually.

Once restrictive genetic modification laws are relaxed, it would be necessary to enable easy market access for GM foods. Under current EU legislation, products containing GMOs need to be labeled as such, and the requirements also apply to non-prepacked foods. It is legally established that such products (soy, for example) not only require written documentation but also should have an easily readable notice about their origin. No such rule exists with regards to foods that are 100% GMO-free, meaning there is explicit discrimination in place giving GMO-free food an unfair advantage on the market.

The EUs strict regulations on the use of GM technology have been, first and foremost, harmful to consumers, depriving them access to innovative options such as Impossible Foods plant-based burger, which so closely mimics meat thanks to an ingredient produced with the help of genetically engineered yeast. Vastly popular in the US and now expanding to Asia, vegan burgers using plant-based substitutes for meat and dairy products, are absent from the European market due to backwards-looking anti-GM rules.

The United Kingdom should strive for the smartest regulation in the field of approval and market access to GMOs. Relaxed regulations on gene-editing methods like CRISPR-Cas9 could also attract massive investment and lead to wide-reaching biotech innovation in the UK.

Enabling gene-editing is an essential part of unleashing scientific innovation in the United Kingdom after Brexit. Skepticism of gene-editing centers around the potential but largely exaggerated adverse effects of the technology and ignores the astonishing benefits that could accrue to both farmers and consumers.

If the UK manages to replace the EUs overly cautious biotech rules with a pro-innovation and prosperity-fostering regulatory scheme, it could become a true global biotech powerhouse. This is an ambitious, exciting, and above all, achievable future.

Maria Chaplia is a European Affairs Associate at the Consumer Choice Center. Visit her website and follow her on Twitter @mchapliaa

Go here to see the original:
Viewpoint: Conservatives say UK could break from 'outdated' EU GMO, CRISPR regulations if they sweep 'Brexit election' - Genetic Literacy Project

Recommendation and review posted by Bethany Smith