Archive for the ‘Male Genetics’ Category

A B.C. transgender teens bid to obtain hormone therapy was legal, B.C.s Court of Appeal ruled unanimously Jan. 10 in supporting a lower court decision.

The child A.B. is able to assert his rights, and has done so in accordance with the law, Chief Justice Robert Bauman and Justice Barbara Fisher wrote in the decision.

The 15-year-old A.B. was born female but wanted to pursue therapy, a move approved by his mother, E.F., but not by his father, C.D. The parents are separated but share parenting duties.

Doctors found A.B. sufficiently mature to make the treatment decision on his own, and C.D. began legal action.

The appeal court had to examine three Supreme Court of BC orders before arriving at its conclusion that ABs consent to that treatment is valid, and no further consent from his parents, in particular CD, is required in that regard.

A February 2019 order declared A.B. validly able to consent to treatment, and that referring to A.B. as a girl or attempting to convince him to halt treatment would be considered family violence under the Family Law Act.

An April 2019 protection order restricted the fathers ability to speak with others, including media outlets and A.B., about his decision to receive therapy.

And, a July 2019 order dismissed C.D.s action initiated by C.D. as vexatious and an abuse of process.

The father appealed.

He claimed the orders violated his Charter-protected freedoms of belief and expression and what he terms parental rights, were procedurally unfair, and not in his childs best interests.

A.B., however, said the decisions were Charter-compliant and in his best interests as well as the statutory right of mature minors to make their own medical decisions.

His mother supported that claim.

The decision said A.B. has identified as male since he was 11 years old and began socially transitioning at 12, enrolling in school under a chosen male name and using male pronouns with his teachers and peers.

Around 13 years of age, after two years of consistently identifying as male, ABs persistent discomfort with his body led him to want to take steps to appear more masculine, the court said.

He was soon diagnosed with gender dysphoria, a recognized medical condition where a person experiences significant distress because the gender identity they experience differs from their genetic or biological gender, and how others perceive them, the court said.

A doctor said he could be a good candidate for treatment and another found such treatment was reasonable and in his best interests.

The process stopped once doctors found out about C.Ds opposition.

Doctors explained to C.D. that minors are permitted to consent to their own medical treatment under a section of the Infants Act.

One doctor asked for an opinion from the Provincial Health Services Authority Ethics Service, which agreed that A.B. demonstrated capacity to understand the treatment.

The teen was further referred to the B.C. Mental Health Centre, which found that he demonstrated detailed understanding of the risks and benefits of the treatment, and that he displayed reasonable judgment and insight.

C.D. filed suit to stop treatment in late 2018. Treatment was ordered stopped until the case could be heard.

The court said where a child has consented to health care under the Infants Act, the Family Law Act doesnt provide authority to start consideration of the childs best interests over medical treatment.

The court said the father continually disrespected his childs choices and in seemed oblivious to the effect of his behaviour on A.B. But, the court added, such effects did not rise to the level of family violence.

The court said C.D.s claims he parental rights under the Charter had been violated had no merit.

jhainsworth@glaciermedia.ca

@Jhainswo

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Trans teen can decide on hormone therapy, court rules - The Tri-City News

Ultragenyx Pharmaceutical saw its shares jump around 27% in trading Friday after announcing positive top-line data out of its gene therapy trial.

Its a small number, just three patients that form part of a third cohort for the phase 1/2 study, as well as another small test but a longer-term look from the second cohort.

In cohort three testing the biotechs drug DTX301, an adeno-associated virus gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency, there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status.

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Meanwhile, in cohort two, one female patient saw a new response after a year. The biotech added that the two previously disclosed responders in cohort one and two also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response, it said in a statement.

RELATED: BIO: In conversation with Emil Kakkis, Ultragenyx CEO

OTC deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme OTC. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood,

According to the National Organization for Rare Disorders, the severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.

Analysts at Jefferies said the data looked better than expected and could be a positive spark to help turn the stock heading into 2020 events. It certainly did in the immediate term, with the biotechs shares up by 27% in mid-morning trading Friday.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, said Eric Crombez, M.D., chief medical officer of the Ultragenyx Gene Therapy development unit.

We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

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Ultragenyx shares jump on 'better than expected' gene therapy data - FierceBiotech

INTRODUCTION

Congenital defects are a leading cause of morbidity worldwide, accounting for the deaths of 330,000 newborns every year. Brain malformations, including microcephaly and holoprosencephaly (HPE), are the most common congenital anomalies and place a heavy burden on the affected individuals and the health care system (13). HPE is a structural anomaly of the developing forebrain affecting 1:250 embryos and 1:16,000 live-born infants. Clinically, HPE encompasses a continuum of brain malformations and is accompanied with a spectrum of craniofacial defects in 80% of the cases; microcephaly and eye defects are among the most common features in affected individuals (4). In the majority of cases, the underlying cause remains uncertain due to the high complexity and the multigenic origin of these anomalies (5, 6). Lately, it has become clear that HPE is caused by a malfunction in key signaling pathways in the early embryo, leading to developmental defects in the organizing centers and midline structures (7). The defects involve a sequence of developmental steps that begin with Nodal signaling to establish the midline progenitors in the developing primitive streak (PS). It then continues with the proper positioning of the forming prechordal plate beneath the neuroectoderm and activation of midline Hedgehog signals to maintain the anterior identity of the forebrain. However, the restriction of HPE genetic determinants to a handful of NODAL and Sonic hedgehog (SHH) pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Expansion of this genetic repertoire has become a necessity to develop therapeutic options and improve molecular diagnosis of HPE.

Genes encoding transcription factors (TFs) and epigenetic regulators are relevant etiological candidates given their central role in integrating signaling cascades and orchestrating multiple biological processes. Deficiency in their function can disturb entire transcriptional programs, involving numerous genes and molecular pathways, leading to a complex pathological outcome. Consistent with this hypothesis, we have recently identified a loss-of-function (LOF) mutation in the transcriptional regulator PRDM15 in patients with a syndromic form of HPE. Here, we combine mouse genetics and epigenomic approaches to uncover the role of this TF in congenital brain malformations. Our findings establish PRDM15 as a key regulator of NOTCH and WNT/PCP pathways in the developing embryo, implicating them in regulation of anterior/posterior (A/P) patterning and forebrain development. In addition, we uncover new genetic variants in key components of these signaling pathways in patients with HPE. Collectively, our findings refine the molecular mechanisms governing forebrain development and set the stage for the identification of new HPE candidate genes.

Homozygosity mapping and whole-exome sequencing on patients with steroid resistant nephrotic syndrome (SRNS) identified three recessive mutations in PRDM15 (NM_001040424.2). These mutations are located in the sequences coding for the PR domain (c.461T>A; p.Met154Lys-M154K and c.568G>A; p.Glu190Lys-E190K) and the 15th zinc finger (c.2531G>A; p.Cys844Tyr-C844Y), respectively (Fig. 1A). Of particular interest, in four consanguineous families that have the variant encoding PRDM15 C844Y, the affected probands exhibited a syndromic form of SRNS consistent with the Galloway-Mowat syndrome (8). Besides renal defects, the patients displayed facial (narrow forehead, microcephaly, abnormal cerebral gyration, and ophthalmic abnormalities) and extracranial defects (heart malformations and postaxial polydactyly) (9).

(A) Schematic representation of the PRDM15 mutation positions and the affected domains. (B) Alkaline phosphatase (AP) staining of ESCs; the respective genotypes are indicated in the lower panel. Data are average of four independent cell cultures (n = 4) SD. Statistical tests were applied on differences observed in the percentage of completely undifferentiated colonies. Students t test (two sided) was used to determine significance. (C) Heat map of differentially expressed genes in ESCs upon the indicated genetic manipulations. (D) mRNA levels of Rspo1 in ESCs; the respective genotypes are indicated by color code. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Data shown are from three independent experiments (n = 3). (E) Enrichment of PRDM15 binding on promoter regions of the target gene (Rspo1) in ESCsrespective genotypes are indicated by color codeas measured by ChIP-qPCR. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) to (E), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15 (hPR15). In (D) and (E), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

We have recently demonstrated that PRDM15 regulates the transcription of Rpso1 and Spry1, two key components of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signalregulated kinase) and WNT pathways, to maintain nave pluripotency of mouse embryonic stem cells (mESCs) (10). To evaluate the effects of these mutations on PRDM15 function, we ectopically expressed the three identified human variants in Prdm15-deficient embryonic stem cells (ESCs) (Prdm15/). Only hPR15-C844Y, which is associated with brain defects in humans, failed to restore ESC self-renewal (Fig. 1B), and most importantly, the global changes in gene expression, induced by loss of endogenous PRDM15 (Fig. 1C and table S1 (A to E)]. These data strongly suggest that hPR15-C844Y is a LOF mutation. While hPR15-M154K and hPR15-E190K rescued Rspo1 expression at levels comparable to the wild-type (WT) human PRDM15 (hPR15-WT), hPR15-C844Y failed to restore its transcript levels [quantitative polymerase chain reaction (qPCR)] and to activate its transcription in a luciferase reporter assay (Fig. 1D and fig. S1A).

To gain further insights into the impact of these mutations on PRDM15 function, we tested the stability of the encoded proteins and their cellular localization. Immunofluorescence staining, in a Prdm15/ background, showed that none of the mutations affected the nuclear localization of PRDM15 (fig. S1B). On the other hand, all three mutants encoded less stable proteins (fig. S1C). We have previously shown that the zinc finger domains are required for DNA binding and transcriptional activity of PRDM15 (10). Thus, we sought to test the ability of the various mutants to bind to chromatin. Consistent with an LOF of the zinc finger mutant, chromatin immunoprecipitation (ChIP)qPCR analysis revealed reduced enrichment of hPR15-C844Y at the promoter region of Rspo1 (Fig. 1E), a result compatible with its inability to promote its transcription (Fig. 1D and fig. S1A).

To gain molecular insights on the effects of PRDM15 LOF during mammalian development, we intercrossed Prdm15lacZ/+ heterozygous mice, which are healthy and fertile. A description of all the Prdm15 alleles and deleter strains used in this study is summarized in fig. S2A. Consistent with a fundamental role of PRDM15 during embryonic development, we obtained no homozygous mutant [Prdm15lazZ/lacZ knockout (KO)] pups (Fig. 2A), while of the hundreds Prdm15lacZ/+ embryos that were dissected at various stages of development, none showed any defects. Timed matings revealed the embryonic lethality of Prdm15lazZ/lacZ (KO) embryos occurs between embryonic days 12.5 (E12.5) and E14.5 (Fig. 2A). Notably, at E12.5, KO embryos were smaller and showed a spectrum of brain malformations affecting predominantly the anteriormost structures of the head, including the eyes (Fig. 2B), consistent with the brain and facial features observed in patients with the C844Y mutation. Coronal sections of the brain at this stage confirmed that the lateral and medial ganglionic eminences were underdeveloped. Furthermore, we noted an abnormal separation of the cerebral hemispheres, reminiscent of HPE (Fig. 2C). Classic HPE encompasses a continuum of brain anomalies caused by neural tube patterning defects that affect the anteriormost structures and is often accompanied by craniofacial defects involving the eyes (4, 11, 12).

(A) Genetic distribution of embryos from Prdm15+/LacZ intercrosses, indicating lethality between E12.5 and E14.5. (B) Phenotypic continuum of brain defects in E12.5 Prdm15lacZ/lacZ KO embryos. (C) Hematoxylin and eosin (H&E) staining of serial coronal sections of E12.5 brains from Prdm15+/+ WT (upper panel) and Prdm15lacZ/lacZ KO (lower panel) embryos. The mutants lack the complex organization of the anterior forebrain, including the lateral (LGE) and medial ganglionic eminences (MGE), the epithalamic and dorsal thalamic neuropeithelium (NE), and eyes. (D) Nestin-Cremeditated deletion of Prdm15 in neuronal precursors does not affect brain development. Representative images are shown in (B) to (D). LGE/MGE, lateral and medial ganglionic eminences; NE, neuropeithelium; NCX, neocortex; E, eye; LV, lateral ventricle; V, ventricle; TOT, total. (B and D) Photo credit: Messerschmidt and Mzoughi.

These results prompted us to delete Prdm15 specifically in the developing brain by crossing Prdm15fl/fl mice to the Nestin-Cre deleter strain. This Cre recombinase is active at ~E11 in neural stem cells/progenitors and would reveal whether PRDM15 is essential for the process of neurogenesis. The resulting Prdm15/::Nestin-CRE embryos did not show any apparent defects at E12.5 (Fig. 2D), were born at the expected Mendelian ratios, and developed into healthy adults (fig. S2B). This suggests that PRDM15 is required at earlier time points of forebrain specification.

Defects in Prdm15 KO embryos are apparent before the onset of neurulation, as mutants were markedly smaller and had an abnormal morphogenesis by E7.5 (fig. S3A). Between E6.5 and E7.5, two signaling centers act sequentially to pattern the forebrain in the mouse embryo (Fig. 3A) [reviewed in (1315)]. The first resides within the extraembryonic lineages and is called the anterior visceral endoderm (AVE). The AVE imparts anterior identity to the underlying epiblast, thereby restricting the site of gastrulationthe PSto the posterior epiblast. During gastrulation, a second specialized population of cells, known as the AME, emerges from the anterior PS (APS). These cells migrate anteriorly, giving rise to the anterior definitive endoderm and prechordal plate mesoderm. Their role is to produce secondary inductive cues that reinforce anterior identity in the overlying neural plate (Fig. 3A).

(A) Schematic of the signaling centers governing A/P patterning in the mouse embryo. (B) At E6.5, Foxa2 is expressed in the AVE (red line) and APS (red asterisk). At E7.5, Lhx1 transcripts label the visceral endoderm (VE) overlying the epiblast including the AVE as well nascent mesoderm and midline axial mesendoderm. In Prdm15 mutants (mut), Foxa2 expression is confined to the distal VE, with little enrichment in the prospective AVE. Lhx1 is detected in the VE and mesoderm of the middle Prdm15 mutant, but only in the VE of the one on the right. (C) Expression of T, Lefty2, Foxa2, Chordin, and Shh in WT and Prdm15lacZ/lacZ embryos at E7.5. In Prdm15 mutants, T is expressed normally in the PS; Lefty2 transcripts are down-regulated in nascent mesoderm; Foxa2 and Chordin expression remains high distally in the region of the APS (angled black-dashed line) but does not extend anteriorly in the midline axial mesendoderm (am); and Shh expression is similarly weak in the anterior midline (asterisk). n, node. (D) Expression of Six3/Shh or Otx2/Shh in WT (upper) and Prdm15lacZ/lacZ KO (lower) embryos at E8.5. Six3 and Otx2 expression highlights the reduction in anterior forebrain (fb) development (angled black dashed lines) in Prdm15lacZ/lacZ KO mutants. no, notochord; mb, midbrain; DVE, Distal Visceral Endoderm. Representative images are shown in (B) to (D). (C and D) Photo credit: Dun and Ong.

We reasoned that loss of PRDM15 might impair forebrain specification during the earliest events of anterior patterning and therefore examined the expression of a panel of marker genes diagnostic for defects in either the AVE or AME in Prdm15 KO embryos. Foxa2 is a marker of both, AVE and APS, in early PS stage embryos at E6.5. In Prdm15 KO embryos, in situ labeling shows expression in the distal visceral endoderm overlying the epiblast in a pattern typically observed 1 day earlier in WT embryos (Fig. 3B) (16). We conclude that Prdm15 KO embryos are developmentally delayed even before gastrulation. At E7.5, Lhx1 is expressed in the nascent mesoderm and anterior midline mesendoderm. In the smaller, delayed Prdm15 KO littermate embryos, Lhx1 is expressed normally throughout the visceral endoderm, including the AVE, as well as in the nascent mesoderm (Fig. 3B) (17, 18). Both FOXA2 and LHX1 are required for the formation and function of the AVE, and their activation provides evidence that the initial specification of the primary anterior-posterior axis by the AVE is normal in Prdm15 KO embryos.

We next examined the expression of PS (T and Lefty2) and AME (Foxa2, Chordin, and Shh) marker genes. By E7.5, Prdm15 KO embryos are easily recognizable due to a characteristic ruffling in the extraembryonic visceral endoderm, with a fully extended PS that expresses both T and Lefty2 (Fig. 3C). At this stage, Foxa2 is expressed in the node, which marks the anterior end of the PS, and the AME that extends rostrally in WT embryos. In contrast, in Prdm15 KO embryos, Foxa2 transcripts are present distally but do not extend anteriorly (Fig. 3C). A similar pattern is observed with Chordin, which also labels the node and AME in WT embryos but is confined to the APS in Prdm15 KOs (Fig. 3C). Shh expression is also diagnostic for the node and AME, but in KO embryos, only a few Shh-positive cells are observed along the anterior midline (Fig. 3C). Together, these results show that loss of PRDM15 specifically affects the production of the anterior AME. Consequently, the crucial refining signals produced by these cells that orchestrate the continued patterning and morphogenesis of the anterior neuroectoderm are lost, resulting in anterior truncations that are evident by diminished forebrain expression of Six3 and Otx2 in Prdm15 KO mutant embryos at E8.5 (Fig. 3D). To further corroborate these findings, we deleted Prdm15 specifically in the epiblast, using the Sox2-Cre transgene (fig. S3B) (19), while maintaining WT extraembryonic tissues. Consistent with an essential role for PRDM15 in the PS-derived AME and not AVE specification, Prdm15/::Sox2-CRE embryos died in utero starting at E12.5 (fig. S3C) and exhibited a spectrum of brain defects similar to those observed in Prdm15 KO embryos (fig. S3D).

To examine the impact of PRDM15 depletion on early embryonic processes, namely, A/P patterning, we sequenced the transcriptome of WT versus Prdm15 KO E6.5 embryos. We reasoned this could be the most critical stage for AME specification as AME cells emerge less than 24 hours later. Unbiased clustering of global gene expression separated WT versus Prdm15 KO embryos into distinct groups, indicating marked transcriptional differences (Fig. 4A and table S1F). Gene ontology (GO) analysis of the significantly down-regulated genes identified Pattern specification process, Head development, and Neural tube development among the enriched terms. Among these genes, several are important regulators of forebrain development and A/P patterning (Fig. 4B and fig. S4A, and table S1, G to H). We noted a striking reduction in the expression of key components of three signaling pathways: WNT, NOTCH, and SHH (Fig. 4C, fig. S4B, and table S1, I and J).

(A) Unbiased clustering heat map of the entire transcriptome in WT (n = 8) versus Prdm15lacz/lacz KO (n = 10) E6.5 embryos, analyzed by RNA sequencing. Heat maps of differentially expressed genes from the indicated GO categories (B) and KEGG pathway (C) identified as top hits in the RNA sequencing. Light and dark blue rectangles on the right side indicate genes whose promoter region is directly bound by PRDM15 in ESCs only or both in ESCs and E6.5 embryos, respectively. (D) Snapshots of representative PRDM15 ChIP tracks (UCSC genome browser). Examples of conserved target genes (binding sites) between E6.5 embryos (blue) and ESCs (orange) are shown.

We have recently shown that PRDM15 recognizes a defined DNA motif present at promoters or enhancers of target genes (10). To define the set of direct PRDM15 transcriptional targets, we performed ChIP sequencing (ChIP-seq) on mESCs and WT E6.5 embryos (table S1, K and L). Despite the limited biological material available from the pre-gastrula embryos, we identified 58 high-confidence promoter-bound targets, the majority of which (~84%) were also bound by PRDM15 in ESCs (Fig. 4D, fig. S4C, and table S1M). In addition, identification of the same PRDM15 consensus binding motif in both systems implies a conservation of its targets. We therefore chose to consider PRDM15-bound promoters identified in ESCs as relevant for our follow-up analyses. Among these, a handful of PRDM15 targets, including Rbpj, Notch3, Maml3 (NOTCH), Vangl2, Wnt5b, Gpc6, Nphp4 (noncanonical WNT), and Gas1 (SHH), were of particular interest as they are significantly down-regulated in the mutant embryos (fig. S4D). Collectively, these data indicate that lack of PRDM15 leads to transcriptional down-regulation of key regulators of developmentally important signaling pathways (NOTCH, noncanonical WNT, and SHH).

These results prompted us to perform a targeted analysis of the down-regulated PRDM15 target genes in a large cohort of patients with HPE (132 trios and 188 singletons). We found heterozygous variants in 99 genes, ~17% of them were likely to be damaging (table S2A). To gain insights on potential functional interactions between these genes, we generated functional protein association networks using STRING. Although the majority of the proteins did not seem to be functionally related, two main networks representing NOTCH and WNT/PCP signaling formed (Fig. 5A and table S2B), supporting their potential involvement in HPE pathobiology.

(A) Functional groups identified by protein association network analysis of PRDM15 target genes mutated in patients with HPE using STRING. (B) mRNA levels of the indicated genes in ESCs; the respective genotypes are indicated in the lower panel. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Rspo1 expression levels were used as positive control in Fig. 1D. Data shown are from three independent experiments (n = 3). (C) Enrichment of PRDM15 binding on promoter regions of the indicated target genes in ESCsrespective genotypes are indicated in the lower panelas measured by ChIP-qPCR. ChIP on the Rspo1 promoter was used as a positive control for PRDM15 binding. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) and (C), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15. In (B) and (C), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

To assess the ability of the PRDM15 mutants to regulate the expression of critical components of both pathways, we took two approaches. First, we performed rescue experiments in Prdm15/ ESCs by reintroducing WT or mutant PRDM15 expression constructs. While hPR15-M154K and hPR15-E190K restored the expression of target genes at levels comparable to the WT human PRDM15 (hPR15-WT), none were significantly rescued by hPR15-C844Y (Fig. 5B and fig. S5A). In addition, ChIP-qPCR analysis confirmed a reduced enrichment of hPR15-C844Y at the promoter regions of these target genes (Fig. 5C and fig. S5B), which is consistent with the failure to promote their transcription (Fig. 5B). Second, to confirm that the C844Y mutation in humans is indeed an LOF mutation, we introduced the corresponding homozygous mutation (C842Y) in mESCs using CRISPR-Cas9 technology (fig. S5, C to E). Although the C842Y knock-in allele did not affect Prdm15 transcript levels, the resulting protein was unstable and less abundant (fig. S6, A and B). qPCR confirmed that Prdm15C842Y cells express PRDM15 target genes (i.e., Rbpj, Notch3, Vangl2, etc.) at lower levels compared with WT (fig. S6C) and that endogenous PRDM15C842Y protein is unable to bind (ChIP-qPCR) to its target promoters (fig. S6D).

Our findings call for a future functional characterization of the NOTCH and PCP gene variants and should motivate targeted genetic mapping for new HPE candidates in regulators of both pathways.

We have identified new mutations in the PRDM15 gene in patients with SNRS. Although the mutations affecting the PR domain of the protein (M154K and E190K) are associated with isolated SRNS cases only, the zinc finger mutation (C844Y) causes a syndromic form of HPE. In our in vitro ESC system, these PR domain mutations reduced the stability of the encoded protein but rescued considerably the phenotypic and molecular changes induced by loss of the endogenous protein. This is consistent with the fact that these mutations in humans cause isolated SRNS only and could imply a context-dependent requirement for the PR domain. Alternatively, the differential impact of the PR versus ZNF mutations on protein stability may support a threshold model, where different levels of PRDM15 expression are required for the development of specific organ systems. On the other hand, the ZNF mutation (C844Y) had marked effects on PRDM15 function in both settings, which we attribute here to impaired binding of the mutant protein to regulatory regions of its transcriptional targets.

Similar to the LOF mutation in humans, genetic deletion of Prdm15 in mice leads to a broad spectrum of brain defects, affecting predominantly the anteriormost structures including the eyes. Such phenotypic continua are commonly assigned to allelism, polygenic origin, and the action of modifier genes. Yet, here we report that perturbation of a single transcriptional regulator can indeed affect an entire transcriptional network, relevant to both normal development and pathological manifestations.

Our findings show that PRDM15 promotes transcription of several regulators of the NOTCH and WNT/PCP pathways to orchestrate formation of midline structures. Perturbation of these transcriptional programs, upon PRDM15 depletion, disrupts forebrain development due to impaired AME specification and lack of SHH signaling, consistent with the sequence of developmental defects associated with HPE pathobiology (7).

Of note are the prominent phenotypic similarities between Prdm15 null embryos and genetic (or microsurgical) modulation of the Nodal signaling pathway in mouse. That is, Nodal hypomorphic alleles, assorted combinations of mutations in Smad2 and Smad3, as well as the mutations in the downstream effectors Foxh1 and Foxa2, all result in embryos with defective AME production and compromised anterior forebrain development (2023).

On the other hand, the characteristic ruffling of the visceral endoderm observed in Prdm15 KO embryos at E7.5 has been observed in other mutants where extraembryonic mesoderm (ExMeso) production during gastrulation is impaired, such as in loss of Smad1 (24), combined loss of Smad2 and Smad3 in the epiblast (21), or Otx2 (chimeric analysis) (25). It is, however, important to emphasize that epiblast-specific deletion of Prdm15 (Prdm15/::Sox2-CRE embryos) equally results in smaller embryos with defects in the formation of anterior structures (fig. S3). It is additionally possible that the developmental delay we observed in Prdm15 KO embryos disproportionally affects some parts of the gastrulating embryo, rather than an overall delay in epiblast proliferation before gastrulation.

On the basis of our molecular analysis, we conclude that like modulation of the Nodal signaling pathway, loss of Prdm15 specifically affects AME specification. Given the requirement of this critical signaling center in providing reinforcing anterior patterning signals, we favor a model in which its lack or dysfunction underlies the Prdm15 phenotype, rather than a paucity of mes(endo)derm produced during gastrulation by a mutant embryo experiencing developmental delay.

The restriction of HPE genetic determinants to a handful of NODAL and SHH pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Recent studies have implicated components of the WNT/PCP pathway in regulating polarity of the node along the A/P axis and linked their deregulation to structural anomalies of this critical organizing center (2629). Thus, it is not unexpected that perturbation of the WNT/PCP pathway affects the specification of APS derivatives, namely, the AME and node (29). In addition, while the links between mutations in PCP signaling and neural tube defects are well established (6, 3032), their involvement in HPE remains uncharted. NOTCH signaling, on the other hand, has been implicated in HPE only recently (33). Besides its established neurogenic role in the developing mouse telencephalon, growing evidence supports the involvement of key NOTCH regulators (for example Dll1 and Rbpj) in node morphogenesis and midline truncations (34, 35).

Our findings prompted us to perform a targeted search for mutations in a large cohort of patients with HPE. Our analysis of exome sequencing data from 132 trios and 188 singletons revealed multiple rare heterozygous variants in PRDM15 transcriptional targets involved in forebrain development. In silico protein association network analysis of these variants identified two major functional groups regulating the NOTCH and WNT/PCP pathways. We expect that our findings will encourage validation of the reported variants/mutations as well as further mining for additional HPE candidates in both pathways.

PRDM15 KO-first mice that harbor the Prdm15lacZ allele were obtained from the European Conditional Mouse Mutagenesis Program. Hemizygous (Prdm15lacZ/+) animal intercrossings were performed to obtain homozygous (Prdm15lacZ/lacZ) embryos. Further details on these animals and the conditional Prdm15fl/fl strain can be found in (10). To generate epiblast-specific Prdm15/ embryos, Prdm15fl/fl mice were first crossed to heterozygous Sox2-CRE transgenic animals [B6.Cg-Edil3Tg(Sox2-cre)1Amc/J; JAX Laboratory] (36). The resulting males (Prdm15/+::Sox2-CRE) were then crossed again to Prdm15fl/fl females. In this generation, a quarter of the progeny is expected to be Prdm15/::Sox2-CRE. The Sox2-CRE transgene was always propagated through male animals. A similar breeding strategy, using Nestin-CRE [B6.Cg-Tg(Nes-cre)1Kln/J; JAX Laboratory] transgenics, was followed to generate Prdm15/:: Nestin-CRE mice. All mice-related procedures were approved by the local Institutional Animal Care and Use Committee (IACUC) and performed in compliance with the respective guidelines (IACUC nos. 151042 and 18/10EGDM/90).

E12.5 embryos were fixed in 4% PFA (paraformaldehyde) for 48 hours before being mounted in OCT (Optimal Cutting Temperature) embedding compounds. Then, serial coronal sections of the brains (anterior-posterior) were made using a cryostat and immediately thaw mounted on poly-l-lysinecoated histological slides for hematoxylin and eosin staining.

Prdm15fl/fl; ROSA26-CreERT2 ESCs have been described in (10). For all experiments, ESCs were cultured in the conventional [serum + Lif (Leukemia Inhibitory Factor) (SL)] medium unless otherwise stated. OHT (4-Hydroxytamoxifen) (50 nM; SIGMA-H7904) was added to the culture medium overnight (O/N) to generate Prdm15/ cells.

Embryos were isolated between E6.5 and 8.5, genotyped, then processed for whole-mount in situ hybridization as described in (37) with the following probes: Foxa2, Lhx1, T, Lefty2, Chordin, Shh, Otx2, and Six3.

Full-length human PRDM15 cDNA (NM_001040424.2) was subcloned into the PiggyBac vector (DNA2.0, PJ549). Clones encoding the various PRDM15 mutations were generated using the QuickChange II XL Site-directed Mutagenesis Kit (Agilent Technologies). The sequence of primers used can be found in table S3.

To introduce the hC844Y/mC842Y point mutation, mESCs were transfected with PX458 [pSpCas9 (BB)-2A-GFP] vector expressing a guide RNA targeting the site to be mutated, along with a single-stranded oligonucleotide containing the target point mutation, to serve as a DNA repair template. Additional eight silent mutations have been introduced to avoid editing of the template by the CAS9 protein. Single clones were sorted and expanded in 2i medium. Genomic DNA was used for screening by digestion with XMN I restriction enzyme. DNA from potential mutants was cloned into the pCR 4-TOPO TA vector following the manufacturers instructions, and 5 to 10 colonies were sequenced. Details of the strategy and the sequence of the oligonucleotides used are described in fig. S5 and table S3.

To assess protein stability, Prdm15/ ESCs expressing either wild or mutant PRDM15 were treated with cycloheximide (CHX; 150 g/ml) (Sigma, no. C-7698), and then collected at different time points (2, 4, and 6 hours) for protein extraction and analysis by Western blotting. Samples collected immediately before treatment with CHX (t = 0) served as reference. Antibodies and dilutions used were PRDM15 (in house, 1:3500) and TUBA (Alpha-TUBULIN) (Sigma T5168, 1:10,000).

To assess ESC self-renewal/differentiation, cells were stained with alkaline phosphatase staining solution (AP detection kit, Millipore, SCR 004). In brief, 500 cells per well (12-well plates) were seeded in triplicates and cultured for 5 days with daily change of medium before being stained as per the suppliers recommendations.

ESCs were seeded on gelatin-coated eight-well glass slides (Millipore, PEZGS0816), at 3 103 per well, and cultured in 2i medium. Three days later, cells were fixed in 4% PFA at room temperature, permeabilized with 0.5% Triton X-100, and then blocked using 2% bovine serum albumin (BSA) for 1 hour at room temperature before O/N staining with anti- PRDM15 (in house, 1:100) at 4C. The next day, slides were washed with phosphate-buffered saline (PBS) (three times) and stained with Alexa Fluorconjugated secondary rabbit antibody at 37C (30 min). Last, slides were washed with PBS (three times) before they were mounted with a DAPI (4,6-diamidino-2-phenylindole)containing mounting medium (VECTASHIELD, Vector Laboratory H1200).

Total RNA from cells was isolated using PureLink RNA Mini Kit (Ambion, 1283-018A) according to the manufacturers instructions. RNA was retrotranscribed into cDNA using Maxima First Strand cDNA Synthesis Kit (Thermo Scientific, K1642) and subjected to quantitative real-time PCR (qRT-PCR) on an ABI PRISM 7500 machine. qPCRs (20 l) contained 10 l of SYBR Green PCR supermix (2), 4 l of a forward and reverse primer mix (final concentration, 200 nM), and 6 l of cDNA (20 ng). Primers sequences are listed in table S4.

The detailed procedure for ChIP experiments has been described previously (38); all steps were performed at 4C and protease inhibitor was added, unless stated otherwise. In brief, 20 to 40 million ESCs were fixed in 1% formaldehyde for 10 min at room temperature before quenching with 0.125 M glycine (5 min at room temperature). Cells were then washed in PBS and harvested in lysis buffer before freezing at 20C O/N. The following day, cells were pelleted by centrifugation, resuspended in ice-cold ChIP buffer, and sonicated for six cycles (30-s ON/30-s OFF) using a BRANSON Digital Sonifier (no. S540D). Lysates were then precleared for 2 hours in Sepharose A beads (blocked in 5 mg/ml BSA) before O/N incubation with PRDM15 antibody (4C). The next day, Protein A beads were added for 4 hours before washing then de-cross-linking in 1% SDS and 0.1 M NaHCO3 (65C, O/N). Last, DNA was eluted in T-buffer (pH 8) using QIAquick PCR Purification Kit, QIAGEN. Sequences of primers used in ChIP-qPCR are listed in table S4. For the E6.5 ChIP, approximately 40 to 50 embryos per experiment were pooled together and fixed immediately after isolation.

TruSeq ChIP Sample Prep Kit (IP-202-1012) was used for DNA library preparation. Sequencing was performed in the Illumina HiSeq 2000 and NextSeq 500 at the Genome Institute Singapore. Details of the bioinformatics analysis can be found in (10). In brief, the sequenced reads were aligned to the mm9 genome assembly using bowtie version 2. Peak calling was done using MACS 2.1.1 (https://github.com/taoliu/MACS). Peaks were then annotated using the ChIPpeakAnno package in Rpromoters were defined to be 5 kb upstream and 1 kb downstream of the transcription start site. Motif discovery was done using MEME-ChIP in the MEME Suite (http://meme-suite.org).

For E6.5 embryo transcriptome analysis, RNA was extracted from 8 WT and 10 Prdm15lacZ/lacZ littermates. RNA from ESCs was collected 3 days after ethanol/OHT treatment. Library preparation was performed following the TruSeq RNA Sample preparation v2 guide (Illumina). The sequenced reads were mapped to mm9 build of the mouse genome using STAR version 2.4.2a. Differential expression analysis was performed using the DESeq2 package in R. Only genes with an average FPKM (Fragment Per Kilobase Million) >1 are considered expressed. Enriched GO terms and KEGG pathway were identified using Metascape. Genes used for GO analysis were filtered based on statistical significance (P < 0.05) and fold change (log2 fold change of 0.322) in E6.5 embryo RNA sequencing. Heatmaps of gene expressions (FPKM) were generated with in-house scripts with R.

To identify potential new candidate genes associated with HPE, we searched for genetic variants in genes/proteins acting downstream of PRDM15. Exome sequencing data from a cohort of 320 patients with HPE (132 trios and 188 singletons) were evaluated. Filter criteria are as follows: allele frequency <0.0001 in ExAC database (39) de novo (if trio available); synonymous changes were omitted; and benign changes by ACMG 2015 (40) criteria were removed. To identify protein networks and functional groups, genes with potential HPE variants were subjected to protein association network analysis using STRING database (https://string-db.org).

All experiments were repeated at least three times with similar results. Each biological repeat was done in at least two to four technical replicates/independent cell cultures, where applicable. Normal distribution was assumed for all statistical analyses. Unpaired Students t test (two sided) was applied using GraphPad Prism (version 7.0) to determine the statistical significance of the observed differences. Changes were considered statistically significant when P < 0.05.

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PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly - Science Advances

How do I get stronger on the bike? you ask. Its that time of year: your races are done and you know where you stand performance-wise. You might find yourself wondering how some girls are so strong on the bike. How some guys ride by you as if youre standing still. Theres at least one explanation: strength. They have more of it than you (at present).

By Adam Johnston

If youre wondering what you can do this winter to improve your cycling (and your running and swimming, by the way), consider adding a regular strength training program to your routine (if youre not already doing so).

The majority of adult age group athletes are not limited by their muscular endurance. Theyre fond of their long training rides. They bump up to their competitive distances (whether it be standard, half or full) as quickly as they can. The ability to perform repeated muscular contractions at low levels of force is not what limits most athletes. Rather it is their muscular strength the ability to contract their muscles forcefully and/or against heavy resistance.

When most people start they typically improve almost regardless of what training they perform. Beginner and intermediate athletes get better quite simply by accumulating miles on the bike, running and in the pool. But once the initial break-in period has come and gone the next step is to focus on muscular strength.

Reams of information are available for the endurance athlete on strength training. This article isnt intended to regurgitate the research and advice thats readily available elsewhere. Rather, its meant to get you thinking of a few strength-related concerns and to consider a few things that you might not have anticipated when it comes to strength training for the endurance athlete.

Consider the following 10 strength training tips:

Be smart, be consistent, and get stronger for 2020.

Adam Johnston is the owner of WattsUp Cycling in Toronto. WattsUp Cycling offers an endurance athlete-specific strength training program on site. Visit http://www.wattsupcycling.ca to find out more.

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10 Ways to Get Stronger on the Bike - Triathlon Magazine Canada

Its well known that most industries are still overwhelmingly dominated by men. For instance, Wall Street, tech, construction, and engineering are only a few of the industries in which women are underrepresented, holding only 9 percent and 6 percent of the senior roles in venture capital and private equity. However, no one needs those statistics to confirm what we already know: There are specific fields in which women havent yet broken the infamous glass ceiling.

The most significant mistake analysts tend to make when discussing male-dominated industries is that they focus on the inequality itself. However, it can be far more fruitful to consider the advantages women bring to the table, both for themselves and for the industries involved.

The outcome of equal female representation in the workforce was summarized quite succinctly by management consulting giant McKinsey in 2018. They found that even though women make up around half of the worlds working-age population, they tend to be underrepresented, especially in the top roles of the workforce. Yet McKinsey estimates that women working at their full potential can add up to $28 trillion in additional global GDP by 2025. On a more micro level, an MIT study on workplace diversity has shown that splitting offices along gender lines drastically boosts productivity.

That gender diversity offers a workplace many benefits has been well covered, but what about the inclusion of women in a companys ranks boosts productivity and propels the business forward?

While there is abundant evidence showing women to be excellent communicators, multitaskers, and critical thinkers, psychological evidence also shows that men and women think slightly differently. Sometimes referred to as the battle of the hormones, there exists a phenomenon in which women and men bring different perspectives to the table due to their different genetic makeup and inherently opposing strengths and weaknesses. In other words, they complement each other in the workplace, joining forces to tackle obstacles neither gender would be able to face alone.

As the CEO of a tech company in the logistics industry, one of the most masculine industries imaginable, I have personally witnessed the wonders women can offer a world traditionally shaped by the minds of men. For example, I have observed how womens creativity improves specific processes inside companies thanks to their innovation, and how women who come from very little strive to achieve greatness, not just for themselves but for their companies, taking nothing for granted. And thats precisely it -- because women are aware that, despite the tremendous progress made in the fight against inequality, they are still afforded less professional opportunities than men, they know they have to work just a little harder. Armed with the mentality of fighting for every inch of progress, its hard to fail.

I also noticed this schism during my time in the Israeli Defense Forces, where I was rewarded for my hard work by perhaps the least likely of fans. Between 1999 and 2001, I served as an instructor of an infantry artillery unit, and afterward as an officer. Yes, the Israeli army has a reputation for gender diversity (as of 2011, 88-92 percent of all roles in the IDF were open to women), but military culture has been shaped by masculinity for thousands of years before any position was open to women, in any military. Also, some units are less used to having a woman around than others.

Units that absorb religious soldiers, for example, are bastions of gender bias because both religion and army culture have historically been patriarchal. And yet, even in these environments, there isnt a gap that cant be closed with a demonstration of knowledge and leadership.

During my time as an artillery training instructor, I trained a group of Yeshiva students -- deeply religious Jewish men who study Torah part-time while serving in the army. In other words, my trainees were accustomed to strict religious rules regulating the interactions between men and women. Every time I entered the infantry fighting vehicle (IFV) to train them, the soldiers backed up out of shock. It wasnt out of malice; its just that the religious rules they live by dont allow them even to touch a woman that is not their wife. Suddenly, they were expected to be trained by a woman soldier within the confined space of an IFV (for those not as familiar, they are quite small).

However, the initial feeling of confusion quickly transformed into mutual respect between the religious soldiers and me. By the end of the month-and-a-half training program, we had grown so close that they gave me a customized helmet and dog tag, with my name engraved on each. They so appreciated my professional contribution to our training sessions together that it changed their view on serving alongside a woman. It probably opened their minds in general.

Psychology is a useful tool and one that shouldnt be limited to individuals in need of guidance. The different perspectives diversity can offer industries such as cryptocurrency, blockchain, finance, and logistics, should be embraced as tried and true tools for propelling those industries forward. Since psychology teaches us about the secrets behind the ways men and women think, one of its central themes is that positivity is more effective than negativity. If were going to break bulletproof glass ceilings in boys-club industries, were going to have to explain why they would benefit from a womans touch once the shattered glass settles on those polished corporate tiles.

Hagar Valiano Rips is the CEO of Ladingo, and an entrepreneur and dynamic professional with more than 14 years of executive experience in business and product development across various industries. She started her first company at the age of 23 and sold it at 25. Valiano Rips also served as a commanding officer of an infantry unit in the Israeli Defense Forces.

Link:
Why Male-Dominated Industries Could Use a Woman's Touch: A Perspective from a Current CEO and Former Soldier - TechDay News

Every holiday, and on Black Friday and Cyber Monday and Random Discount Wednesday and Oh God Buy Stuff The High Street Is Dying Thursday, a load of miserable Opinions-For-Hire types churn out diatribes about why you absolutely should not buy anyone, including yourself, a DNA test in the sales or otherwise. And I'm here to tell you why they're wrong.

Before we get to why DNA tests are officially a good thing, let's run through some of the downsides those op-eds always bring up.

Yes, some people have found unexpected skeletons in their cupboards and sparked giant, multigenerational family arguments. But that's very rare most of us, for better or worse, don't have family histories that'd make a good daytime soap. And even if it does happen, wouldn't you rather know the truth? Where you really come from, and why you were lied to about it? It could have enormous impacts on your life choices.

Another concern is data security. Doom-mongers envisage a future where your genetic information is sold to health insurance companies, who jack up your premium as a result but that's much more of a concern for countries like the US than the UK, which still (at the time of writing, at least!) has a National Health Service. The NHS itself is on board with genetic testing, getting ready to offer a service of its own in return for contributing your anonymised data to lifesaving research.

Image: Nosha via Flickr CC

It's worth noting, too, that not all DNA testing is created equal. Some services are more geared towards looking at your ancestry and ethnicity information, while others only give surface-level results like "may be slightly more likely to have [X]", in which X can be anything from Alzheimer's to asparagus-scented wee. So depending on which service you've gone for, the information might be all but useless unless someone's trying to prove you ticked the wrong box on the ethnicity form when you applied for your job.

OK, so maybe not insurance companies, but what about your test results getting into other bad actors' hands? Well, yes, every damn company holding sensitive data has security issues, it seems the NHS very much included. However, I'm not overly worried that someone's going to download my info, insert it into some kind of biological 3D printer and start creating counterfeit versions of me. Even if that were possible, they'd needwaymore information than they'd get from a home DNA test.

The idea that your DNA test results constitute the source code for everything you are is a misconception. For starters, the tests only look at a tiny fraction of the human genome, but even if they didn't that's not how genes work. Yes, some problems and tendencies are genetic, but many are only influenced by your genes (often more than one), and some have absolutely sod-all to do with DNA whatsoever, being entirely caused by environmental factors. When you get the flu, does your DNA suddenly say "this person has the flu"? No. Is there a gay gene? No. Nobody's going to post your base pairs on Pastebin and recompile you.

As someone who's done many of these tests, I don't feel that my DNA is some kind of proprietary code I need to defend; in fact I'd open-source it if it meant we could work together on debugging some of the shit bits. Heck, maybe we can even fork me into a better person.

DNA data getting into evildoers' hands is one of those possibilities that sounds awful in theory, and it might well be awful in a few years when the whole system is more refined, but right now it would amount to "the terrorists have found out that you... HAVE A MODERATE CHANCE OF BEING BLUE EYED!" Not such a great Bond movie, is it?

You might also have seen some outcry when a popular DNA site was acquired for the purposes of solving crime, but assuming you and yours aren't massive criminals, that's probably not a huge worry either. In fact, DNA testing of relatives and descendants of suspects has solved a surprising number of cold cases in the US alone in the last few years, as well as identifying quite a few nameless bodies. Surely we can all agree that's a good thing.

While most of the worries about DNA testing are premature or arguable at this point, there are benefits that are real and tangible.

In my case, since my father is dead and I have no contact with my mother, a lot of the information I've found through DNA testing just wasn't available to me in other ways. There are plenty of people in similar situations folks who don't know who their birth parents were, have no contact with them, or aren't able to talk to them about matters of health and ancestry for one reason or another, for instance. DNA testing gives us a way to make family connections, in both the data and the relationship sense.

Last month, someone I share DNA with added me on Facebook. For some people, that might be strange and unnerving (in which case I'd say don't make your name public on your DNA profile I did because I wanted to find relatives), but for me it was wonderful. Being estranged from part of my immediate family means these connections mean more to me, and it's fascinating to look at the surnames, traits and lives of people all over the world who share my DNA segments.

For instance, until I had my DNA tested and analysed, I had zero idea about my considerable Jewish heritage. That led to a lot of genealogical research, ultimately helping me trace my family tree back to the 1700s. Now, when a new DNA relative contacts me (and they do, often it's like having email penpals), we can frequently figure out where our family trees connect, and fill each other in on cool details about our ancestors.

The health information can be life-changing too. In my case, I carry two genetic diseases that would make having a biological child pretty unwise. I already knew this from trying to donate my eggs a few years prior to the first test, and I don't want kids anyway, so it wasn't a nasty surprise but if I'd been planning babies, it would have been invaluable information. From this viewpoint, it seems almost crazy that most people go ahead and mix their genes with no idea what they might contain.

Of course, someone else with my results might have been devastated, but I would still argue it's better to know what you're facing. The same goes for the more serious heritable conditions that DNA tests can show. Yes, it's scary to think you might have a higher chance of getting a particular type of cancer, but it's not a certainty, and it might help you make those lifestyle changes you swear to every January. Or at least start living like you're not immortal, because newsflash: you're not.

In any case, the limited information you can get from home testing services can only give you clues, not the full picture, and some services are more accurate than others. As I mentioned, there's a lot besides raw DNA that makes a difference to how you turn out (see the whole field of epigenetics, for instance). Over time, we'll likely get more sophisticated information, which might one day mean we can start patching ourselves or at least developing medicines and treatments that interact with our unique makeup. But that's a long way off yet.

For now, there's a lot of valuable and fascinating data to be gleaned from testing your DNA, and a relatively low chance you'll ruin the next family reunion. Only you can decide what makes the most sense for you, and no test or article can tell you that.

Main image: Andy Leppard via Flickr CC

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Home DNA Tests Are Not the Devil - Gizmodo UK

More uniform response in Cohort 3 with two confirmed responders and one potential responder

New female responder in Cohort 2 for a total of three confirmed female responders across all cohorts

Up to six responders across all nine patients dosed in study

Prophylactic steroid cohort to begin in first half 2020; data expected in second half 2020

Ultragenyx to host conference call today at4:30 p.m. Eastern Time

NOVATO, Calif., Jan. 09, 2020 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, today announced topline positive safety and efficacy data from Cohort 3 and longer-term data from Cohort 2 of the ongoing Phase 1/2 study of DTX301, an investigational adeno-associated virus (AAV) gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency. In Cohort 3 (n=3), there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status. In Cohort 2, one female patient has newly demonstrated a response starting at Week 52 which was confirmed at Week 78. The two previously disclosed responders in Cohort 1 and Cohort 2 also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

Cohort 3 Efficacy Summary (as of December 9, 2019 cutoff date): One complete responder, one responder, and one potential responder

Patient 7 (complete responder, female): Patient 7 demonstrated a clinically meaningful 79 percent change in rate of ureagenesis, from a low of 24 percent of normal at baseline to the 51 to 64 percent range, and staying at 44 percent of normal at Week 52. During this period, she reported feeling significantly better and discontinued her alternate pathway medications and liberalized her protein-restricted diet. She has remained clinically and metabolically stable without a rise in ammonia.

Patient 8 (responder, female): Patient 8 demonstrated a significant and consistent 90 percent reduction in ammonia levels, time-normalized over a 24 hour period, from a high of 184 umol/L at baseline to 19 umol/L at Week 24, which is within the normal range. Potentially aberrant high baseline ureagenesis values inconsistent with her known more severe clinical status make her ureagenesis results uninterpretable. This patient was on a tapering course of steroids at the time of last assessment and has not yet discontinued alternate pathway medications or liberalized her diet. The investigator reported that her family says her health is the best it has ever been.

Patient 9 (potential responder, male):Patient 9 showed a 123 percent increase in rate of ureagenesis, from 25 percent of normal at baseline to 56 percent of normal at Week 12 while still on a steroid taper. Steroids have been shown to suppress rate of ureagenesis in other study patients. This patient has not yet discontinued alternate pathway medications or liberalized his diet. His ammonia levels have remained in the normal range and response status will be confirmed after additional follow-up.

Cohort 2 Efficacy Summary: Two responders including new responder and previously-disclosed male complete responder

Patient 6 (new responder, female):Patient 6 has now shown a 218 percent improvement in rate of ureagenesis, from 20 percent of normal at baseline to 61 percent at Week 52 and maintained at 64 percent at Week 78. In addition, she has shown a significant 74 percent reduction in ammonia levels from 156 umol/L at baseline to 40 umol/L at Week 78. She has started to taper her alternate pathway medications and liberalize her diet. With this new responder, there are two confirmed responders in cohort 2 out of three total patients.

Story continues

Safety SummaryAs of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All adverse events have been Grade 1 or 2. All three patients in Cohort 3 had mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy. All three patients have been responding to reactive tapering courses of steroids, and all patients remain clinically stable.

Initiating Prophylactic Steroid Cohort As previously disclosed, a fourth cohort will enroll three patients at the 1.0 10^13 GC/kg dose, using prophylactic steroids. Patients will receive an 8-week tapering regimen of prophylactic steroids, starting at least 5 days prior to dosing with DTX301 at a starting steroid dose of 60 mg/day. The first patient is expected to be enrolled in the first half of 2020, and data from the prophylactic steroid cohort are expected in the second half of 2020.

Potential Phase 3 Study DesignUltragenyx is continuing discussions with the U.S. Food and Drug Administration (FDA) regarding the potential Phase 3 study design. Ammonia is expected to be a primary endpoint based on direct FDA feedback to date, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications.

Conference Call and Webcast InformationUltragenyx will host a conference call today, Thursday, January 9, 2020, at 4:30 p.m. ET/ 1:30 p.m. PT during which Emil D. Kakkis, M.D., Ph.D., the company's Chief Executive Officer and President, will discuss the new data from the ongoing DTX301 Phase 1/2 Study. The live and replayed webcast of the call and slides will be available through the companys website at http://ir.ultragenyx.com/events.cfm. To participate in the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 5583103. The replay of the call will be available for one year.

About the OTC Phase 1/2 Study (DTX301)The Phase 1/2 study evaluates the change in the rate of ureagenesis, ammonia levels, neurocognitive assessment, biomarkers, and safety of DTX301 in patients with OTC deficiency. Three patients have been dosed in each of three dose cohorts of 2.0 10^12 GC/kg (Cohort 1), 6.0 10^12 GC/kg (Cohort 2), and 1.0 10^13 GC/kg (Cohort 3). Patients in the first three cohorts received steroids to reactively manage ALT elevations. In the fourth cohort, three patients will receive a 1.0 10^13 GC/kg dose and will all receive a prophylactic tapering course of steroids.

About OTC DeficiencyOTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 patients are affected by OTC deficiency worldwide, of which approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

About DTX301DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug Designation in both the United States and Europe.

About Ultragenyx Pharmaceutical Inc.Ultragenyx is a biopharmaceutical company committed to bringing to patients novel products for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyxs strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the Company's website atwww.ultragenyx.com.

Ultragenyx Forward-Looking Statements Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations regarding the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical drug development process, including the potential for substantial delays and the risk that earlier study results may not be predictive of future study results, the lack of predictability in the regulatory approval process, the timing of regulatory filings and approvals (including whether such approvals can be obtained), and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations and the availability or commercial potential of our products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 6, 2019, and its subsequent periodic reports filed with the Securities and Exchange Commission.

Contact Ultragenyx Pharmaceutical Inc.Investors & MediaDanielle Keatley415-475-6876

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Ultragenyx Announces Positive Topline Cohort 3 Results and Improved Longer-Term Cohort 2 Results from Phase 1/2 Study of DTX301 Gene Therapy in...

Cara Gormallys pregnancy was shadowed by grief. As a queer woman wanting to have a baby, the biology professor had figured finding a sperm donor would be the only obstacle she and her partner faced. But thanks to Gormallys organizational skills and love of making lists, the couple landed on a donor with relative ease.

Then, Gormally struggled to conceive. Each month brought fresh disappointment and loss.

So much of the process depended on random, heart-breaking chance, she says. The emotional and financial roller coaster was exhausting.

But it wasnt the hardest part. The couple had accepted that, as much as they wanted a baby, their child wouldnt be biologically related to Gormallys spouse.

I grieved that our child wouldnt be genetically related to both of us, Gormally says. I longed for the biologically impossible.

But now, a new set of technologies have the potential to change whats possible allowing same-sex partners to have kids who share their genetic material, just like straight couples.

In mammals, pretty much every cell in the body carries two sets of genetic material. One set comes from mom and the other from dad. Eggs and sperm are the only exceptions; they have just one set. Then, when a sperm fertilizes an egg, those two sets combine, restoring the usual number to two sets per cell.

Gormally and other same-sex partners are currently barred from their dreams by a phenomenon called genomic imprinting. It uses a distinct tag from each parent to mark the DNA that mammals pass on to their offspring. The process ensures that, for a small percentage of genes, we only express the copy of genetic material provided by our mother or our father. When this imprinting process goes awry, kids can end up with inactive gene regions that cause miscarriages, developmental defects and cancer.

(Credit: Jay Smith/Discover)

During this genomic imprinting, moms distinct collection of tags typically turns off certain genes, so that just dads copy is expressed. And dad imparts his own marks that leave only the maternal copy on. (Most imprints silence gene expression, but some activate it.) Thats a problem for same-sex couples who want to have a baby. If both sets of an offsprings genes come from maternal DNA, for example, then both copies of imprinted genes will be off. So, the embryo cant make any of the genes products.

We dont get the full set of [gene] products that we need to undergo proper development unless we have both a maternal and paternal contribution to a fertilized egg, says Marisa Bartolomei, a geneticist at the University of Pennsylvania in Philadelphia, who discovered one of the first imprinted genes in mice.

Scientists discovered genomic imprinting in mammals about 30 years ago. During experiments in the mid-1980s, researchers removed either the maternal or paternal genetic contributions from newly fertilized mouse eggs. Then, they transferred in a second set of genes from another mouse to create embryos with either two sets of female genetic material or two sets of male genetic material. A surrogate mouse was able to gestate the embryos, but none survived. The finding showed normal development requires genetic material from both a father and the mother. More than that, the outcomes revealed that maternal and paternal genetic material differ from each other in meaningful ways.

Later experiments revealed mice developed differently depending on whether they happened to receive both copies of certain regions of DNA from one parent (rather than one copy from each parent).

Mice with hairpin-shaped tails were telling examples. When researchers deleted the gene region responsible for a hairpin tail from a mothers genome, mice embryos grew large and died partway through gestation. In contrast, deleting the same region from the paternal genome had no effect on the rodents growth or development.

In the three decades since, researchers have found more imprinted genes (they suspect there are between 100 and 200 such genes) and the molecular tags that silence them. Scientists have also taken strides connecting imprinting defects to developmental disorders in humans. But all along, researchers have known that imprinting prevents same-sex parents from having children.

In October 2018, researchers overcame this impossibility in mice. By deleting imprinted regions, Wei Li and a team at the Chinese Academy of Sciences in Beijing produced healthy mice from two moms. The researchers also created mouse pups from two dads for the first time. However, the offspring died just a few days after birth.

Despite the loss, Li is optimistic. This research shows us what is possible, he says.

To overcome the imprinting barrier, Li and his fellow researchers turned to CRISPR, a gene-editing technique thats made altering genomes easier than ever. They used the tool to delete gene regions from embryonic stem cells from mice mothers. The researchers then injected these modified stem cells into the egg of a female mouse and then used a third surrogate female mouse to carry the fetus to term.

The team had already seen some success two years earlier when they created mouse pups with two genetic mothers by deleting two imprinted regions. Although these bimaternal mice also grew to adulthood and produced pups of their own, they developed growth defects. On average, the bimaternal mice were 20 percent lighter than their hetero-parental counterparts. In their latest study, Li and his team also deleted a third region from the mothers genes, which restored the animals growth to normal.

But the scientists had to clear a few more hurdles to generate mice with two genetic fathers. They found, through a process of trial and error, that they needed to remove twice as many imprinted regions in the bipaternal mice as the bimaternal mice. In total, the team deleted seven imprinted regions to successfully create mice from two dads.

Still, the numbers were not in their favor. Only two and a half percent of embryos made it to term and less than half of one percent lived for two days. None made it to adulthood.

The produced bipaternal mice are not viable, which implies more obstacles are needed to cross to support their postnatal survival, if possible, Li says. The lower birth rate, on the other hand, implies the existence of an unknown barrier hindering the development of bipaternal embryos.

In contrast, the bimaternal mice fared much better. These mice grew to adulthood and were healthy enough to have pups of their own by mating with typical male mice. They also behaved the same as the control mice. As far as the researchers could tell, the bimaternal mice appear as healthy and normal as any other laboratory mice.

It does not mean that they are normal in every aspect, Li cautions. One cannot investigate all the aspects under restricted experimental conditions with a limited number of animals.

Despite the researchers success, Li says the technique is not ready for use in humans. It is never too much to emphasize the risks and the importance of safety before any human experiment, he says, particularly in regard to the bipaternal offspring, which currently are severely abnormal and cannot survive to adulthood.

The bimaternal offspring hold more promise. The team is now working to translate their findings to monkeys. And that work could bring the impossible one step closer to feasible for humans.

Lis research is encouraging but its a long way from helping Gormally and her spouse. However, its also not the only shot for same-sex couples. Another new technology called in vitro gametogenesis, or IVG, may be an alternative potential path for same-sex couples to have their own kids.

Scientists use the technique to make eggs and sperm from other cells in the body. To do so, biologists first reprogram adult skin cells to become stem cells. Then, they stimulate the skin-derived stem cells to develop into eggs or sperm.

Researchers from Japan have now perfected the technique in mice. And in groundbreaking work, Katsuhiko Hayashi and Mitinori Saitou and their team generated functional eggs from mice tail cells.

The researchers then fertilized the eggs with sperm from male mice and implanted the embryos into surrogate mothers. The offspring grew up healthy and fertile. In principle, this approach could allow a womans skin cells to be engineered into sperm and used to fertilize her partners egg.

IVG could transform same-sex couples ability to have their own children. If it had been possible at the time, we definitely wouldve have tried to do it, says Gormally, who is now a proud parent to a toddler thanks to her and her spouses sperm donor. [Its] a total game-changer.

This story is part of "The Future of Fertility" a new series on Discover exploring the frontiers of reproduction.

Read more:

Can Humans Have Babies in Space?

George Church Wants to Make Genetic Matchmaking a Reality

Human Gene Editing is Controversial. Shoukhrat Mitalipov Isn't Deterred

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The Slow March Toward the First Same-Sex Couple to Have a Baby - Discover Magazine

Researchers say theyve discovered six genetic variants associated with the development of anxiety disorders in what they call the largest study of anxiety traits to date.

In a study published Tuesday in the American Journal of Psychiatry, researchers examined genetic and health data from 200,000 U.S. veterans. The data was compiled by a research program, the Million Veteran Program, funded by the government to determine how genes, lifestyle and military exposures affect health and illness.

While there have been many studies on the genetic basis of depression, far fewer have looked for variants linked to anxiety, disorders of which afflict as many as 1 in 10 Americans, Murray Stein, a staff psychiatrist in the VA San Diego Healthcare System, said in a statement.

In the analysis, researchers discovered six genetic variants associated with higher risks of developing anxiety disorders. The variants related to anxiety disorders were found on chromosomes 1,3,6,7 and 20. The studys authors called it an important step forward in understanding how genes contribute to mental conditions.

The variant on chromosome 7 is identified to be correlated with higher occurrences of bipolar disorder and schizophrenia.

Its also associated with the reception of estrogen, but researchers were reluctant to draw the conclusion on if this could explain perhaps why women are twice as likely than men to be affected by anxiety disorders. Thats because while women veterans were included in the study, more than 90 percent of the participants were male. The studys authors say more research is needed on the issue.

The study also found five of the genetic variants were found in white Americans, while an additional variant was found in African Americans.

Minorities are underrepresented in genetic studies, and the diversity of the Million Veteran Program was essential for this part of the project, Dan Levey, of the VA Connecticut Healthcare Center and Yale University said in a statement.

The genetic variant we identified occurs only in individuals of African ancestry, and would have been completely missed in less diverse cohorts.

According to the Anxiety and Depression Association of America, nearly 40 million people in the U.S. experience an anxiety disorder in any given year.

See more here:
Scientists discover six genetic links to anxiety - The Hill

A new collaborative research study of over 200,000 military veterans has discovered six genetic variants that are linked to anxiety.According to statistics from the Anxiety and Depression Association of America, anxiety disorders are the most common mental illnesses in the U.S., affecting a staggering 18.1% of the population each year.

Suffering from an anxiety disorder can have major adverse effects on an individual's quality of life; it may prevent them from being able to socialize, to work, or to engage in relationships, for example. Individuals with an anxiety disorder are three to five times more likely to go to the doctor, and six times more likely to be hospitalized when compared to those who do not suffer from an anxiety disorder.

Anxiety disorders like all psychiatric conditions are complex in their pathophysiology. We don't know exactly what causes them, and therefore, our knowledge on how to treat them is somewhat incomplete. A variety of pharmacological and non-pharmacological treatment options are available; however, they are often limited in success and may only benefit certain individuals.

An increasing amount of research is focusing on the contribution of genetics to the development of mental health conditions. Murray Stein, San Diego VA staff psychiatrist and Distinguished Professor of Psychiatry and of family medicine and public health at UCSD points out "While there have been many studies on the genetic basis of depression, far fewer have looked for variants linked to anxiety, disorders of which afflict as many as one in ten Americans."

Stein is the senior author of a new study, published in the American Journal of Psychiatry, that explores the contribution of certain genetic variants to the development of anxiety disorders.

The research, a genome wide association study (GWAS), analyzed the genomes of approximately 200,000 military veterans from the Million Veteran Program (MVP). From the data, they discovered six genetic variants linked to anxiety. Five were identified in European Americans and one was identified in African Americans.

A selection of these variants has also been previously linked to other conditions such as bipolar disorder, schizophrenia and posttraumatic stress disorder.

"This is the richest set of results for the genetic basis of anxiety to date," said co-lead author Joel Gelernter, the Foundations Fund Professor of Psychiatry, professor of genetics and of neuroscience at Yale. "There has been no explanation for the comorbidity of anxiety and depression and other mental health disorders, but here we have found specific, shared genetic risks."

The MVP offers the opportunity to study a large data set that would otherwise be difficult to gather and collate. Thus far, several studies have utilized the MVP data to make interesting discoveries relating to genetics and psychiatric disorders. Gelernter says, "This is a rich vein we have just begun to tap."

Also of note is the fact that some of the genetic variants identified were linked to genes that regulate hormonal activity, specifically in relation to the sex hormone estrogen. As more females are affected by an anxiety disorder than males, this is an intriguing finding. However, the scientists emphasize that the research sample from the MVP largely consists of men, which could be considered a study limitation.

Nonetheless, the research serves as a contributor to the pool of research expanding our knowledge of the molecular underpinnings of psychiatric disorders.

"One of the goals of this research is to find important risk genes that are associated with risk for many psychiatric and behavioral traits for which we don't have a good explanation," Yale's Daniel Levey, a postdoctoral associate and co-lead author of the study, concludes.

Reference: Leveyet al. (2020). Reproducible Genetic Risk Loci for Anxiety: Results from ~200,000 Million Veteran Program Participants. The American Journal of Psychiatry. DOI:https://doi.org/10.1101/540245.

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Richest Set of Results to Date Pinpoint Six Genes That Are Linked to Anxiety Disorders - Technology Networks

Are humans basically good kind, generous and peaceful? Or are we essentially evil cruel, selfish and aggressive? Evolutionary science is uncovering the answer, and it provides important guidance about how we can best live together.

But it should not be oversimplified.

In a recent column on evolution (Could our real advantage be survival of the friendliest? Nov. 28), Cass Sunstein discussed the human self-domestication theory. Summarizing a recent article by Duke anthropologist Brian Hare and a book by Hares former teacher, Harvards Richard Wrangham, Sunstein presents their findings that we homo sapiens are a domesticated version of earlier, more aggressive, human species, just as dogs are a docile version of wolves.

Like dogs, we evolved to have lower levels of reactive aggression toward those around us, which enabled the cooperation and communication that have propelled our species to world domination.

Sunsteins column was a feel-good piece about how we are hard-wired to get along with each other. Thats great and ought to be celebrated.

The story of human domestication is much more interesting than Sunstein let on, however, and it has troublesome implications.

Hares and Wranghams answer to the age-old puzzle about human nature is that we have separate neurological pathways for good and evil, and they come to the fore in different contexts and for different reasons. Hitler was kind to his secretary and inconsolable at the death of his dog.

Hare shows that whether people are helpful or hurtful to others depends on how similar the others in question seem to themselves. Instinctive antagonism toward outsiders co-evolved through the same biological mechanisms that molded group solidarity. Think of parents, who are the soul of gentleness with their own children, but would readily kill to protect them.

Thus, armed conflict with neighbors usually sneaky night raids and ambushes is a feature of nearly every human society ever studied. And recent brain imaging studies confirm that we literally think differently about infractions committed by members of our group than about those committed by an out-group.

Wranghams book isnt called Human Goodness but The Goodness Paradox. The paradox is that domestication has a dark side it evolved through lethal violence against bullies, nonconformists and outsiders. Once language developed, coalitions of subordinate males could plot to oust the aggressive alpha males of the kind that dominate groups of apes. And once male coalitions discovered their overwhelming power, they could employ it against all kinds of troublemakers.

Some 12,000 generations of capital punishment that is, homicide systematically culled from the gene pool the tendencies to domineer or deviate.

Indeed, in nomadic hunter-gatherer societies people have been killed by male coalitions for a wide range of social transgressions things as seemingly trivial as a woman treading on the mens secret path. The moral sense itself could be considered the instinct to look over our shoulders we survivors of this culling process have a healthy vigilance about who might be watching. Simply putting up a picture of human eyes has been shown to deter bicycle theft and littering.

Sunstein briefly acknowledges that while domestication reduced reactive aggression, it did not affect our unique capacity for proactive aggression. But he implies that sort of behavior consists only of aggression that involves a lot of advance planning. In fact, it is the threat of aggression by groups of males that underlies all the coercive, hierarchical institutions of human history.

Thus, the truth is far from Sunsteins rosy picture: We evolved to be nervous conformists who get together to murder troublemakers and outsiders.

Heres the important thing. Genes dont determine behavior, they create tendencies that can be countermanded by culture and choice. Recognizing our dark tendencies, there are things we can do to curb and control them.

To start with, the self-domestication theory provides a lens through which to see more clearly our nations important challenges.

Take immigration. We must recognize that our views on immigrants are not entirely rational but are subtly influenced by a genetically based hostility toward outsiders.

Or consider the intolerance toward unpopular speakers that is infecting college campuses. We need to be alert that our instinctive, nervous herd mentality may be operating there.

And anyone who listened to any of the congressional deliberations on impeachment has to have seen that the adversaries were literally thinking with different parts of their brains.

Be aware that nationalism is a mixed bag. It brings out our best instincts for loyalty and service, but it will always stimulate a genetic threat to international peace.

The thought experiment for how group solidarity is forged in response to an adversary is to imagine what would happen if hostile alien spaceships appeared over major cities. Those sneaky Russians and monolithic Chinese would quickly start to feel like our kin. Climate change is another kind of worldwide threat which, depending on how we address it, could forge bonds across boundaries or could lead to the mind-set of every man for himself.

As for our nations history of persecuting nonconformists and reformers, we need to take to heart the language of a case that new law students study, Papachristou v. City of Jacksonville.

Back in 1972, Jacksonville had a vagrancy ordinance so broad that it allowed the police to sweep up just about anyone they considered undesirable. Supreme Court Justice William Douglas, a bit of a nonconformist himself, would have none of it. He wrote that the choices to be a nightwalker or a loafer are unwritten amenities of American life that have dignified the right of dissent and have honored the right to be nonconformists and the right to defy submissiveness. They have encouraged lives of high spirits, rather than hushed, suffocating silence.

Dare I offer the best vision for the future for a domesticated species? It would be a time when we are all citizens of the world with robust protections for individuality and nonconformity.

Evolution built us. All in the service of promoting the most base reproductive success, it engineered beings capable of great love and loyalty, works of beautiful creativity and worldwide collaboration, and awe and wonder at the mysteries of the universe. But it also endowed us with the pain of guilt and shame, anxiety about our reputations, insatiable acquisitiveness and the potential for intolerance and cruelty.

Still, the story can be more empowering than discouraging. Knowledge is power. We are finally at the point in history where we can start to see our own evolution. And seeing it, we can refuse to be its slaves and start being its master.

Bruce Peterson is a senior district court judge who teaches a course on Lawyers as Peacemakers at the University of Minnesota Law School.

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OPINION EXCHANGE | We mustn't be naive about evolution - Minneapolis Star Tribune

Childhood exposure to the air pollutant nitrogen dioxide (NO2) is associated with an increased risk of developing schizophrenia, according to the findings of a recent study which appeared in JAMA Network Open.

This population-based cohort study comprised of 23,355 individuals (51.3% male) with schizophrenia and a randomly selected sub-cohort.Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia (the primary endpoint), emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019 using adjusted hazard ratios (AHRs) for schizophrenia with 95% Cis according to NO2 exposure. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file.

According to the results of the study, during the period of the study, 3,531 subjects were diagnosed with schizophrenia. The researchers observed that higher polygenic risk scores were linked with higher childhood NO2 exposure (=0.0782; 95% CI, 0.065 to 0.091; P <.001). Moreover, they found that a 10-g/m3increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15 to 1.32) along with a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23 to 1.35) were both independently correlated with an augmented risk of developing schizophrenia.

Potential biological mechanisms for the association between air pollution and schizophrenia remain uncertain, but air pollutants have been purported to cause inflammation of the tissue of the nervous system, oxidative stress, microglial activation, protein aggregation, subclinical cerebrovascular disease, and disruption of the blood-brain barrier, the study authors wrote.

With the complex clinical features of schizophrenia, it is likely that genetic variation may play a role in determining an individuals susceptibility to the damaging effects of air pollution. However, our findings suggest that a polygenic risk score based on common variants related to schizophrenia cannot account for the association between childhood NO2 exposure and schizophrenia.

They added that these results demonstrate the utility of including polygenic risk scores in epidemiologic studies.

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Childhood Exposure to Air Pollution Linked to Increased Risk of Schizophrenia - DocWire News

Its not King Herod decreeing that male children should be killed, but it certainly is eyebrow-raising: Chinas ever-growing, totalitarian surveillance state is now requiring blood samples from boys in provinces across the nation.

This is according to Bitter Winter (BW), a magazine on religious liberty and human rights in China. BW reports that one explanation given to concerned parents of schoolboys was that the program was designed to prevent children from being lost or abducted. Of course, though, since girls can be abducted, too, this excuse only further raises suspicions.

Providing background, BW wrote yesterday that since the beginning of 2016, the government ofXinjiangUyghurAutonomous Regionhas been collecting DNA samples fromUyghursand other Muslims to build databases fortracking and monitoring them. As this measure in the name of maintaining social stabilityspreads across mainland China, theCCP [Chinese Communist Party]is collecting biometric data on an ever-increasing scale. All males, including young children, are now mandated to give blood samples.

BW continues:

Residents of Guigang, Guilin, Hechi, and Cenxi cities in southern Chinas Guangxi Zhuang Autonomous Region reported toBitter Winterthat local police uniformly collected blood samples from primary and middle school boys in November. This has been done without informing their guardians.

Isnt it the doctors duty to take blood? Why did the police do it? a parent of a primary school student asked. Blood samples have been taken from students in many schools, as part of the governments massive operation. No notice or written communication has been issued to parents. We felt very unsafe.

When parents demanded to know the reasons for the collection of blood samples from their children, the schools explained that it was needed to prevent children from being lost or abducted and sold.

If it is to prevent children from being lost or abducted, why have samples been taken only from boys and not girls? Because girls wont be lost? Its really strange!

Reporting on the program in October, shortly after a government announcement relating to it was made, the Epoch Times wrote that China is building a massiveDNAdatabase on its citizens.

The announcement stated that the effort is part of the public securitys basic information work to improve the precision and controllability of population management, and the samples would be collected either by group or door-to-door, the Times related.

The program is just one of the most recent compulsory DNA collection initiatives, which critics of Chinese authorities say are a gross violation of privacy and serve to further the regimes plan to control the genetic makeup of its population, the Times continued.

The Times also informs that the goal of the male-oriented program is to develop a comprehensive Y-STR database. Y-STR stands for Y-chromosome short tandem repeat analysis, which relates to DNA information passed down along the male descendants of families, the Times tells us.

Bitter Winter reports on the most plausible explanation for the current program, quoting a teacher from Guilin. The collection of blood samples is demanded in a government-issued document, which proclaims that they will be used by law enforcement to find criminals, related BW. No matter where they escape, the police can locate them.

Since boys and men are not only more likely to commit violent crimes but, note, are also more likely to be the revolutionaries opposing state tyranny the current focus on a Y-STR database may make sense.

On an even darker note, BW writes that because schools were secretive and couldnt provide adequate explanation for the blood-collection program, some parents worried thatDNA samples will be used for organ harvesting.

(Note: It could occur to a person that since Chinas recently scrapped one-child policy led to a sex imbalance in which males notably outnumber females, the Beijing government may view boys as more expendable. Just a wild thought.)

This said, the latest initiative is apparently just part of a wider effort to collect DNA on Chinas entire population. The purposes, though, would still largely be nefarious.

Bitter Winter writes that one motivation is to facilitate religious persecution. For example, In July, the police harassed the parents of a member ofThe Church of Almighty Godwho has been on the run to escape persecution and forcibly collected their blood samples, claiming that this will help them to track down the believer, the site relates.

As to another motivation, Steven Mosher, an expert in population control [and] president of U.S.-based think tank Population Research Institute said the term population control has always had an eugenics element, the Epoch Times reports.

The regime wants to ensure quality births, Mosher told The Epoch Times, adding that one way to achieve that is by tracing who is related to whom, so authorities can eliminate those carrying recessive genes that produce birth defects.

With the advent of genetic testing, [this practice] is about to get a high-tech boost and become much more comprehensive, he said, the site further related.

Eugenics, the science of improving the human gene pool via selective breeding (and now genetic engineering), gained much credence in the early 1900s, especially in Britain and the United Sates. It was later discredited when the Nazis in Germany pursued it, killing innocents and violating human rights in the process.

The Chinese authorities are similarly disposed, using deception, threats, and even physical force to collect reluctant subjects blood. Yet this is just part of Beijings wider development of an all-encompassing surveillance state that seems to mistake George Orwells 1984 for an instruction manual. As Sarah Cook, a senior China analyst at U.S. human rights advocacy group Freedom House, put it while addressing the massive DNA collection program, the fascistic Beijing regime treats the Chinese population as nothing more than slaves, with whom you can do exactly as you please.

Yet is this surprising? China is not only the worlds most irreligious country, but atheism is its governments official position. This matters because atheism has a certain corollary: that we have no souls and then are, essentially, mere organic robots, some pounds of chemicals and water.

And, of course, what could be wrong with altering an organic robots software (social engineering) or, more to the point here, its hardware (genetic engineering)? For that matter, what could be immoral about terminating an organic robots function? Material things are there to be used, after all and discarded when no longer needed.

It really is no surprise that men who believed our rights come from God forged the United States and that a godless state proceeds as if people are objects that have no rights.

Selwyn Duke (@SelwynDuke) has written for The New American for more than a decade. He has also written for The Hill,Observer,The American Conservative, WorldNetDaily, American Thinker, and many other print and online publications. In addition, he has contributed to college textbooks published by Gale-Cengage Learning, has appeared on television, and is a frequent guest on radio.

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Bleed the Males? China Currently Demanding DNA from Boys and ONLY Boys - The New American

If it looks like a duck and quacks like a duck, then its probably...Brad Pitt.

The Once Upon A Time...In Hollywood star and genetic experiment in perfection has done the remarkable. Hes taken a hairstyle associated with 60-year-old male radio show hosts and college freshman who dont yet know how to make their own barber appointments and made it red carpet-worthy.

Frazer Harrison

The ducktail hairstyle, also known as the ducks ass, peaked in popularity in the late 1950s with the rise of the bad-boy Greaser look (Think: Elvis Presley and Sodapop from The Outsiders.) It's styled by slicking back shaggy hair on both sides of your head to create a ridge at the back, allowing the bottom edges to subtly flip out at the ends. Its almost moving into mullet territory, with a bit of Donald Trump at the edges. Joe Dirt would find the style aspirational.

Carl Iwasaki

Beautiful Brad wasnt alone in his efforts at the Golden Globes Sunday night. Famous men like Ansel Elgort, Adam Driver, and Joaquin Phoenix added to the hairsanity. We're a mere week into 2020, and several Hollywood dudes have started sporting the style, with a slight update: the new version includes less duck and more tail, creating a neck curtain of sorts. These are men of flair, drama, and panache: the curtain rises and falls even on their distinguished necks.

Daniele Venturelli

Daniele Venturelli

Steve Granitz

Michael Kovac

This is the kind of hair that makes you believe if you went home with these grown men, you might wake up on a futon. It's a style for men who think basketball shorts are formal wear, who eat from the communal nuts at a bar, rub their noses, then grabs another handful. It is, in short, the hair of men who used to fart and claim Safety immediately after. It is not at all the 'do of a movie star, which is perhaps exactly its point: We dare you to still find us attractive, Pitt and his A-list cohorts seem to be saying. Unfortunately, in spite of their best efforts, we do.

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Are Male Celebrities Trying to Ruin Their Hotness With Bad Hair? 'Cuz It's Not Working - ELLE.com

This is not a good time to be a wolverine.

The infamously scrappy, snow-adapted mustelid a relation of badgers, martens and otters is barely hanging on in the contiguous United States, where its population has dipped to mere hundreds. Decades of habitat loss and trapping reduced the wolverines numbers, and now diminishing snowpack from climate change is adding insult to injury.

And we can add one more surprising threat to the list: roads.

Yes, even though wolverines (Gulo gulo) thrive in remote, snowy wildernesses, roads can still pose a problem but perhaps not in the way you might think.

Researchers studying wolverine populations in Canada found that roads serve to diminish the animals genetic diversity, because females refuse to cross them, although young males still readily disperse and find new territories.

This has important consequences for U.S. wolverines, which may depend on Canadian travelers for their genetic health and future population growth.

Anthony (Tony) Clevenger, a scientist at Montana State Universitys Western Transportation Institute and an expert in the field of road ecology, was one of three researchers involved in the study.

We talked to him about the challenges facing wolverines and whats being done to boost their recovery.

What attracted you to the field of road ecology?

Pure chance. I was out of work, living in Europe where I did my Ph.D. on a small population of brown bears in northern Spain, and I heard Banff National Park was hiring a conservation biologist to study underpasses and overpasses for wildlife. I got the job [in 1996] and became fascinated with studying how roads affect nature around us. It opened up a new world for me.

Your recent study focused on wolverines and the Trans-Canada Highway. What prompted this? What were you hoping to learn?

The final twinning [from two to four lanes] of the Trans-Canada Highway ends at the Continental Divide. This stretch of the highway enters subalpine areas home to wolverine and lynx species that we knew very little about.

We knew in the lower 48 some 2-lane highways limited wolverine movement. Little was known about wolverines in the Canadian Rockies and much less about how a major 4-lane highway may affect movements and gene flow.So this was a unique opportunity given the number of interstate highways and expanding roads in the southern part of wolverine range.

What did you find out about how roads affect wolverines, and is it different from how roads affect other animals?

After three years of noninvasive genetic sampling within our 3,088 square-mile study area [around Banff, Kootenay and Yoho national parks], we found that the Trans-Canada Highway is not a barrier to male wolverine movement but is a strong barrier to female wolverine movement.Females are more sensitive todisturbance, particularly human activity.

This is important since females need to cross the highway, survive and breed for there to be functional connectivity.

This is the same response that others have found for grizzly bear movements and genetic structure across highways, and also jaguars in Central America. Getting breeding females to cross and connect subpopulations is key, and we hope that crossing structures can help that function.

What are the implications for wolverine populations in North America, and specifically in the United States, where numbers are low?

The prospects are not good in the lower 48 where the population is [currently] estimated at 300 but we all believe that is far too high. Habitats are highly fragmented, unlike wolverine range in southern Canada (Alberta and British Columbia). The population in Canada is in the thousands.

Trapping still occurs in southern Canada and we published a paper recently that demonstrates that the trapping of wolverines in southeast British Columbia and southwest Alberta is not sustainable. Governments there are starting to change trapping regulations.

These populations are the lifeline for wolverine populations in the United States. We lose that and we lose everything.

What is being done or can be done to help? Are there particular kinds of crossing structures that would be most beneficial for wolverines?

Crossing structures have been built in the Canadian Rockies along the Trans-Canada Highway, which will help the mountain park wolverines. The critical piece of the puzzle is located in multi-use lands between the mountain national parks and the United States border (near Glacier and Waterton Lakes national parks).

This area is still trapped for wolverines, and forest cutting and motorized recreation are extensive and in some places there is oil and gas exploration activities that limit wolverine movement, reproductive success and survival. The provincial government of British Columbia is changing trapping regulations and we hope Alberta will follow suit its a good thing and necessary.

Overpasses and underpasses are also being planned for the British Columbia section of Highway 3, a critical linkage zone in the Yellowstone-to-Yukon ecoregion. The public is more informed of the plight of wolverines in this critical area, as are trappers.

Working together we can help provide a more viable future for one of our icons of wilderness and intact ecosystems.

Originally posted here:
Road to Nowhere: Highways Pose Existential Threat to Wolverines - The Revelator

Cincinnati's thousand-pound toddler turns 3 years old this January, overcoming every obstacle thrown her way.Fiona the hippo will celebrate her third birthday this month. It's a big deal for the half-ton of pure hippo sass, considering she weighed a fifth of what a normal baby hippo should weigh when she was born Jan. 24, 2017."Fiona is remarkable for being unremarkable now," said Cincinnati Zoo curator of mammals Christina Gorsuch. "She's just like most other 2-year-old hippos, except for the fact that she's a celebrity in Cincinnati and beyond!"Fiona weighed 29 pounds when she was born, which is about 25 pounds lighter than the lowest recorded birth weight for this species. The normal range is 55-120 pounds.She has become an ambassador for her species and a great example of why zoos exist. She survived because of her animal care team's tireless efforts to save her and has inspired many to care about her species and wildlife, which is Cincinnati Zoo's mission.She now weights well over 1,000 pounds. Once Cincinnati's little baby, the hippo has reached a certain level of maturity as she nears three as her tusks begin to come in.But don't worry, Cincinnati. She's not old enough to date yet.She needs to be at least 5 before she starts thinking about boys, according to Wendy Rice, the head keeper at Cincinnati Zoo's Africa Department.And although she has hippo admirers across the country, Rice said Fiona is still a few years away from picking up a boyfriend.Of those hippo admirers, one such hippo is still laying it on thick. Timothy, a 3-year-old hippo from San Antonio, still pens Fiona weekly love notes on Facebook.But what ultimately will decide Fiona's potential future romance? It may not be cute love notes."The genetics are basically what's going to matter most," Rice said. "If and when Fiona were to get a breeding recommendation someday, it would be based entirely on who was genetically the best match for her -- that may or may not be Timothy."Fiona's genes are valuable in the world of Nile hippopotamuses. And eventually, Rice said the goal is to have Fiona breed if she can. But we're talking way down the road, when Fiona is at least 5 years old.What happens then?"We obviously don't want her going anywhere," Rice said. "We love her. She's our baby and this hometown loves her. We're fairly certain people would riot if we said Fiona was leaving. We're hopeful that if she gets a breeding recommendation, that a male would be brought here for her so she wouldn't have to leave Cincinnati."

Cincinnati's thousand-pound toddler turns 3 years old this January, overcoming every obstacle thrown her way.

Fiona the hippo will celebrate her third birthday this month. It's a big deal for the half-ton of pure hippo sass, considering she weighed a fifth of what a normal baby hippo should weigh when she was born Jan. 24, 2017.

"Fiona is remarkable for being unremarkable now," said Cincinnati Zoo curator of mammals Christina Gorsuch. "She's just like most other 2-year-old hippos, except for the fact that she's a celebrity in Cincinnati and beyond!"

Fiona weighed 29 pounds when she was born, which is about 25 pounds lighter than the lowest recorded birth weight for this species. The normal range is 55-120 pounds.

She has become an ambassador for her species and a great example of why zoos exist. She survived because of her animal care team's tireless efforts to save her and has inspired many to care about her species and wildlife, which is Cincinnati Zoo's mission.

She now weights well over 1,000 pounds. Once Cincinnati's little baby, the hippo has reached a certain level of maturity as she nears three as her tusks begin to come in.

But don't worry, Cincinnati. She's not old enough to date yet.

She needs to be at least 5 before she starts thinking about boys, according to Wendy Rice, the head keeper at Cincinnati Zoo's Africa Department.

And although she has hippo admirers across the country, Rice said Fiona is still a few years away from picking up a boyfriend.

Of those hippo admirers, one such hippo is still laying it on thick. Timothy, a 3-year-old hippo from San Antonio, still pens Fiona weekly love notes on Facebook.

But what ultimately will decide Fiona's potential future romance? It may not be cute love notes.

"The genetics are basically what's going to matter most," Rice said. "If and when Fiona were to get a breeding recommendation someday, it would be based entirely on who was genetically the best match for her -- that may or may not be Timothy."

Fiona's genes are valuable in the world of Nile hippopotamuses. And eventually, Rice said the goal is to have Fiona breed if she can. But we're talking way down the road, when Fiona is at least 5 years old.

What happens then?

"We obviously don't want her going anywhere," Rice said. "We love her. She's our baby and this hometown loves her. We're fairly certain people would riot if we said Fiona was leaving. We're hopeful that if she gets a breeding recommendation, that a male would be brought here for her so she wouldn't have to leave Cincinnati."

Excerpt from:
Fiona's greatest hits: 3 years of sassy hippo bliss - WLWT Cincinnati

The clotting disorder hemophilia A may become the third gene therapy that the US Food and Drug Administration approves, joining treatments for a form of retinal blindness in 2017, and spinal muscular atrophy in 2019.

Biomarin Pharmaceutical Inc. has submitted a biologics license application to FDA and documentation of clinical trial results to the European Medicines Agency, with reviews slated to begin early this year at both organizations.

An article in the January 2 New England Journal of Medicine from a UK research team presents the findings of a phase 3 analysis of continuing success of a phase 1/2 trial (instead of a new phase 3 trial). The hemophilia gene therapy called valoctocogene roxaparvovec for now can mean a one-time infusion that replaces the more than 100-150 infusions of clotting factor a patient takes each year, and can also alleviate the painful joint bleeding that is the hallmark of the disease.

The different clotting disorders result from mutations in different genes in the pathway that knits a clot from protein fibrils. Hemophilia A is a deficiency of clotting factor VIII, and is also called classic hemophilia. It accounts for 80 percent of people with the disease. The clotting disorder that threaded through the royal families of Europe was hemophilia B, which is a deficiency of factor IX.

Both hemophilias are transmitted by genes on the X chromosome, and therefore affect only males. One in 10,000 males has hemophilia A, and it arises as a new mutation (rather than being inherited), in about a third of cases.

The world focused on hemophilia A with the sad case of Ryan White. Born in 1971, Ryan was diagnosed at 3 days of age when his circumcision wound wouldnt stop bleeding.

Like many people with hemophilia A at the time, Ryan received weekly factor VIII pooled from donors. That would prove tragic, as President Reagan was late to the game of testing the blood supply for viruses. He refused to even utter the word AIDS until actor Rock Hudson died of it in 1985.

That was too late for Ryan White.

HIV as the cause of the mysterious new epidemic was identified in 1983, although for a time it was known by different names.

In 1984, Ryan had a lung biopsy to diagnose severe pneumonia that revealed that he was HIV positive. Nearly 90% of people with hemophilia who received clotting factors from pooled donor blood between 1979 and 1984 contracted HIV and/or hepatitis C.

Ryan survived longer than predicted, until the end of 1990. In the intervening years he catalyzed AIDS activism when he was denied admittance to school, and he and his family fought the discrimination and ignorance.

Hemophilia A gene therapy has been twenty years in the making.

By the end of the decade that began with Ryan Whites death, the first gene therapy for hemophilia A was being tested in a clinical trial in Pittsburgh. I was fortunate to interviewthe first patient soon after he received the gene therapy.

Like Ryan White, Don Miller had nearly bled to death when he was circumcised. He recalled other frightening incidents.

I fell at my grandmothers house and had a one-inch-long cut on the back of my leg. It took five weeks to stop bleeding. It leaked slowly, so I didnt need whole blood replacement. But if I moved a little the wrong way, it would open and bleed again.

Millers treatments paralleled the history of countering hemophilia, from whole blood infusions, to plasma replacement, to cryoprecipitate (a frozen plasma product containing clotting factors). Then he injected pooled factor VIII three times a month. But somehow he never contracted HIV, and thats what got him into the gene therapy clinical trial.

I lucked out, Miller told me. Besides his good fortune at dodging the HIV bullet, he was in the right place at the right time. Hed been a librarian at the University of Pittsburgh, where the clinical trial was to take place.

On June 1, 1999, Don Miller received the first of three injections of retroviruses engineered to carry factor VIII. Chiron Corp., one of the original wave of big biotech companies that was absorbed into Novartis in 2006, designed and manufactured the vector.

The goal of this first round of hemophilia A gene therapy wasnt to cure the disease, but to boost factor VIII levels a scant 2 to 7 percent, which was expected to dampen bleeds.

Don Miller hadnt had any side effects when I spoke with him, but I dont know how he fared. At the time, he spoke freely to the media, but I contacted his physician and she couldnt provide an update due to HIPAA regulations.

But that first hemophilia A gene therapy was safe. Some patients had transient increases in factor VIII, and for 5 of the 13, bleeds became less frequent.

When the gene therapy field emerged from several setbacks that began with the death of Jesse Gelsinger in 1999, the hemophilia strategy changed to a safer and more efficient vector. The clinical trial leading to the current FDA submission began with 15 patients who received the factor VIII gene delivered in adeno-associated virus serotype 5, starting in June 2015. A year later, 13 of the men treated with a single infusion had normal or near-normal levels of factor VIII.

The AAV5 vector coaxes greater expression of the gene than does the retrovirus used in the earlier trial. Plus, an added bit of control DNA (a promoter) directs the vector to the types of cells that normally make the factor in the liver and to white blood cells.

AAV5s capacity is only about 4,700 DNA bases, so the big factor VIII gene is trimmed a bit (as it was for the earlier trial too). Still, it had to be delivered in two viral shipments, with some assembly required, like sending a cell phone and its charger in separate Amazon prime boxes.

Unlike other vectors (lentivirus and retroviruses), AAV remains separate from the cells chromosomes, forming a DNA circle called an episome.

Two of the 15 patients received doses too low (6 or 20 trillion viruses per kilogram of body weight) to have an effect. But six men receiving an intermediate dose of 40 trillion viruses had no bleeding events; the annual number of needed factor VIII infusions for the three-year study period fell from 155 to 0.5, and only one man had a bleed in a large joint.

The high-dose (60 trillion viruses) men did the best: none required factor VIII infusions, bleeding events, or large joint bleeds.

Analysis of factor VIII levels and various biomarkers of the gene indicated that of the 13 men who responded, one is considered to no longer have hemophilia, eleven have mild disease, and one has moderate disease.

It all adds up to what the researchers call a sustained, clinically relevant benefit. Said lead author John Pasi, from the Royal London Haemophilia Centre, Barts Health NHS Trust:

Our 2017 paper showed that gene therapy could significantly boost factor VIII levels in men with hemophilia A. Our new data are critical in helping the scientific and medical communities understand this pioneering technology. This latest study confirms both safety and long-term beneficial impact. A long-term treatment that effectively ends the life-long regular injections can transform care and massively improve the quality of life of hundreds of thousands of people born with this challenging genetic condition.

Once an advisory committee to FDA agrees, valoctocogene roxaparvovec will debut with a catchier brand name. It may cost in the $400,000 to $1 million range (or higher) of other gene therapies in the US and Europe, but considering that current therapies for hemophilia A are about $270,000 annually without complications and can exceed $1 million if there are, a one-and-done gene therapy for hemophilia A sounds like a good deal.

Ricki Lewis is the GLPs senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis

Read the rest here:
Will 2020 see the debut of promising gene therapy for hemophilia A? It's up to the FDA. - Genetic Literacy Project

Changing landscapes, habitat loss, fragmentation, and global climate change have been listed as the main reasons for biodiversity decline worldwide. Now, a new study from the National Centre for Biological Sciences (NCBS), Bengaluru, has added to the growing knowledge that anthropogenic activities can impact genetic connectivity or the movement among habitat patches usually resulting in mating and genetic exchange.

In several mammalian carnivores, juveniles disperse away from their mother's territory to establish their own territory. Males are known to travel longer distances than females. Isolation of habitat patches (due to habitat destruction and fragmentation) can restrict animal movement among habitat patches and thus reduce genetic exchange and increase the probability of extinction. Hence maintaining connectivity is critical to ensure long term persistence of a species, Prachi Thatte explains. Dr. Thatte is the first author of the paper published in Diversity and Distributions and now works with WWF-India on connectivity conservation

Four wide-ranging mammals Jungle cats, leopards, sloth bears, tigers were investigated for the genetic differentiation in central India, which is a critical landscape for several species. The DNA extracted from faecal samples were used for understanding genetic connectivity. The samples were collected from nine protected areas during the period 2012-2017.

The team looked at how land-use, human population density, nearby roads and traffic affected the genetic structure. The paper notes that tigers were impacted the most by high human footprint. Although known to travel long distances and move through agricultural fields to some extent, tigers in central India do not have equally high genetic exchange throughout the landscape. Some protected areas like Bandhavgarh tiger reserve seem to be getting relatively isolated (the 2014 tiger census report also shows the same), explains Dr. Thatte.

Jungle cats were found to be the least impacted. That is likely because in central India, they occupy a variety of habitats including forests, scrublands, grasslands and even irrigated agricultural fields close to the forests, she explains.

Despite being the least impacted by human activity, the team encountered several jungle cat road-kills while carrying out fieldwork. She explains that with increasing infrastructure and traffic, systematically studying the impact of roads on smaller species like jungle cat and jackals and ensuring the presence of mitigation structures like underpasses and overpasses would be crucial to ensure that we don't fragment the currently well-connected populations.

IIndia has also started paying attention to wildlife corridors and encouraging engineering reforms to promote wildlife movements. Last year, the Ministry of Environment along with the Wildlife Institute of India released a document that lays out the regulatory requirements for developing roads, railways, powerlines while recognising the impacts on wildlife and people. NHAI and all PWDs have been instructed to follow the guidelines.

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See the original post here:
How humans affect genetic connectivity of four mammals - The Hindu

They have been poisoned, shot at, and stumbled into traps laid by those who regard them as a ruinous blight on the countrys woodland and wildlife.

But now, the grey squirrel is facing arguably its biggest threat yet, with plans to harness the cutting edge of genetic science to bring their destructive reign to an end.

Researchers at the University of Edinburghs world-renowned Roslin Institute say it is possible to cull numbers of the mammals by editing their DNA to ensure that all future females are born infertile.

The institute, famous for creating Dolly the Sheep, the worlds first mammal cloned from an adult cell, hoped to create gene-edited male squirrels that can be released into the wild.

The mammals would be altered to contain a so-called gene drive designed to spread throughout the population, and render all females to inherit it sterile.

Males, however, would be unaffected, so as to allow them to keep spreading the new genetic code, and ultimately hastening the greys demise.

The initiative is supported by some as a humane means of stopping the spread of the invasive species and protected the red squirrel, which is native to the UK, but survives only in isolated strongholds, with the vast majority found in parts of Scotland.

However, animal rights campaigners dismissed the idea as reprehensible, and warned it would not solve long standing ecological problems.

The project, which is part-funded by the European Squirrel Initiative, a charity that promotes research into the conservation of red squirrels, would also have implications for efforts to rid Britain of other invasive species, such as mink, muntjac deer, and ring-necked parakeets.

The team at the Roslin Institute point to the fact that the grey squirrel is a carrier of squirrel pox, which is lethal to the red squirrel. Without conservation efforts, it is predicted that reds could be lost from the UK altogether by 2030.

Professor Bruce Whitelaw, the institutes genus personal chair of animal biotechnology, is spearheading the squirrel project.

A potential application of gene drives is to control invasive vertebrate pests, such as cane toads and rabbits in Australia, grey squirrels in the UK, possums in New Zealand and rodents around the globe, he explained in a journal article co-authored with Gus McFarlane, a fellow researcher.

They have asked a team of genome engineers, population modellers, ecologists, ethicists and conservation experts to design gene drives as a potential tool to eradicate grey squirrels.

We are investigating strategies that could humanely control the UK grey squirrel population, Mr McFarlane said. One is spreading female infertility.

Another possible drive changes the sex ratio, favouring the birth of males over females until the population becomes mostly male.

Andrew Kendalll, a spokesman for the European Squirrel Initiative, said: The aim would be to create a few thousand gene-edited greys and then release them so the gene spreads, slowly wiping the species out in the UK. We want to reverse the invasion.

It is very humane - there is no need for trapping or shooting - they just stop reproducing.

However, Jennifer White, a spokeswoman for People for the Ethical Treatment of Animals, said: People accept that genetically engineering humans is morally unconscionable and doing the same to squirrels using gene-drive technology is just as reprehensible.

It wont solve our ecological problems but will lead to misery for intelligent, sensitive beings.

Follow this link:
Dolly the Sheep scientists hope DNA editing can wipe out grey squirrels - Scotland on Sunday

A white lion famously donated to the Cincinnati Zoo by magicians Siegfried & Roy has died. The zoo says the lion named "Prosperity" was "humanely euthanized" Monday.

The 22-year-old animal had "extended age-related health issues," the zoo writes in a Facebook post. The median life expectancy for a white lion is 16 years, according to the post.

Prosperity came to Cincinnati in 1998 when the famous magicians and entertainers Siegfried & Roy decided the lion cub should be raised around other cubs.

"Prosperity was a very special lion from the very start," writes zookeeper Laura Carpenter. She was born on Christmas Day in Las Vegas, Nevada, in the care of the famous entertainers, Siegfried and Roy. Her inexperienced mother failed to care for her, so she was hand-raised by Roy Horn himself, along with his staff of animal caregivers and trainers."

Carpenter goes on to say she had worries about Prosperity's ability to assimilate given she was used to eating off a silver platter, flying in private jets, and riding in limousines, but she says the lion bonded with the zoo's two young males, "Sunshine" and "Future," who were loaned to the zoo that same year by the magicians.

Prosperity sired four cubs with Sunshine, three of which were transferred to the Toledo Zoo. A daughter remains in Cincinnati. "Gracious," now 18 years old, is being monitored by zoo staff. The zoo says the Association of Zoos and Aquariums (AZA) recommends against transferring Gracious to live with other lions because of her age.

"(Prosperity's) longevity, and that of her 18-year-old daughter Gracious, can be attributed to the special geriatric enrichment, diet and TLC that she has received from her care team," the zoo says.

Prosperity outlived her two male companions and her three male cubs.

"Prosperity always rolled with the changes with a calm reserve and was the most wonderful lion. She holds the distinction of being named the official mascot of the U.S. Senate, where the most powerful lawmakers are known as lions," Carpenter eulogizes.

"We will miss you, our most special of lions, you have been the best lion anyone could have hoped for. I am most honored to have gotten to take care of you these many years. Farewell, my beautiful lion. May you have a special spot in Heaven that is most fitting for the Queen that you are."

White lions are caused by a rate genetic mutation. They are not albino, rather their coloring comes from a recessive gene called a color inhibitor. The AZA banned intentional breeding of white tigers in 2011 because of inbreeding concerns and problems.

Link:
Cincinnati Zoo Euthanizes White Lion With Ties To Siegfried & Roy - WVXU

Male elephant seals are among the loudest mammals ever recorded, and they can weigh more than two tons. (Photo by Steve Zamek, Feather Light Photography)

On a sparkling blue January morning, I meet marine biologist Patrick Robinson, who will escort me around Ao Nuevo State Park, a patch of dunes and bluffs an hours drive south of San Francisco. As we start along a sandy path toward the beach, he explains that his role is not only to protect me from the thousands of elephant seals currently camped out here, but to protect the elephant seals from me. That sounds sensible enoughuntil we come over a rise and I see what they actually look like in the flesh.

Blocking the path is a massive blob of quivering blubber, braying like a donkey. This hunk of chonk, the size and shape of Jabba the Hutt, is a male northern elephant seal. He might weigh as much as 4,500 pounds, and he can flop his jiggly body across the sand as fast as we can run. Robinson warns me to watch where I walk, and to be careful not to invade any seals personal space. I make eye contact with Jabba, who watches us with mild curiosity, his dark eyes lustrous over the dangling snoot that gives the species its name. I am not even slightly tempted to get closer.

A few hundred yards more down the path there are seals everywhere, lolling and scratching. We weave among them, trying not to get too close. But every rounded dune comes alive as a seal back or flank; what looks like driftwood sighs deeply and twitches a flipper. There are just so many of them. Like clockwork every winter, more than 2,000 adults congregate on these shores for their annual sealapalooza of fighting, birthing, nursing, matingall of lifes main events in just a few months. Sort of like Jersey Shore, but for seals.

When they come together in space and time, everything is very extreme. The level of competition is extreme, the level of risk is extreme. These animals are fasting, with no food and water, so the physiological constraints are extreme.

While the males battle for breeding rights and the females nurse their newborn pups, none of the adults eat or drink, losing more than 30 percent of their body weight. This ultra-endurance event is just one of the many extraordinary things elephant seals do. When they come together in space and time, everything is very extreme, says behavioral ecologist Colleen Reichmuth of the Institute of Marine Sciences at University of California Santa Cruz. The level of competition is extreme, the level of risk is extreme. These animals are fasting, with no food and water, so the physiological constraints are extreme.

Because it is both amazing and convenient to study, the northern elephant seal, which ranges throughout the North Pacific, is one of the best-measured of all marine mammals. Over the years, using harnesses and marine glue, straps and cattle-ear-tag guns, scientists have attached all sorts of gizmos to the creatures mighty heads and shoulderscameras, GPS tags, depth sensors, heartbeat monitorsto measure where theyre going and what theyre doing way out there in the ocean. Every time we turned around, wed uncover some really cool fact or observation, says UCSC evolutionary biologist Daniel Costa, who first began studying these mammals in the mid-70s and now supervises all Ao Nuevo elephant seal research. Scientists here and elsewhere learned that elephant seals dive deeper (nearly 6,000 feet), swim farther (averaging more than 9,000 miles a year), and hold their breath longer (up to two hours) than any other seal. Only their cousins, the southern elephant seals, can hold their breath for as long as they canup to two hours. (Harbor seals, by comparison, can hold their breath just a half hour and go no deeper than 1,500 feet.) Males are more than three times the size of females, one of the biggest sex-based size differences among mammals. They arent just polygamous, but maybe the most polygamous of mammals, forming harems in which one male might mate with up to 100 females.

The extraordinary nature of this animal has already forced scientists to question the supposed limits of mammal physiology. These deep-diving, breath-holding, long-fasting creatures are closely related to other marine mammals that cant pull off such feats. The implication is that minor tweaks to mammal biology can translate to huge differences in ability. Elephant seals may even teach us how our own bodies function and what we might be capable of. For now, though, the question that preoccupies the scientists of Ao Nuevo is what will happen to the animals in a warming world. Climate change is poised to disrupt everything in the ocean in coming decades, from ocean currents to the location of the most and best fish. A new wave of research projects here probe whether these unusual mammals are resilient enough to keep thrivingwhether they will be extraordinary enough to cope with the huge changes heading their way.

The sands of Ao Nuevo were not always jammed with dozing seals. In the late 1880s, the northern elephant seal was thought to be extinct, decimated by blubber-hunters, until some naturalists found a tiny band of holdouts on an island off Mexicoand promptly killed most of them to take them home as specimens.

But elephant seals are nothing if not gritty, and a few survivors held on, slowly rebuilding their numbers. By the 1970s the seals began pupping and breeding at Ao Nuevo, just 30 minutes drive north of UC Santa Cruz and its world-class marine biology department. That proximity was a lucky stroke for researchers: The animals tolerate the humans who tiptoe amongst them. And as biological outliers, they offer a singular chance to study the outer fringes of mammalian performance.

The portly creatures that Robinson and I sneak past dont look like stupendous athletes. Yet for up to eight months of the year, they roam the remote eastern and central North Pacific, plunging way below the surface on nearly continuous foraging dives. Blubber analysis conducted by Chandra Goetsch in Costas lab indicates they eat deepwater prey like lanternfish, squid, and viperfish, and they eat a lot of it. In roughly seven months of migration, female seals gain an average of nearly 600 pounds, which can mean they nearly double their body weight.

As they dive, their hearts slow to below five beats a minute while blood flow to the muscles shuts offa trick that interests anesthesiologists who would like to stop circulation to a body part during surgery, then restart the flow without damage. Elephant seals can also surface from marathon dives to breathe for less than five minutes, then dive again. Theres a lot we dont understand about how they do that, says behavioral ecologist Birgitte McDonald of Moss Landing Marine Laboratories. The behavior seems to break physiological rules: If a Weddell seal, for instance, dives for more than 20 minutes, it uses up all its oxygen. Its muscles start dumping lactate into its blood, and the seal must breathe for 90 minutes or more before diving again.

The fact that these seals wander so widely, dive so deep, and reliably return to Ao Nuevo means they can also be employed as sensors to probe parts of the ocean that are difficult or expensive to measure. One student in Costas lab recently explored using data gathered by fluorescence meters attached to the seals to cheaply chart chlorophyll levels out in the North Pacific, measuring that all-important first link of the food chainthe phytoplankton and algae that ultimately feed everything else in the ocean, from baby fish to blue whales, and which indirectly reflect how windy or warm ocean conditions are.

Robinson and I reach our first destination: an observation deck overlooking Bight Beach, where roughly 75 northern elephant seals sprawl in the sun, females honking and rasping, their chocolate-brown pups beside them mewling and trilling. Theres just one enormous male down near the water, keeping watch. It looks like a day spa with a really scary bouncer.

In three-quarters of confrontations one of the males backs down before things get violent. In a species famed for aggression, theres actually way more talk than action.

He looks tense, for good reason. The privilege of breeding is reserved for just a few dominant males like him; 99 percent of elephant seal males never mate. This guy vanquished the competition, but the also-rans just wont stop trying. Elephant seal combat can be brutal: the bulls square off, rear up, then smash their chests together, rassling and shoving and gashing at one anothers shoulders and flanks with their teeth, leaving each other raw and bloody.

Even now, a male with a big glob of dried blood on his shoulder lurks at the top of the cove. Chances are, Scary Bouncer Seal caught him trying to get with his ladies and taught him a lesson. But although it is spectacular, bull vs. bull is rare, because it is just too draining. Reichmuth and her former graduate student Caroline Casey discovered a few years ago that the big brutes prefer to roar at each other rather than waste their energy on physical attack.

Here at this beach, the variety of sounds is indescribable, although I try: Asthmatic lion, I scribble in my notebook. Old outboard motor. Gargling drain. Strangling a Pomeranian. Above it all rises the long, throbbing snort-roar of that big guy near the water. (Bonus elephant seal freak fact: They are among the loudest of any land mammal.)

To understand what those calls mean and how they relate to breeding success, Reichmuth and Casey first mapped the bull hierarchy. They filmed confrontations between tagged males, recording the outcome of each standoff or fight. Because not all bulls fight one another directly, and because she couldnt track every last conflict, Casey used a method borrowed from competitive chess called the Elo system to assign each bull a comparative rank.

Next, they recorded each males voice and did playback experiments. The seals evidently understood the bellows: Middle-status males charged toward the speaker when they heard recorded calls of low-ranking bulls, but those same mid-rank guys fled from sounds made by alpha males. We were like, What is going on here? What are they saying to each other? Casey says. We wanted to decode the language of male elephant seals.

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Top males did not have lower voices or longer calls or share any other obvious characteristic. What Caseys analysis showed instead is that each males voice is distinctive and stays the same from year to year. The kicker: When she drove up to Point Reyes National Seashore and played her Ao Nuevo recordings to the elephant seal colony there, the bulls didnt react either way.

Her interpretation is the bulls recognize the voices of bulls theyve met and keep a mental ledger of whom theyve fought and who won, so as to avoid unnecessary and exhausting rematches. Its amazing, she says. It means that they have really good memory, and are able to manage and remember a lot of unique calls. Its also an effective conflict-avoidance strategy: in three-quarters of confrontations, she found, one of the males backs down before things get violent. In a species famed for aggression, theres actually way more talk than action.

While the bulls bluster and brawl, elephant seal females endure their own physiological marathon. Without eating or drinking, a mother produces nine pounds of milk per day during the roughly four weeks she nurses her pup. The rich milk fattens the pup, preparing it to survive alone on the beach for months after the mother returns to the sea.

Mother seals draw on their own fat reserves to do this, so its essential they arrive here at a healthy weight. The researchers at Ao Nuevo are careful not to disturb the animals too often or for too long, particularly mother-pup pairs. So to track their health, Robinson is developing creative ways to weigh them without disturbing them, such as using drones that estimate their size with photography. Today were hoping to weigh seal #9454, one of two dozen females who has been carrying a satellite tag that tracked her path through the Pacific. Robinson plans to link her route to her weight for a multidimensional view of where and how well she ate.

We spot her among a dozen other mothers, her chin propped on her plump days-old pup. The small satellite device epoxyed to her head gives her an aristocratic, eccentric look, like a drunken duchess at a garden party. As Robinsons drone hums above her, snapping pictures, she regally ignores it.

Weighing her unobtrusively is important because her reproductive success requires her to conserve her energy. All mothers move around, jockeying for space on the beach and warding off intrusive males. But much of a mothers energy goes into milk. When pups are first born, McDonald found, mothers produce milk thats 20 percent fat, skyrocketing to nearly 60 percent right before weaning. (By comparison, cows milk is only about 4 percent fat.) Despite the physical toll of producing milk while also fasting, elephant seal mothers will sometimes nurse both their own pup and an orphaned onean effort doomed to fail. To nurse a pup thats not your own, thats really difficult to explain, given what we know about elephant seals, says Reichmuths postdoctoral student Juliette Linossier.

One possibility is that the mothers just dont notice the difference. But that doesnt seem to be the case, Linossier has found. She shows me a video from last winter, in which she plays a recording of calls made by a random stranger pup to a seal mother, who barely reacts. But in response to a recording of sounds from her own pup, the mother snaps her head up and whips around to stare at the source. She flops a foot or two toward the speaker, clucking and barking and swiveling her head in search of her baby, which is actually right beside her.

Linossier is trying out scent-recognition tests too, using a fake pup fashioned from old wetsuits. To imbue her model with eau de pup, she creeps up on a sleeping baby and rubs it with a towel so gently that it doesnt wake up. She then attaches the towel to the neoprene suit and places it near the mother. (How does a baby elephant seal smell? Worse than a dog, Linossier reports.)

Its painstaking, slow-moving research, because she must be careful not to upset the sealsboth for the animals sake and in order to truly understand mother-pup interactions. Linossier has yet to analyze her data, but what shes seen so far suggests that seals hear and maybe even smell the difference between their own and another mothers pup. If nursing a strange pup is no dumb mistake, one possible explanation lies in the genes. Since one male can sire dozens of pups each year, many of the seals on the beach are related, and the mothers may be actually feeding distant kin. Linossiers next plan: genetic tests to determine relatedness.

The northern elephant seal population now numbers about 150,000 and is spreading north. The seals normally molt on California beaches, but last summer, two elephant seals from Southern California were spotted onshore in Alaska, where theyve almost never been seen before. Its a hopeful sign. Maybe they will be able to seize new opportunitiesan essential skill in an era when climate change may transform everything these animals know.

Elephant seals seem to be creatures of habit, returning to the same spots to feed and to breed every year. In a changing world, that faithful tendency could become a problem. Their preferred pupping grounds may get swamped by rising seas. The beaches where they haul out to molt may get too hot. And in the future, as waters warm and currents shift, their favorite foraging spots may no longer provide fish by the ton. During El Nio years when the central Pacific becomes warmer than usual, the seals have had trouble finding foodpossibly a preview of whats to come.

Are they too preprogrammed to adapt, or are they flexible enough to say, This space isnt working out, Ill go somewhere else? asks graduate student Rachel Holser, whose research focuses on decision-making. To investigate this question, she cant interfere with the seals fishing grounds or experimentally warm the water the creatures swim in. Instead, she uses a type of experiment common in behavior research: measuring an animals response to something its never seen before to determine how risk-averse it is. Its responses tend to be consistent across different situations: A bold animal will probably be more willing to explore new places; one that flees from an unfamiliar object will tend to stick with what it knows.

For the test, she stripped a radio-controlled toy truck down to its chassis, outfitting it with a speaker and a GoPro video camera. Then she loaded it up with a recording of the T. rex roar from Jurassic Park. (Alternative experimental stimulus: the screech of Godzilla.)

Are they too preprogrammed to adapt, or are they flexible enough to say, This space isnt working out, Ill go somewhere else?

At her desk in the Institute of Marine Sciences in Santa Cruz, she shows me video of the experiment. The GoPro image jolts and shudders as the tricked-out car crawls across the beach toward a cluster of seals. It halts roughly 10 feet from a female, who stares into the camera and grunts.

A few minutes later, we hear the bellow of T. rex, and all six seals pivot toward the camera. Holser says this is about as big a reaction as she gets out of most seals, who quickly lose interest in the contraption. That female with the death stare, however, is one of the exceptions. Another dinosaur roar, and she charges right at the camera, pink mouth gaping wide, grunting angrilythe video captures her whole palate vibrating as she barks.

After decades of research, Ao Nuevo scientists have a pretty good idea of how much disturbance the animals can tolerate without lasting effects. They carefully weigh any potential impact on fitness, like the energy wasted on confronting a radio-controlled gizmo, against the gain of better understandingin this case, how this seal and her kin might deal with other unexpected situations. The majority of animals return to normal behavior within two to five minutes, Holser says, and this seal is no exception. While shes clearly not thrilled about the interruption, the whole drama blows over very quickly.

Holser must still analyze these data, but you dont need to be a scientist to grasp that this particular seal has little fear of the unknown. Whats less clear is what that implies about her future, that of her pups, and, really, of the whole colony at Ao Nuevo. Is an aggressive female a better mom, because she protects her pup, or is she worse because shes running around the beach wasting her energy? says Holser. We dont know what the answer is.

On the screen, the seal grunts one more time, then backs off with a last dirty look. And then this extraordinary animalthis exceptional survivor, this rule-breaker among mammals, this fearless challenger of unexpected scientific thingamajigslays her head back down on the sand and drifts back to sleep.

Continued here:
Meet The Deep-Diving, Ear-Splitting 4,500-Pound Rock Star of Ao Nuevo - - Bay Nature

Many of us biologists conduct fieldwork in diverse places, from Alaska to the tropics, from aiming to understand how microbes are responding to climate change in the boreal soils to learning about life history strategies and co-evolutionary arms races of bats, their ectoparasitic flies, and the ectoparasitic fungi living on those flies.

The days before fieldwork tend to be hectic: make a checklist to make sure you have everything you need, think about a plan B (and a plan C, just in case), anticipate drawbacks and plan on how to address them, and the list goes on and on. The day comes. You make it to your field site, you collect the samples you want, obtain the data you need, everything works out just like planned, and you make it back to the lab safe, on time, and without going over your planned budget. This is how it should be, but it never really goes like that.

Fieldwork is one of the most exciting experiences about doing research. It is also, in many cases, high-risk. During fieldwork, many things can go wrong, and most of those things cannot be helped. We cannot control the appearances of massive puddles in the middle of the road, critically damaging our transportation vehicles. We cannot control the thunderstorm that makes our study organisms disappear when we finally arrive at a remote field site after hours of climbing a mud-covered mountain.

Sadly, this is not always the case for threats to our integrity as human beings, and we, as a scientific community, have done far too little to address this problem. People from underrepresented groups in the sciences such as people of color, women, and those who identify as LGBTQIA+ or gender nonconforming often are at higher risk of suffering abuse during fieldwork. This comes in the form of sexual harassment, sexual abuse, discrimination, and intimidation. Scientists who have experienced abuse often fear talking about it because they are traumatized and because they fear retaliation and backlash, especially if the perpetrators of abuse are colleagues or superiors advisers and people at higher career stage.

In Spring 2018, we carried out an anonymous survey to collect testimonies of what scientists, specifically from the LGBTQIA+ community, experience during fieldwork. The idea for such a survey sprouted from concerns that sexual orientation or gender identity may play an unwanted or unwarranted role in peoples professional career. Especially during fieldwork, when Diversity and Inclusion Offices from our university campuses are far away, LGBTQIA+ researchers are exposed to people who may not agree with their sexual orientation or who do not understand why he may want to be addressed as they.

Responses revealed experiences ranging from discrimination to situations that made researchers decide to no longer perform fieldwork outside of safe places. This adds a whole new level to fieldwork stress, namely having to evaluate sites for their tolerance towards LGBTQIA+. In one story from fieldwork, men voiced discomfort because an openly gay man would share a room with them while, simultaneously, women felt uncomfortable due to the possibility of having to share a room with someone from the opposite sex. Another survey respondent described that they were fearful to carry out fieldwork in places that are recognized for their homophobic culture. These experiences leave people feeling isolated and rejected.

We present a few strategies that we can instill in STEM fields to avoid cases like these:

1) INFORM PEOPLE ABOUT LGBTQIA+. Erase any misinformation that may exist. For example, a gay man is not a threat to the sexuality of cisgender males. Institutions can facilitate trainings on diversity and inclusiveness and provide information on the LGBTQIA+ community to eliminate negative stereotypes.

2) HAVE SUFFICIENT FUNDING AVAILABLE FOR FIELDWORK. Although sometimes it's unavoidable to share rooms due to limited budget or space, if there is the possibility to do so, provide individual lodging for people traveling to fieldwork or conferences. Especially for those who ask for it.

3) DEVELOP AN EMERGENCY PROTOCOL. As a lab, department, or institution, develop a protocol that scientists can follow as a response to experiencing a threat to their integrity. Protocols like this should be part of a broader departmental or university-wide mission statement about equity in field work. The bar has been set high by this example of a mission statement written by University of California Irvine professor Kathleen Treseder.

4) AVOID INTOLERANT AREAS. It is important to note that this does not only apply to countries like Niger and Tunisia where discriminatory laws expose LGBTQIA+ individuals to the risk of death penalty. It also applies close to home, in the USA, where there is an ongoing debate about public restrooms and which one transgender people and people who identify as gender-nonconforming should use.

5) IMPLEMENT A ZERO-TOLERANCE POLICY. Inform everyone in your lab, department and institution that there is a zero-tolerance policy regarding abuse. A code of conduct with expected versus unaccepted behavior and practices should always be made available through trainings and in field stations.

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DNA barcodes help identify fish eggs and inform conservation - Massive Science

A newly discovered mutation in the gene EGR2causes a severe form of Charcot-Marie-Tooth disease type 3 (CMT3), according to a case report of a 56-year-old patient.

The report, titled A de novo EGR2 variant, c.1232A>G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy), was publishedinScientific Reports.

Mutations in more than 90 genes have been documented as causing CMT, and influence the way the disease presents itself from patient to patient. Among the known CMT-causing genes is EGR2 (early growth response 2), which codes for a protein of the same name.

EGR2 is a transcription factor a protein that helps regulate how genes are expressed in a cell, that is, which genes are turned on or off. Specifically, EGR2 helps control the expression of genes needed for neurons to function properly.

Mutations that impair the ability of the EGR2 protein to perform this function have previously been linked to CMT3, also known asDejerine-Sottas diseasein its more severe forms, and to CMT4E.

The severity and onset of peripheral neuropathy [nerve disease] caused by EGR2 variants is highly heterogenous [varied], and it is yet to be determined why this broad phenotypic [symptomatic] variability exists, the researchers wrote.

In the case report, they describe a male patient who was 56 at the time of publication.

His symptoms, including abnormal fatigue and difficulty walking, were first noted when he was two. A nerve biopsy at the age of six confirmed a diagnosis of severe CMT3.

The patient experienced ongoing complications throughout childhood and into young adulthood, including the development of scoliosis, recurring migraines, and difficulty walking. At age 15, the patient required ankle surgery to stabilize the joint.

Examinations performed when he was in his 30s showed physical abnormalities, including muscle wasting in the extremities, lack of normal reflexes, and tremors. Additionally, nerve conduction studies (which measure how effectively nerves in the body can transmit electric signals) revealed significant functional deficits, and imaging of the brain revealed multiple lesions indicative of damage, including severe demyelinating (loss of the protective myelin layer around nerves) motor and sensory neuropathy.

By age 56, the patients motor functioning was severely impaired, and he was unable to write, or use a knife and fork.

Genetic sequencing studies were performed to identify the underlying cause of his severe form of CMT. Initial studies identified several genetic variations that were possible candidates; however, further analysis revealed that some of these were present in the patients relatives who did not have any of his symptoms, making it unlikely that those variants were the cause.

The analysis did suggest one variant as the cause: a mutation in EGR2called either c.1232A>G or p.Asp411Gly, referring to the specific substitution at the DNA and protein levels, respectively.

Further analyses including computer modeling and a comparison of EGR2 sequences across various species indicated that this mutation changed a particular part of the EGR2 protein that is likely important to the proteins ability to function properly. As such, it would be expected that the mutation, by altering this crucial part, would stop the protein from working as well.

To test this idea, the researchers constructed a model using cells in lab dishes. In simple terms, the cells were engineered with a gene encoding a fluorescent protein that could be turned on by the EGR2 protein. The cells were then given either mutated or wild type (normal) versions of EGR2, and the researchers measured how much of the fluorescent protein was produced indirectly measuring how well each type of EGR2 protein turned the gene on.

Cells with the mutated protein produced significantly less of the fluorescent protein, supporting the idea that the mutation impairs the proteins ability to function.

[W]ehave determined that a de novo missense EGR2 variant, c.1232A>G p.Asp411Gly, causes a severe and early onset [CMT3] phenotype by reducing the capacity for EGR2 to function as a transcription factor, the researchers wrote.

The phenotype [observable profile] is complicated by clinical features of white matter lesions and FMH [familial hemiplegic migraine] which may be a chance association, although it would be important to consider the possibility of central nervous system involvement in future cases of EGR2-related neuropathies [nerve diseases], they said.

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.

Total Posts: 13

Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Tcnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

Read the original post:
New CMT Type 3 Mutation Discovered in EGR2 Gene in Severe Case - Charcot-Marie-Tooth News

Cholesterol-lowering statin medications have been at the forefront of managing cardiovascular disease for several decades now. Why? Its because a large body of research supports their benefits in reducing the risk of heart attack and stroke.

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The drugs have become so universally used that if you havent been prescribed a statin already, chances are you will at some point.

Preventive cardiologist Luke Laffin, MD, says statins lower your LDL ( or bad) cholesterol, which is associated with a reduced risk of atherosclerotic cardiovascular disease. (Thats the buildup of cholesterol, fatty cells and inflammatory depositson the inner walls of your arteries aka hardening or clogging of the arteries).

Additionally, statins lower inflammation, which we know is a factor that causes atherosclerosis and cardiovascular disease, Dr. Laffin says.

Yet, despite their many benefits, statins (like all medications) have some important side effects you need to know about. So, review the risks and benefits of these important medications with your physician, and discuss your need for statin therapy.

Statins inhibit the action of an enzyme thats responsible for cholesterol production in your liver. In the process, they significantly reduce LDL and total cholesterol, while also having beneficial effects on HDL (good) cholesterol, triglycerides and inflammation. Some evidence suggests that high-intensity statin therapy may help to slow, and potentially reverse, the growth of artery-clogging atherosclerotic plaques. They may also make them less prone to rupture and cause heart attacks and strokes.

There are good data to suggest that the more LDL lowering we can achieve, the lower the risk of adverse cardiac events such as strokes and heart attacks, Dr. Laffin explains.

Although statins all belong to the same drug class, they differ in how potent they are and how much they can lower LDL cholesterol.

Your doctor will use a tool like the American College of Cardiology/American Heart Association risk calculator and other factors to gauge your long-term risk of atherosclerotic cardiovascular disease, determine if you need statin therapy, and if so, which one.

The statins are generally taken once daily and are available in generic forms. Its important to note that atorvastatin and rosuvastatin really are the workhorses of cardiology and statins at this point, Dr. Laffin adds. A lot of pharmacies typically will have one of the high-intensity statins. Theyre inexpensive and easy to obtain. In my experience, 99% of insurance companies cover at least one of them, and more than 75% cover both of them.

Guidelines from the American College of Cardiology and American Heart Association recommend statin therapy for:

* These factors include a family history of ASCVD, LDL levels persistently 160 mg/dL, triglyceride levels persistently 175 mg/dL, chronic kidney disease, ethnicity, inflammatory diseases, metabolic syndrome, and (in certain people, if measured) results of high-sensitivity C-reactive protein, lipoprotein(a), and apolipoprotein B. Note: The guidelines recommend considering coronary artery calcium scoring for people at intermediate risk in whom a decision about starting statin treatment remains uncertain.

Elevated liver enzymes. In addition to more common side effects such as headache and nausea, statins occasionally may cause increases in liver enzymes, suggesting liver inflammation. However, the latest ACC/AHA guidelines recommend liver-enzyme testing only for statin users who are at higher risk or have symptoms that may suggest liver toxicity. Furthermore, statins may cause small elevations in blood sugar, enough to push some people into the range of type 2 diabetes. But, we know that the benefits of statins outweigh that small increase in blood glucose across multiple populations, Dr. Laffin notes.

Mental fogginess. While some studies have identified positive effects of statins on cognitive function, some users have reported problems like mental fogginess and forgetfulness, which go away after stopping the drug. Overall, though, large-scale clinical trials dont suggest an increase in cognitive problems associated with statin use, Dr. Laffin says.

Muscle pain. One of the most noteworthy side effects associated with statin therapy is muscle aching and stiffness, which can be more severe as the statin dose and potency increase and may make some people intolerant to the drugs. Certain statins in particular, atorvastatin and simvastatin are more likely to cause these side effects, while others, like rosuvastatin and pravastatin, have less of an effect.

Some treatable conditions (like thyroid dysfunction and severe vitamin D deficiency) may contribute to statin intolerance. So may consuming large quantities of grapefruit (or juice) and taking certain medications. Addressing these factors may ease or prevent statin-related muscle effects. Also, some people have found that taking coenzyme Q10 supplements may help, although the ACC/AHA guidelines dont recommend their use.

Its important not to stop taking your statin and to report any muscle side effects to your physician. Your doctor may switch you to a less-potent statin, change the dose, or explore alternative dosing strategies. This may include taking the drugs every other day or less frequently. With some perseverance, you and your physician can develop a statin regimen that works for you.

Usually, you can find at least some dose of statin that people can tolerate, even if it is just a couple times a week, Dr. Laffin says. If you absolutely cannot tolerate a statin at any dose, then we have other medications we can use, such as ezetimibe (Zetia) or newer drugs known as PCSK9 inhibitors: alirocumab (Praluent) and evolocumab (Repatha).

Age is the most significant risk factor for atherosclerotic cardiovascular disease. However, the risks and benefits of statins must be carefully considered in older populations, especially those with health problems.

Older adults, as a whole, may be more likely than their younger counterparts to experience serious side effects from statins. Many seniors take multiple medications, making them more likely to experience adverse medication interactions with a statin. Importantly, seniors with other medical conditions that shorten their life expectancy may not reap the benefits of statin therapy.

So, if youre over age 75 and especially if you have other health problems discuss the pros and cons of statin therapy with your physician, Dr. Laffin advises.

The effects of statins are usually over the long termwere talking five to 10 years in terms of cardiovascular risk reduction, he explains. So, you have to balance the risk of taking another medicine versus whether you are going to die from something else in those five to 10 years. I think its very reasonable for someone who has other competing comorbidities to talk about deprescribing statins.

This article first appeared in Cleveland Clinic Mens Health Advisor.

Original post:
What You Should Expect From Statin Therapy - Health Essentials from Cleveland Clinic

It happened quickly and quietly. In fact, it was the silence that made David Brosh wonder why the familys two white Westies, taking a quick bedtime potty break, hadnt barked to come back inside.

On a frigid Sunday night in early December, he let them into the tiny yard behind their Parker home. It was dark until Chloe and Chuffys presence activated the motion-sensor floodlights. Beyond the 42-inch split-rail fence, webbed with wire fencing so the dogs wouldnt get out, a large swath of open space near Newlin Gulch had been blanketed by a recent snow.

Minutes later, when David stepped outside to check on the dogs, a coyote turned to meet his gaze just as it trotted into the shadows beyond the reach of the floodlights. It appeared to have Chloe, all 17 pounds of her, in its mouth.

David grabbed a flashlight, hopped the fence and followed the tracks as far as he could into the gulch, until they mixed with lots of other tracks and disappeared into some low brush. No sign of Chloe. When he returned to the yard, he saw 25-pound Chuffy lying in the snow, seriously injured. He called to his wife, Mardee, that they needed to get to the vet.

From there, the hours unraveled in a nightmare of tenuous hope for Chuffys survival from his neck wounds and the continued search for Chloe that yielded little more than a trail of reddish splotches in the snow.

Daylight revealed what looked like tracks from two coyotes in the Broshes yard. Meanwhile, surgery on Chuffy ended with a hopeless diagnosis. The couple made the decision to put him down.

They were the heart of our family, Mardee says, and got me through so many difficult times. You know, you get really attached to your dogs.

On top of their sorrow, word of similar coyote encounters throughout the rapidly growing community southeast of Denver heightened the couples concern. Theyve lived in their house for more than eight years and perhaps twice have seen coyotes venture this close until suddenly, reports of sightings, and particularly attacks on dogs, have spiked.

Wildlife experts say the situation reflects a recurring phenomenon, a cycle of coyote activity that ebbs and flows throughout the so-called urban-wildland interface and now, well into the urban core literally from Los Angeles to New York.

It does seem periodic, says Kristin Cannon, an area wildlife manager with Colorado Parks and Wildlife. Well go several years where theres no issues, or very minor ones. Coyotes are pretty ubiquitous anymore, but as far as conflicts with people, and with pets, that seems to flare up every few years one place or another. Because conflicts are so common, its hard to quantify.

Many communities along the Front Range have an official coyote management plan, which largely defines levels of interaction with the animals and prescribes at what point, and how, action may be taken to mitigate problems.

Attacks on humans tend to be the tipping point. And while lethal removal looms as an available tool, the emphasis remains on education and adapting human behavior. That strategy reflects the reality that coyotes, despite historical campaigns to eradicate them, have been a fixture on the continent for upwards of five million years.

And theyre not going away. As longtime coyote researcher Dan Flores, author of Coyote America, succinctly puts it: Resistance is futile.

The flurry of coyote activity in and around Parker marks yet another chapter of a centuries-long conversation surrounding the uncommonly adaptable creatures, one that ranges from todays real-time online postings to historical writings that freighted it with cultural meaning.

Its been an animated dialogue, in every sense.

Early periods of enthusiastic hostility toward the animal have dissolved into more recent arguments for coexistence. European explorers scouting the West initially didnt know what to make of coyotes, or even what to call them. From that uncertainty, the coyote eventually became a fixture in American culture, for better and worse.

MORE: Read more wildlife stories from The Colorado Sun.

In many Native American cultures, the coyote appears as an avatar for humans. Tales handed down through generations employ it as a four-legged metaphor, precisely for the way it holds a mirror to human behavior. Native to North America, the coyotes howl, Flores contends, is our original national anthem.

In early America, the disparagement of coyotes grew from the cross-pollination of politics and culture. Flores traced references to coyotes in 19th-century American literature and settled on Mark Twains humorous excerpt from Roughing It in 1872 as the launching pad for what became coyotes dismal reputation.

Twain writes, in part: He is always hungry. He is always poor, out of luck and friendless. The meanest creatures despise him He is so spiritless and cowardly that even while his exposed teeth are pretending a threat, the rest of his face is apologizing for it.

By the 1920s, even Scientific American inserted the coyote as the shifty trickster-villain in a contemporary political allegory in which it argued that good Americans, if they spy one, should shoot it on sight for patriotic reasons because the coyote is the original Bolshevik.

Much disdain for coyotes originated within the livestock industry, whose assets run afoul of predatory animals. And that, Flores says, led to an agency of the federal government, then called the Bureau of Biological Survey, seizing on the opportunity to brand itself, in the early 20th century, as the antidote to predation. It proved an effective strategy to guarantee congressional funding.

Colorado played a pivotal role in the extermination efforts that followed. The Eradication Methods Laboratory, which designed and manufactured the means to kill massive numbers of mostly wolves and coyotes, began producing strychnine in Albuquerque. But in 1921 it moved operations to Denver where, Flores writes in Coyote America, it would go on to perfect an amazing witchs brew of ever more efficient, ever deadlier pesticides.

Even the eradication campaign came with what Flores calls a concerted PR effort to demonize coyotes. Powered by a series of pre-packaged stories from the Biological Survey, he says, major publications all across the country ran fictionalized accounts that cast certain nuisance animals, including the coyote, as Al Capone-style gangsters. Those who would destroy them were cast as heroic G-men.

Its a Frankenstein story thats of our own making.

Wolves were essentially wiped out in the U.S. by 1925. But coyotes, despite lacking a public relations campaign of their own, more than survived attempts to snuff them. They flourished. So what did they have that wolves didnt?

In simple terms, coyotes can live in groups, when its advantageous. But when its not, they can disperse into pairs or even solitary individuals and scatter across the landscape, making them difficult to locate and eliminate.

Wolves are pure pack animals, and hunters discovered if you can track one of the animals in a pack, you can use its scent to prepare bait and get every one in the pack, Flores says. But coyotes dont have the same pack adhesion. Thats the single advantage over wolves that allowed them to survive.

So the eradication strategy backfired. Not only did the campaign not wipe them out, but it triggered colonization. When coyotes sense their numbers dwindling, the number of pups in their litters grows larger a phenomenon called compensatory breeding.

MORE: Colorado Springs downtown creek has long been viewed as a blight. Then one man started catching trout in it.

Coyotes migrated all over the country and grew comfortable in urban areas, where they face no natural predators, no hunters shooting at them from helicopters, no leg traps or poisons. Plus, urban areas attract plenty of smaller animals, like rabbits, squirrels, rats and mice, that provide a ready food source.

Its a Frankenstein story thats of our own making, Flores says.

But by the early 1960s, a cultural icon took a stand for the lowly coyote. Walt Disney, whose catalog of film and television productions adopted ecological advocacy in its infancy, in 1961 produced an hour-long feature for Walt Disneys Wonderful World of Color, a show that already had a reputation as appointment TV. The animated piece was called The Coyotes Lament and marked the first of six TV or movie features Disney would produce on coyotes.

And while that was happening, you had the Wile E. Coyote and Roadrunner cartoon, Flores notes.

While not exactly heroic, Wile E. Coyote presents at least a sympathetic image of the coyote. Hes humiliated by the Roadrunner at almost every turn, and his efforts to employ technology fail miserably. But he never gives up.

After a four-decade campaign to brainwash Americans, suddenly the pop culture movement portrayed the coyote in a different light, Flores says. That makes a lot of difference.

Considering their tarnished reputation, coyotes ability to adapt and survive has been nothing short of astounding.

For all the talk of how human development has encroached on animals natural habitat, the coyote has turned the tables. A recent story in National Geographic reported that coyotes actually have increased their range by 40% since the 1950s, can be found in every state except Hawaii, have become established in Central America and are expected to appear soon in South America.

Mary Ann Bonnell, a ranger for Jefferson County open space, has published research on coyotes and stars in widely viewed YouTube videos on wildlife that make her an in-demand source on dealing with urban arrivals. She can almost track their territorial expansion simply by picking up the phone.

Currently, its the D.C. area and New York City, she says of the calls seeking advice. Here in Colorado, we already went through that whole arc: In the early 2010s people were going, Heres this apex predator thats moved into the neighborhood, what does that mean? What happens to my dog? All these burning questions, all valid. Those residents have a quick learning curve to figure things out and make changes and understand what it means to have coyotes in the community.

Meanwhile, researchers in Colorado continue to keep tabs on coyotes everything from their interaction with humans to their diet and genetic clues that may offer insight into their adaptive behavior. But whats going on when we see an uptick in coyotes encounters with people and unusually fearless behavior that can include attacks on pets?

Stewart Breck, a researcher with the U.S. Department of Agricultures National Wildlife Research Center based in Fort Collins, also specializes in urban coyotes. He has a good idea whats going on. In fact, he sees two things.

First, urban coyotes tend to be bolder and more explorative, he notes. Breck drew this conclusion from research comparing coyotes in Denver to those that inhabit rural areas, which confirmed the behavior pattern. Similar studies have been repeated in many areas around the country.

Currently, its the D.C. area and New York City. Here in Colorado, we already went through that whole arc.

Second, researchers have identified certain problem individuals that appear periodically in urban environments. These bad actors tend to be responsible for most of the unusual conflicts with people. Studies on this phenomenon kicked into gear locally 10 years ago, when multiple people in Broomfield reported being bitten by coyotes. In 2011, coyotes in the area also bit three children.

That got a lot of people asking the same question youre asking, Breck says.

Cannon, the wildlife manager for CPW, says that when the first child was bitten in Broomfield, CPW made an effort to lethally remove the culprit. The problem is that coyotes tend to look the same and live in social groups, making it difficult to pinpoint the problem. When the second child was bitten, CPW responded again and eliminated more coyotes and repeated the process again after the third biting incident.

Finally, we were able to catch up with the correct coyote and the behavior stopped, Cannon says. Its hard to say why theyre behaving that way, if there was one or more than one, but it took multiple operations on our part before we eliminated the one. It wasnt for lack of trying, but its difficult to lethally manage coyotes in an urban setting.

Despite the troubling incidents, Broomfield has maintained a fairly conservative, hands-off approach with regard to coyotes that leans on measures like education and sometimes closing down open spaces if issues arise leaving removal as a last resort, Cannon says.

In 2009, Greenwood Village responded to a years worth of sightings and attacks on dogs which culminated with a teenage boy fending off a coyote in a local park by hiring Jay Stewarts Animal Damage Control to kill the problem animals. The subsequent media attention activated animal rights advocates, and their protests ignited what Stewart recalls as a fiasco that demonstrated the strong feelings humans have on both sides of the coyote issue and aborted his efforts.

Later, Stewart notes, a client who lived adjacent to the park where the well-publicized attack on the boy had occurred told him that people in the area had felt sorry for the coyotes and had been feeding them. Its not unlike the problem that has vexed wildlife authorities in other areas, where the same type of human behavior also has emboldened many bears, which then become so comfortable around people that they have to be put down.

Things go south when that happens, Stewart says. Even though it was a bad thing in the park with that kid, that problem was human-caused. Because they were being fed, it probably walked up to that kid thinking it would get something.

Stewart gets far fewer calls about coyotes than he used to because many jurisdictions have developed coyote management plans that emphasize education and hazing the animals as a primary means of dealing with them. When they need removal, they turn to state and federal agencies to handle the situation, or even local police.

Greenwood Village, which draws on Bonnells expertise, fine-tuned its coyote management plan over the past several years. It has seen a remarkable decline in incidents, says Cmdr. Joe Gutgsell, who oversees coyote management for the citys police department.

Since 2013, Greenwood Village has hosted an annual community meeting to familiarize residents with policies and recommendations for how to minimize coyote problems. It also has started a detailed reporting program that allows Gutgsell to chart location and frequency of incidents and, as a result, respond more effectively when necessary.

When circumstances do call for removal, Gutgsell says the police department has a selective and organized process that calls on two designated officers both firearms instructors to handle the problem. The city no longer contracts removal or relies on CPW.

Bonnell speaks at the yearly neighborhood meetings, and the city provides both printed and digital versions of an informational brochure that cover topics like normal coyote activity, leash laws that can help protect pets and admonitions against feeding wildlife.

We dont remove coyotes for being coyotes. We dont lethally control a coyote that becomes habituated to people and comfortable in urban neighborhoods.

While Gutgsell acknowledges that some of the recent decline in incidents may be due to simple luck and natural migration, the numbers over the past five years have been encouraging. In 2015, the city fielded 26 reports of coyote incidents involving pets, a number that includes both injuries and fatalities. When that number spiked the next year to 46, more than 100 residents showed up to the annual meeting, where they got a heavy dose of prevention education.

In 2017, the number fell to 20, then to five and finally, last year, to just a single reported incident.

There was no cause to remove any of the animals and only a few residents even showed up for the annual management meeting.

Bonnell calls it a model program, and notes that the city learned a lot from the 2009 debacle. She adds that communities in the Denver metro area that have taken advantage of templates offered for management plans (among others, the Humane Society of the United States has produced a sample plan) and that stress education tend to be best equipped to deal with coyotes as opposed to those that wait for a problem to emerge and then call Colorado Parks and Wildlife for help.

Coyotes are smart creatures and tend to work the system, she says. You have to be proactive. But because humans are hard to train, we usually dont do anything till something bad happens. Its hard to sell coyote education if nothing bad is happening.

CPWs Cannon notes that most plans she has seen respond to sightings with education or signs warning of coyotes presence. And some plans allow for lethal response when coyotes pose a threat or injure a person and often delegate that job to her agency.

We dont remove coyotes for being coyotes, she says. We dont lethally control a coyote that becomes habituated to people and comfortable in urban neighborhoods. And we dont remove coyotes that prey on pets. Theyre similar to its natural prey source, so its natural behavior for coyotes, unfortunately, and the onus is on the pet owner to supervise their pet when they live near coyotes.

While measures such as motion-sensor flood lights and even noisemakers like air horns are encouraged, especially for people living alongside open space or parks, the question of a homeowner using firearms to try to eliminate a problem coyote can raise legal issues. State law allows use of lethal force to prevent damage on your own property, but many urban jurisdictions have laws regarding discharge of firearms that could conflict with that method.

MORE: Remember the Fort Collins trail runner who killed an attacking mountain lion? Heres what his life has been like since.

For all practical purposes, its not an option, Cannon says.

The USDAs Breck adds that in most cases, elimination doesnt solve what people might think it will. Consider what experts call coyote math: 1 minus 1 equals 1. And the adage that holds: If you kill one coyote, six will come to the funeral. Targeting bad actors is one thing. Culling the pack is a pipe dream.

In light of that calculus, one helpful tactic is hazing, which involves non-lethal measures from making noise when coyotes become too comfortable to chucking rocks to intimidate them into shying away from humans.

Most coyotes in urban areas are not going to be a problem, Breck says. Theyll do what coyotes do, and youll hardly notice theyre around. The idea that we need to get in there and shoot them is not what Im recommending. That is not going to work, and not necessary.

On a national scale, coyotes still are eliminated, but primarily to protect livestock. Farmers and ranchers claim millions of dollars in economic losses. In 2018, according to the USDA, more than 68,000 coyotes were killed by a variety of methods. Nearly half were shot from either fixed-wing planes or helicopters. In five agricultural states, not including Colorado, more than 5,600 were poisoned with so-called cyanide bombs, a method re-approved for use last month by the Environmental Protection Agency (with some additional safeguards) over objections from conservation groups.

No coyote attacks on humans have been reported in Parker, according to police. But suddenly, neighbors throughout the area were seeing coyotes everywhere. And some exhibited unnerving behavior including additional attacks on dogs.

Parker police noted an uptick in sightings, but remained unaware of the dog deaths until the Broshes filed their report on Chloe. In fact, since mid-November, they have a record of just six calls for service involving coyotes five sightings and one dog fatality.

Meanwhile, a multitude of postings on the online neighborhood bulletin board Nextdoor warned when coyotes were spotted and reported incidents including attacks on dogs. Mardee says a neighbor filtered all the various accounts and counted 10 unique cases of dogs that were killed in the area in and around Parker.

That disparity with law enforcements records underscores the need for further public education, says Parker police spokesman Josh Hans. While law enforcement can post notices on Nextdoor, it isnt allowed to monitor the bulletin boards, so it relies on direct reporting from residents.

From the information reported to us, it doesnt make (coyotes) seem like an issue, Hans says. In the next month or two, we need to start getting some messaging out. Its great that people are letting their neighbors know so they can be watchful. But if theyre not telling us, we cant do anything about it.

In recent days, the Broshes installed video cameras outside their house in the hope of learning more about coyote activity. They would prefer a back fence higher than just 42 inches along their border with open space, but neighborhood covenants dictate the lower, split-rail style that leaves pets more vulnerable. They had the motion-activated flood lights installed, and always checked before letting Chloe and Chuffy loose in the backyard.

I dont want to have to worry about going to the mailbox and having to take pepper spray. I just want to be safe in my own neighborhood.

Mardee figures one or more of the coyotes from what appears to be a den in the gulch simply traced the fence line, checking the yards for possible prey. And when they got to mine, they just hopped the fence because my dogs were there. So we think theyve been actively hunting in the yards.

But her concerns run beyond her own loss.

Weve heard from other folks, people walking on the trail down here being harassed when theyre hiking with their dogs, which I can see because that den is very close to where the trail runs through, she says. And now people are saying theyre seeing them further up into the neighborhood.

Its not that I hate coyotes, she adds. We thought they were cool. I just dont want them in my yard. And I dont want them attacking people when theyre walking their dogs on the trail. I dont want to have to worry about going to the mailbox and having to take pepper spray. I just want to be safe in my own neighborhood.

Bonnell, the Jeffco open space ranger, conjectures that possibly a new pair of coyotes which mate for life moved into the neighborhood and were denning in preparation for a litter of new pups. And at least one is dog-aggressive, protecting territory by removing competition, she says.

The timing, if this has all happened in the last couple of months, makes sense, she adds. Right around the time we switch from daylight savings to standard time, you begin to see the dog awareness where coyotes are escorting dog walkers away from their den or even attacking and killing dogs. Theres an increase in conflict right around that time. Theyre establishing territory for the family thats coming.

CPWs Cannon empathizes with the frustration of people worried for their pets.

Theyre not wild animals, theyre family members, she says. And its extremely difficult when people are facing tragedy like that, for us to come in and say, Well, thats a coyotes natural prey source.

On top of that, she recognizes the inconvenience of having to constantly keep an eye on your pets, even on your own property, to ensure they dont fall victim.

I have dogs and a big backyard I like to let them run around in, she says. I understand what a burden that is, to think in order to protect your pet, you need to go out with them every single time and keep them on a leash. I just dont know that theres an alternative solution thats going to alleviate that. Its kind of a reality.

And so the conversation about coyotes continues. The interaction of humans and wildlife has become a hot area of research, and Joanna Lambert, a professor of environmental studies at the University of Colorado Boulder, has bitten off a considerable chunk almost literally.

Shes looking at what coyotes eat in different environments and how that may have changed their genetic makeup, which in turn might explain certain behaviors, particularly in urban environments. More precisely, her research examines whether there are particular genes involved with the digestion of carbohydrates in human food.

Dogs evolved the capacity to extract energy from starchy carbs, in a way wild wolves dont, Lambert says. Were looking at whether theres evidence of the same process in coyotes. A lot of other questions asked about coyotes are very difficult to distinguish between whether the behaviors were seeing are the result of learned behavior or genetics. Its very complicated. Were tackling that problem from a slightly different angle, looking at the food part and if the genome has shifted toward human food.

Lambert also has two graduate students pursuing studies related to coyote-human interaction in the Denver and Broomfield areas. One seeks input from people who frequent local parks and open space about their perceptions of whether coyotes have become more aggressive, curious or bold. Another student is tracking whether coyotes are more or less likely to avoid humans when more humans are present such as during a busy day in the park.

None of the studies has yet been completed and published.

Cities in some ways represent a refuge from natural predators, from human hunters, Lambert says. But they also offer a whole new array of food sources. These can be anything from birdseed, occasionally human garbage, cats and small dogs. It could also be almost certainly the case that theyre eating other animals that have adapted to humans, like house mice and rats, urban animals. Thats part of the big question.

Were used to a culture where you swipe your credit card and a problem goes away. This is not one of those problems.

Coyotes have learned to read human behavior, explains Coyote America author Flores, noting that while coyotes have no fear in cities, where theyre not being hunted, their behavior can be much different in rural areas. If you see coyotes while driving in rural New Mexico, he explains, and then pull your car over, theyll sprint away from the car running in a switchback pattern an evasive maneuver learned because in such situations they can expect gun shots.

I encourage people to keep them wild, keep them thinking that were a little too weird for them to trust, he says. When I see them standing around and not moving, Ill raise my arms and shout, maybe throw a rock. Its good for them to be a little spooked rather than nonchalant.

By the same token, it can be helpful for humans to understand something about coyote instincts. From May until August, roughly, they have pups to protect. So if a coyote emerges from the bushes to escort a hiker and their dog away, following but not quite threatening, it likely means they approached too close to a den. Its happened to Flores in the canyon near his home while running with his 135-pound malamute.

Bonnells interest in coyotes was piqued before she took her Jeffco ranger job, when she was working in Aurora and came across people who essentially treated the wild canids as pets, even naming them as they trotted up to windows to touch noses with their house pets. So when she talks about basic truths about coyotes, arguably the most significant one isnt about coyotes at all. Its that humans are extremely difficult to train.

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Coyotes figured out how to survive in the city. Can urban Coloradans learn to coexist? - The Colorado Sun