Archive for the ‘Male Genetics’ Category

It remains one of Northern Irelands most notorious cold-cases, still unsolved after 31 years.

It was in April, 1988 when a pretty young blonde schoolgirl from Munich named Inga Maria Hauser, a budding singer with intrepid spirit to match, decided to go backbacking during the Easter break, and full of the anticipation of adventure, primed to see something of other countries and cultures, she set out to visit England, Scotland and Ireland.

Her friend Walter Schreiner, who first met Inga in their local youth club in the mid-1980s, said of the budding young adult: Every person who knew her loved her. She was always smiling, she was always shining and was very intelligent.

A girl with charm and wit and all before her then, setting off to see new sights and meet new people in a different culture to her own; a brave soul, unfazed by the prospect of travelling alone.

Poignantly, Inga had already noted the friendliness of the local people.

During her travels one of the 18-year-olds postcards home from England said: The people here are so helpful and lovely that I cant imagine anything bad could happen to me.

A note in her diary added: The day after tomorrow I am going on to Ireland. Im looking forward to that the best.

She got the ferry from Stranraer, arriving in the port town of Larne on April 6. But she would never make it to her next destinations of Belfast and then Dublin.

Two weeks after she was last seen alive, her dumped mutilated body, having, acorrding to Police, been subjected to a vicious and ruthless sexual and physical assault, was found by a sheep farmer in a remote part of Ballypatrick Forest near Ballycastle.

Here was the life of a beautiful girl cut senselessly short, her dreams and hopes for the future callously denied and a family back in Germany plunged into unimaginable grief.

In the 31 years since the horrific murder both of Ingas distraught parents have died without seeing justice served.

Her mother Almut passed away in October of this year. Her father, Josef, died in 2006 from cancer. Both were hearbroken that the case was never solved; that they were denied answers, a perpetrator or perpetrators brought to justice.

Ingas sister Frederika was particularly badly affected by her sisters death, her son Viktor told a BBC programme last year:

Siblings always have a little tension around them. But they were really close, even though they were quite different. There is a German saying - ein Herz und eine Seele - one heart, one soul.

Of the pursuit of justice for Inga, Viktor said: It would be especially important for my mother. I hope if the murderer gets caught, my mother can finally leave this behind and we can be free of this curse.

SDLP MLA for East Londonderry John Dallat has been involved in the campaign to find Inga Maria Hausers killer for many years; for him the quest to find those responsible for Ingas death has become a life-long priority and passion project.

He was instrumental in getting the case reopened by the PSNI last year after the files were closed due to lack of progress.

John said: I remember when Inga was murdered and my heart went out to her family. I was a young father then to a young girl who I hoped would grow up also and travel the world - and she did. Every parent expects their child to be able to travel without being murdered in the brutal way that Inga Maria was. After ten years of campaigning the parents said they werent coming back and so I assumed that role fighting for justice for Inga. And it has been a long struggle.

This is a personal and emotional struggle for me and it has been a great privilege getting to know Ingas only sister Frederike Leibel. She has one son, Victor, who visited last year, and stayed with us.

In all the years since Inga was murdered they only received a series of letters in English and werent even aware for a long time that they were entitled to legal representation. The support they received was not good.

But we want to focus on getting whoever did this heinous crime to be brought to justice.

Since a memorial stone to Inga was erected in Ballypatrick Forest Park on the 30th year of her death, well-wishers have left tokens at the site, flowers, soft toys, cards, religious objects.

This week John Dallats granddaughter Caitlin laid a wreath at the headstone to mark 31 years. The hope is to send the Hauser family a festive message of support - that their beloved sister and aunt has not been forgotten; the difficult quest for answers continues.

The also plan to erect a German flag to acknowledge Ingas home country and to signify that she was the only international student to die here in Ulster during the Troubles.

Christmas means nothing to the Hauser family since they lost their beloved Inga in one of the most brutal murders ever recorded and all the more reason why we need to show that we really care, continues John.

The family know that Inga hasnt been forgotten and they have recovered hope that justice may still be done.

In May last year, a 59-year-old man was arrested on suspicion of the murder by police investigating the case and later released on bail pending further inquiries.

Detectives said they believe several people may have been involved directly in the murder, or in the subsequent cover-up, and said they only need fractional piece of evidence to bring the chief suspects to justice.

Police also found a male genetic profile at the murder scene, although have yet to find a match.

The Public Prosecution Service is now in receipt of a lengthy file of evidence against the chief suspect.

Dallat continued: The fact that a file has gone to the Public Prosecution Service after 31 years is welcome news and offers some hope to the Hauser Family.

It represents the first chink of light in a long struggle for justice for their daughter Inga who died a most brutal death at the hands of a killer who was intent on raping a young girl over here during a school break to find out about a country that her parents loved.

Perhaps the saddest thing about the murder of Inga is the silence of those who know who did it, but that silence cannot be sustained for much longer.

Hopefully the file which has gone to the Public Prosecution Service will be a historical development which will bring closure to a family who have suffered in silence for far too long, Mr Dallat added.

It is our responsibility and that of the police and courts to redouble our efforts to ensure that those involved in Ingas murder are brought to justice.

I am so sorry that my efforts and that of others havent achieved their purpose so far.

But I remain confident that sooner, rather than later, that justice will be done and that the retribution Almut and Josef were denied will be delivered.

Dallat is clear about what he would like to say to those responsible for, or who know something about, Ingas murder:

I urge them to admit their guilt. Its not easy to give evidence against people who were perhaps once friends. But we believe there are witnesses out there who must do the right thing and demonstrate some level of decency.

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Inga was a beautiful girl with her whole life in front of her, her death was a national shame - Belfast Newsletter

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Have you finished your holiday shopping yet? Sometimes, the hardest people to buy for are your significant other, or those closest to you. Theres always that one big gift you know they want, the one youre sure to givebut what comes next? Sure, you could load up on stocking stuffers, or settle for gift cards. But heres a better idea: Give the gift of health, knowledge, and insight. Give them a 23andMe Health + Ancestry Kit.

The 23andMe Health + Ancestry Kit ($129; was $199) is full of fascinating information on ancestry and family lineage. But it also provides a wealth of biological and genetic insight to help your loved one live a happier, healthier life.

DNA home test kits are all the rage, and with good reason. Its fun to trace your lineage, to track where your ancestors came from, and how you got where you are today. Thats why these kits are so popularespecially this time of year.

Holiday gatherings can be a slog. But sharing ancestral info with family and loved ones is a fantastic conversation piece. Showing up at the family get-together with a family tree, with names, dates, and places of those who came before, is definitely fascinating and fun. But for the seniors in your family, it can be far more than that.

If youve ever watched your grandmother or grandfather reminisce about the old days, you know what we mean. Imagine the faces of the seniors in your family lighting up when you remind them of places and people in the past, of memories theyd forgotten and people theyve missed.

Reminiscing about old times, reliving memories of ancestors passed on, of homes and towns they once adoredor hated!is sure to bring a smile to everyone gathered around the holiday table. Its sure to be a heart-rending, emotional moment. And it will make this holiday season one you, and they, will cherish for the rest of your lives.

Thats why the 23andMe Health + Ancestry Kit makes an unbeatable gift. And right now, you can save $70! Regularly $199, through December 26 you can pick one up for just $129. Thats only $30 more than the Ancestry + Traits kit alone. Thats a 23andMe December deal you cant pass up!

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Theyll learn how their DNA could affect their chances of developing certain health conditions like Type 2 diabetes*. Theyll find out how their DNA relates to their lifestyle, like muscle composition, diet, and sleep. Particularly valuable is the Carrier Status test, which will let them know if their DNA indicates they may be a carrier for genetic variants linked to certain inherited health conditions.

Of course, the 23andMe Health + Ancestry Kit has the Relative Finder, the Family Tree, and the Ancestry Reports that are so fun and fascinating to share at the holidays. But the valuable information from the more than 150 Trait, Health Predisposition, and Carrier Status reports goes far beyond fun and fascination. Its the kind of knowledge that can help your loved one live a fuller, healthier life. Thats the kind of holiday gift no stocking-stuffer or gift card can possibly beat.

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The Unbeatable Holiday Gift: Save $70 on a 23andMe Health + Ancestry Kit Today - Men's Journal

PHILADELPHIA -- One out of eight couples has trouble conceiving, with nearly a quarter of those cases caused by unexplained male infertility. For the past decade, research has linked that infertility to defective sperm that fail to "evict" proteins called histones from DNA during development. However, the mechanisms behind that eviction and where this is happening in the sperm DNA has remained both controversial and unclear.

Now, researchers at Penn Medicine show, using newer genome-wide DNA sequencing tools, the precise genetic locations of those retained histones, as well as a key gene regulating it. The findings were published in Developmental Cell.

Taking it a step further, the researchers created a new mouse model with a mutated version of the gene, Gcn5, which allows investigators to closely track the defects in sperm from the early stages of sperm development through fertilization and on. This is an important step forward as it could lead to a better understanding of not only infertility in men -- and ways to potentially reverse it -- but also the suspected epigenetic mutations being passed onto the embryo from males either naturally or through in vitro fertilization.

Epigenetics, the factors influencing an organism's genetics that are not encoded in the DNA, play a strong role in sperm and egg formation.

"For men who have unexplained infertility, everything may look normal at the doctors: normal semen counts, normal motility. Yet they can still have problems conceiving," said first author Lacey J. Luense, PhD, a research associate in the lab of study senior author, Shelley L. Berger, PhD, the Daniel S. Och University Professor in the departments of Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute. "One explanation for persistent problems is histones being in the wrong location, which may affect sperm and then early development. Now, we have a really good model to study what happens when you don't get rid of the histones appropriately in the sperm and what that may look like in the embryo."

Healthy sperm lose 90 to 95 percent of histones, the main proteins in chromatin that package DNA and turn genes on and off, and replace them with protamines, which are smaller proteins able to properly pack the DNA into tiny sperm. Given the role of retained histones in infertility and embryonic development, there is great interest in determining the genomic locations so they could potentially be utilized for further study and ultimately treatment.

Past studies have produced conflicting results on the whereabouts of histones. A technology known as MNase-sequencing that uses an enzymatic reaction to pinpoint location has placed the retained histones on important gene promotors. Other studies with the same approach found histones at DNA repeats and placed in so-called "gene deserts," where they play less of a role in regulation.

"There has been controversy in the field trying to understand these discrepant data," Luense said. "In this new study, we found that both of these previously described models are correct. We find histones on genes that appear to be important for embryo development, but we also find them at repetitive elements, places that do need to be turned off and to prevent expression of these regions in the embryo."

The researchers applied a technology known as ATAC-sequencing, a more precise and faster approach, to track waves of histones at unique sites across the genome during the early and late stages of sperm development in mice. ATAC-seq can identify parts of the genome open and closed -- in this case, regions that retain the sperm histones -- and then make a cut and tag the DNA, which can then be sequenced.

In the mouse models created with the mutated Gcn5 gene, the researchers found these mice to have very low fertility. The researchers also showed that retained histones in normal mice sperm correlated with histone positions in very early embryos, supporting the hypothesis that paternal histones transfer epigenetic information to the next generation.

Having this type of mutant model gives scientists a tool to closely study the mechanisms underlying the mutated sperm's trajectory and understand what effect it may have on the embryo and in development. It also opens an opportunity to study potential therapeutic targets.

"Right now, the burden of IVF and other assisted-reproductive technologies fall on women. Even it's the male factor, it's still women who have to go through hormone injections and procedures," Berger said. "Now imagine being able to apply epigenetic therapeutics to change the levels of histones and protamines in males before embryogenesis? That's one of the questions we want to explore and this model will allow us to move toward that direction."

There are numerous available epigenetic drugs used to treat cancer and other diseases. Given their mechanisms, treating sperm with drugs to increase histone eviction is one potential route to explore.

Limitations with human embryos in science have led to a lack of overall research on infertility and the role of the father's epigenome on embryo development, which underscores the importance of studies such as this, the researchers said.

"There are a lot different factors that can alter the sperm epigenome: diet, drugs, alcohol, for example," Luense said. "We are just now starting to understand how that can affect the child and affect development. These initial, basic studies that we are doing are critical, so we can better understand what's driving these epigenetic mutations."

Read the rest here:
Penn researchers uncover defective sperm epigenome that leads to male infertility - Science Codex

As a 30-year-old, Caroline Henaghan was busy. She was working for the UKs Home Office while training to be a barrister, and wondered if the frequent stress and anxiety she was experiencing were just products of overwork and getting older. It felt like getting on a hamster wheel and not being able to get off, she recalls.

Eventually work got to be too much and she took an uncharacteristic short leave of absence. But Henaghans mood didnt improve. She woke up each morning with enormous anxiety, leading to social withdrawal. I would essentially do a disappearing act so I wouldnt have to be around people, she says. She was never suicidal, she stresses. But she did fantasise about leaving things behind. It would be a case of if I could go to sleep and never wake up. Thats how dramatic it was for me.

Though the psychiatric symptoms were the strongest, there were odd physical patterns as well. Henaghan would get bloated and fatigued, sleep excessively, and as a keen gardener shop erratically, for instance buying plants that were out of season. Her family noticed her increasingly strange behaviour as well. She thought it might be bipolar disorder, given the cyclical nature of her ups and downs. For instance, she might spend two weeks each month putting right the damage from the previous week: the fights with loved ones, the untidy home, the slippages at work. Eventually, after what she calls a mini-breakdown, she realised that the recurrence of all these symptoms was linked to her menstrual cycle.

Her doctors dismissed her concerns. She visited five GPs, all male, after the first one commented: Oh, its just PMS. My wife gets that.

But it wasnt just premenstrual syndrome (PMS). Henaghan had to do what many women overlooked by the medical establishment do: her own research. Through her online study, she learned about a condition called premenstrual dysphoric disorder (PMDD).

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PMDD is much more intense than its better-known relative, PMS, with physical symptoms including fatigue and migraines, while the psychological symptoms can include the severe mood swings and anxiety that plagued Henaghan. The disorder can be so debilitating that 15% of those with PMDD have attempted suicide, and some young women affected are opting for hysterectomies.

Read the rest here:
The overlooked condition that can trigger extreme behaviour - BBC News

A memorial has been held for a German teenager who was murdered in Northern Ireland more than thirty years ago.

The body of Munich teenager Inga Maria Hauser was found dumped in a remote part of Ballypatrick Forest, outside Ballycastle, Co Antrim, 14 days after she was last seen alive on a ferry from Scotland.

The 18-year-olds death in April 1988 remains one of the regions most high-profile unsolved murders.

A tribute was paid to Ms Hauser on Saturday at the spot where her body was found.

Mourners laid a Christmas wreath and German flag at the memorial plaque dedicated to her.

Phoenix Law solicitor Claire McKeegan, who attended the memorial, tweeted: Our thoughts are with the Hausers who are pressing the @thePPSNI for a decision on the suspect file. #justiceforINGA.

Last year, on the 30th anniversary of the crime, detectives said they believed a number of people may have been involved either directly in the murder or in the subsequent cover-up, and said they only need fractional pieces of evidence to bring the chief suspects to justice.

Detectives investigating the killing have passed an evidence file on a 59-year-old suspect to the Public Prosecution Service (PPS). The PPS have yet to decide whether there are grounds to prosecute the man.

He was originally arrested in connection with the murder last May and later released on bail pending further inquiries.

Police have a male genetic profile found at the murder scene.

A number of years ago, in one of the largest DNA screenings undertaken in the UK, 2,000 samples failed to produce a definitive match.

Ms Hauser had travelled through England and Scotland and, according to diary entries, intended to travel south to Dublin after her ferry docked at Larne, Co Antrim.

For reasons as yet unexplained, she ended up going in the opposite direction and was found dead in remote woodland two weeks later.

It is understood the IRA carried out its own investigation into the killing 30 years ago.

It is believed republican paramilitaries had considered passing information about the alleged murderer to the RUC at the height of the Troubles, but did not follow through.

Keep up-to-date with all the very latest news, what's on, sport and everything else in Belfast and beyond with the Belfast Live app.

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Inga Maria Hauser memorial held as those involved in death continue to avoid justice - Belfast Live

Dr Leigh estimates two-thirds of the Wollemi-Hawkesbury koala population has been lost, along with the decimation of several other koala populations around the state.

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Volunteer rescuers included experienced State Emergency Service workers and a specialised climbing team that was called in from Victoria. In total, three males and five females, along with four joeys, were saved.

"We put in some very long hours and we're delighted we've got a good ratio of males and females, and also some joeys," Dr Leigh said.

Koalas are a threatened species and vulnerable to extinction across most of their range inAustralia .

Dr Leigh said that although they were a once-thriving community of 3 to 4 million animals, koala numbers are now as low as 300,000 - the World Wildlife Fund have said that koalas could be extinct in NSW by 2050.

"Saving each and every koala population is vital to the species' survival, she said.

In total, three males and five females, along with four joeys, were rescued.Credit:Taronga Zoo

"We just thought it was really critical even though we got a relatively small number. We just needed to do something and we've done the best we can."

The koalas are being cared for behind-the-scenes by the Taronga Wildlife Hospitals veterinary team and Taronga koala keepers until it is safe to release them back to the wild.

"We are committed to caring for these important koalas to ensure some of this vital genetic diversityfrom the Blue Mountains can be preserved and that the future of this iconic species is secured, saidNick Boyle, Taronga Conservation Societys director of welfare, conservation and science.

"This weeks forecast has multiple days above 40 degrees in western Sydney with gusty andchangeable winds, so it was important that we rescued these animals from impending danger."

Matt Bungard is a journalist at The Sydney Morning Herald.

Original post:
Handful of Blue Mountains koalas successfully relocated to Taronga Zoo - Sydney Morning Herald

Written by Divya Goyal | Ludhiana | Updated: December 17, 2019 11:14:13 am Union Minister for animal husbandry, dairying and fisheries Giriraj Singh said that the plan is to provide dairy farmers with sexed semen for cattle for as cheap as Rs 100 per straw by 2020.

During the recently held 14th Progressive Dairy Farmers Association (PDFA) International Dairy and Agri Expo 2019 at Jagraon, Union Minister for animal husbandry, dairying and fisheries Giriraj Singh had said that the plan is to provide dairy farmers with sexed semen for cattle for as cheap as Rs 100 per straw by 2020. The Indian Express explains the technology behind sexed semen pioneered by the United States, how and when it entered Punjab and if it can help in solving the stray cattle problem:

What is sexed semen, and what is the technology behind it?

Sexed semen is specially processed semen of bulls from which Y chromosomes in sperm cells which lead to the birth of a male calf are either removed through a sorting process or killed. Semen which has only X chromosomes can ensure that a female calf is born.

Dr Prakash Singh Brar, dean, College of Veterinary Sciences, Guru Angad Dev Veterinary and Animal Sciences University (GADVASU), said, The reproduction system of cattle is similar to humans. Cows carry XX chromosomes while bull semen carries both X and Y. If the egg fertilises with an X chromosome, a female calf is born and if with Y, a male is born. There are two techniques to produce sexed semen: One is the sorting process in which X and Y chromosomes are separated. X are retained and Y discarded. The other is in which Y chromosomes are altogether killed. Both technologies are pioneered by the United States-based companies and use an instrument called Flow Cytometer. Cows are impregnated using sexed semen through the artificial insemination process with consumption of one straw per cow.

Why is this method being used?

Considered a financial burden, male calves are either killed or abandoned on the roads by farmers as they do not give milk. This had led to an increasing number of cattle roaming the streets, which has caused fatal road accidents as well. Cows are also abandoned when they stop giving milk. If a commercial farmer owns a hundred cows and even fifty of them give birth to male calves, he cannot afford to raise them. They become a burden, said an expert.

Who pioneered the semen sorting technology and its large scale application on cattle?

George E. Seidel, a reproductive physiologist at Colorado State University (CSU) in the US is credited for his pioneering research in the sorting process. According to one of his interviews, some original research had taken place in the 1980s at the Lawrence Livermore National Laboratory in California and their studies of sperm led to discoveries regarding differences between sperm cells carrying X or Y chromosomes. However, for cattle, it was in the late 1990s that Seidel and his team at CSU developed a process for creating sex-sorted cattle semen for freezing and use in artificial insemination and also got patent rights. Through the CSU Research Foundation, they formed a company, XY Inc., which was later sold to Sexing Technologies (ST), based in Texas.

The sperms are pumped through a Flow Cytometer (cell sorter) in tubing past a detector that measures the brightness of individual sperm exposed to laser light. That information is processed by the computer and used to sort sperm, one at a time, at a rate of about 25,000 sperm/second, reads Seidels research paper titled Sex-selected semen.

Currently, ST has rights over semen sorting technology and it installs the entire set-up after taking the royalty amount, said Dr Inderjeet Singh, director, animal husbandry, Punjab and additional CEO, Punjab Livestock Development Board.

After ST, another US-based company ABS Global (formerly American Breeding Services) came up with a cutting edge technique that kills Y chromosome, he added.

Does sexed semen have a 100 per cent success rate?

No, the guarantee of a female calf being born is never 100 per cent. It can be up to 90 per cent. In 10 per cent cases, a male calf might be born despite using sexed semen because even after sorting/killing, some Y chromosomes may pass, said Dr Brar.

The pregnancy rate with sexed semen also reduces as sperm count goes down after sorting or killing. While one straw of conventional semen contains 10-20 million sperms, the count is down to 2-4 million only in sexed semen straws (0.25 ml each). So, while conventional semen will impregnate 60-70 animals out of 100, the rate is 45 to 50 with sexed semen, said Dr Narinder Singh, assistant animal physiologist, GADVASU.

How did sexed semen enter Punjab for farmers? When did the government start procuring and giving it on subsidy?

It was in 2008 that the Progressive Dairy Farmers Association (PDFA), the largest association in Punjab with more than 7,000 registered commercial dairy farm owners, had first imported sexed semen from the US. They have been doing it every year since then. Daljit Singh Sadarpura, president, PDFA, said, We first imported 25,000 sexed semen straws in 2008 from the US. The success rate is better on heifers than adult cows. Since then we are regularly importing it from the US and this year we gave it for Rs 1,500 to 1,700 per straw including transportation cost. Currently, very few rich farmers use it, he said.

In December 2011, the Punjab government imported 5,000 straws followed by 6,280 straws in 2014 and 25,000 straws in 2016- all from the US. Till August last year we were giving straws to farmers on 50 per cent subsidy, so a straw costing Rs 1,200 ($16-17 each) was being given for Rs 600. However, later the subsidy was reduced and it was being given for Rs 1,000. Now we have again proposed more than 75% subsidy and it might be given for Rs 300 only. We have floated tenders to procure sexed semen this year too, says Dr Inderjeet Singh.

How costly is sexed semen compared to conventional ones?

High quality conventional semen straws are available for just around Rs 20-40 per straw only whereas sexed semen costs at least Rs 1,200 per straw without subsidy. It is a costly affair till manufacturing does not start in Punjab itself and currently it is at least 60 times costlier than conventional semen, said Dr Narinder Singh.

Can sexed semen be used for indigenous cattle and buffaloes?

Dr Prakash Singh Brar from GADVASU said, In the 1960s, we bred our indigenous cows with foreign breeds to increase milk production but now governments focus is on promoting pure indigenous breeds. Cross-breeding can be done but it is not highly recommended. Sexed semen units are currently more focused on foreign breeds like Holstein Friesians (HF) and cross-bred bulls and sexed semen is mostly used on HF or cross-bred cows only. It can be produced for indigenous cow breeds like Sahiwal, Gir and also buffaloes like Murrah but in Punjab, majority farmers own foreign cross-bred cattle and problem of abandoning or killing male calf lies with cross-bred not indigenous cattle.

How can sexed semen solve the stray cattle problem in Punjab?

According to the latest Livestock Census 2019 data, there are 25.32 lakh cattle in Punjab of which only 4.26 lakh are indigenous breeds.

It is mostly foreign or cross-bred like HF and Jersey bulls and non-lactating cows which are abandoned by farmers on roads. If a male calf is born, it is also abandoned or killed. Farmers rarely abandon indigenous breeds. If sexed semen is used widely for cross-bred, stray cattle problem might be solved to some extent, says Dr Brar. Over one lakh stray cattle is on roads in Punjab approximately.

If only female calves will be born, can it lead to semen shortage?

No, say experts. We need a controlled male population with high quality genetic potential and they are being bred at semen stations. Semen is frozen and supplied to farmers. Controlled male population is enough to meet semen demand, said Dr Brar.

Sexed semen assures 90 per cent female births not 100 per cent. Also, it wont be possible to cover entire cow population with sexed semen so male births will be there anyway, says Dr Inderjeet Singh.

Is Giriraj Singhs statement to provide farmers with sexed semen Rs 100 per straw viable?

Experts are clueless on the calculation used by the minister here. Even if manufacturing starts in Punjab, initial project installation will cost crores. According to our initial estimates, we might have to pay royalty of $13 per straw (Rs 900 approx) to the operating company. Providing it to farmers for just Rs 100 seems too far-fetched as of now even if 50 per cent subsidy is given, said an official.

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Explained: What is sexed semen and how does the technology work? - The Indian Express

For marginalized people, the tech worlds constant barrage of innovations is getting exhausting. It seems like every week, science and tech pioneers are revealing new projects that pose a clear threat to anyone not white, cisgender, or malewhether its porn deepfakes or algorithms that judge womens boobs.

Enter Harvard Medical School, where researchers are creating a new dating app that matches people based on their DNA. The goal is to create a system that screens out matches that would result in a child with an inherited disease, according to a report aired Sunday night on 60 Minutes.

In other words, its a dating app for eugenicsthe disturbing ideological practice of systematically discriminating against people based on genetic qualities judged to be undesirable or inferior.

The app is being developed by a team of geneticists led by George Church, who, in the same interview, defended accepting money for his lab donated by convicted pedophile Jeffrey Epstein. Churchs lab is most famous for its work on the gene-editing technology CRISPR/Cas9, and its researchers are looking at ways to make humans immune to viruses, reverse the effects of aging, and de-extinct animals. Its 7,000 diseases, its about 5 percent of the population, [and] about $1 trillion a year worldwide in medical expenses, Church told 60 Minutes.

But for anyone not white, cis, able-bodied, or male, its obvious where all this is going.

Eugenics has long been a fascination of Nazis and white supremacists, who dream of creating a white and genetically pure master race. Dystopian sci-fi tales like Gattaca have also warned of the horrifying dangers of organizing society based on the perceived desirability (or undesirability) of peoples genetic code.

For people who exist outside mainstream gender norms, these dangers are very real. Last week, Newsweek reported on a team of researchers at the University of Michigan who are attempting to identify regions of the brain associated with gender dysphoriathe discomfort which occurs when a persons gender does not match the sex they were assigned at birth.

Many, but not all transgender people experience gender dysphoria, and it has been used to establish a system of medical gatekeeping that pathologizes trans people and controls access to treatments like hormone replacement therapy and gender-affirming surgeries. But even if scientists identified some hypothetical trait that causes people to be trans, choosing to edit out those traits would be an attempt to effectively erase trans people from existence.

Meanwhile, research into trans medical treatments remains severely underfunded. The federal government is also trying to make it legal for medical providers to refuse to treat trans patientswhether for gender dysphoria or a broken arm.

In other words, these cis researchers, funders, and policymakers seem more interested in curing or erasing trans people than finding better and cheaper ways of treating themor anyone else labeled as falling outside the norm of biologic desirability. Churchs lab, for example, recently received over $100 million for its work on gene-editing.

Church says he is being careful, and claims his lab has appointed a full-time ethicist on its staff to work toward the goal of genetic equitywhere all people have access to genetic technology, regardless of race or economic status.

But for marginalized people suffering under deeply unequal and discriminatory systems of power, that mission seems dangerously naive. If the people who risk being most harmed by these innovations arent intimately involved in their development, maybe its better toyou knownot make them at all?

More:
A Genetic Dating App Is a Horrifying Thing That Shouldnt Exist - Free

Chun-Jun Guo

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Jill Roberts Institute for Research in Inflammatory Bowel Disease, Department of Medicine, Weill Cornell Medicine, NY 10021, USA.

Breanna M. Allen

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kamir J. Hiam

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Dylan Dodd

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Will Van Treuren

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Steven Higginbottom

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kazuki Nagashima

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.

Curt R. Fischer

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Justin L. Sonnenburg

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Matthew H. Spitzer

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Michael A. Fischbach

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

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Depletion of microbiome-derived molecules in the host using Clostridium genetics - Science Magazine

Incidence rates for hormone receptor positive (HR+) breast cancers are considerably higher in black men than white men, which is in stark contrast to lower incidence rates of those cancer subtypes in black versus white women to according to a new American Cancer Society appearing in the journalJNCI Cancer Spectrum.

In this study, researchers examined subtype specific breast cancer incidence rates in both black and white men in the U.S. using a contemporary nationwide database.

According to the study results, found that rates for all subtypes were higher among black than white men, with rates for HR+/HER- breast cancers about 41% higher among black men compared to white men; about 65% higher for HR+/HER2+, more than 2.5 times higher for HR-/HER2+, and 2.27 times higher for triple-negative breast cancer. Conversely, among women, rates in blacks were 21% lower for HR+/HER2- and comparable for HR+/HER2+, but 29% and 93% higher for HR-/HER2+ and triple-negative subtypes, respectively.

Reasons for the elevated risk of breast cancer in black men are largely unknown but may involve multitude of risk factors including genetic and non-genetic factors, the authors wrote according to a press release. Racial differences in the prevalence of mammography and menopausal hormone supplements are thought to have contributed to the historically higher incidence rate of HR+ cancers in white women, but these are not factors in breast cancer in men.

Well-known risk factors for male breast cancer include family history of breast and/or ovarian cancers, pathogenic mutations in BRCA2, radiation exposure, and conditions that alter hormonal balance such as Klinefelter syndrome and gynecomastia, and potentially obesity and diabetes. Moreover, previous studies have found higher level of estradiol was found to be associated with increased risk of male breast cancer after controlling for body mass index, suggesting a presence of estrogen-mediated carcinogenesis in male breast cancer. However, whether associations of these risk factors vary by tumor subtypes remains unknown and should be considered in future etiologic studies.

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Breast Cancer Incidence Differs Among Black and White Males - DocWire News

Hemp seed production is vital, as growers get ready to ramp up production. The question is, is there enough feminized hempseed to go around.

Western Farms Seed LLC in Scottsbluff will help in filling the demand, by growing seed for producers at its greenhouse.

The newly created business is owned by cousins, P.J. Hoehn, Mike Hoehn, their uncles Ed and Art Hoehn, and business partner Mark Johnson.

The business kicked off when Mike Hoehn received one of the 10 permits the Nebraska Department of Agriculture allotted to individuals in 2019 to grow hemp. Nebraska did a lottery where they allowed only ten businesses or individuals to grow hemp after the 2018 Farm Bill legalized the plant.

Hoehn grew a one-acre test plot outside of Mitchell, with three varieties of hemp seed.

The current varieties are Wife, Franklin, and Montana, we also have T1s, said P.J. Hoehn, president of the company. Well be crossbreeding them and making new varieties.

The three varieties have been proven to perform well for growers out in the field for the last couple of seasons.

Feminized seeds are bred explicitly in a way that eliminates the male chromosomes, drastically decreasing the chances of producing a male marijuana plant. Male marijuana plants are not desirable to any degree, except for pollination.

The genetics, which we have chosen are specific for industrial hemp, said Johnson, public relations for the company. We feel pretty safe that we wont have an impact from industrial hemps cousin (marijuana).

Western Farms Seed is also working in collaboration with the University of Nebraska-Lincoln through the Panhandle Research and Extension Center on hemp production.

Were producers ourselves, so we want to number one make sure the quality is there and everything else, our germination, our testing will all be there, Hoehn said.

He adds they are also making sure they will be able to advise growers on the equipment, such which as plates to use and vacuum. So, when farmers go to plant, they are ready, and if needed, Western Farms Seed would provide support in the knowledge of equipment, planting, and harvesting.

In terms of growing the crop, Johnson said a hemp crop is similar to corn or dry edible bean crops. Hemp should be planted by May or June and harvested after a 90 to 110 day growing period before frost.

We found hemp to be very resilient after our two hail storms this summer, said Johnson. The crop was able to recover from both hail storms in really good fashion. Ending up producing a nice crop in light of Mother Nature.

The business, with winter, has moved growing operations into the greenhouse. The five interconnected greenhouse buildings have 21,000 sq feet of growing spaces and house the female plants.

The plants will need light at different times, and when they enter the vegetative stage will need light for up to 16 hours a day.

Industrial hemp has two different growth stages, vegetative, which requires more light, and reproductive growth, said Johnson. So people might notice the greenhouse lights being on longer when we go to the next stage of production.

Both Hoehn and Johnson say producers should start small with an acre or so and of course, make sure they have a buyer before they even plant.

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Ag business to grow and market hemp seed - KTIC

While wrestling with the Christmas lights under his tree recently, a wave of sadness washed over Neil Turner. He couldnt help but think of his daughter Colby, who died in 2010 at just two years oldfrom a rare genetic disorder.

Suddenly, the thought of another Christmas without her swept in and replaced my frustration with tears, says Turner, an engineer in Oklahoma and father of two. Not a day goes by that I dont miss her and think about her. But if I focus on just the loss and the heartache, suicidal thoughts come quickly.

Grief isnt linear. It can hit by surprise. It is ongoing and it evolves, says Turner. It is acomplicated emotion for many people, and it can be particularly complex for fathers. Even today, dads might feel pressured to be strong for others and put their own feelings aside after a loss, which can have damaging psychological consequences. And although the expectations regarding so-called masculine behaviorare evolving for the better, many men still feel isolated in their grief and less comfortable opening up about it.

There is a deeply ingrained social conditioning that will take some work to undo and reverse, says David Klow, a licensed marriage and family therapist in the Chicago area and author of You Are Not Crazy: Letters From Your Therapist. A number of men are working to define new models of masculinity, but theres still a lot of work to be done.

Men are generally less willing to talk about their grief, more reticent to express emotion, and less likely to seek support, says Jan Everhart Newman, JD, Ph.D., a psychologist in Charlotte, North Carolina.

Sadly, this pattern can be reinforced when boys and men seek comfort after a loss around more vulnerable emotions such as sadness and are rebuffed and given messages like Dont cry or Stay strong, Newman says. Often, my male clients will report that another family member is more outwardly expressive of intense emotions and that they felt that they couldnt put any more stress on that person [by expressing their own grief].

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Grief from a male perspective has received little research interest, but some of the articles that have been written suggest that mens grief is often diminished or even dismissed. The authors of arecent study of combat veterans noted that grief is a long-overlooked toll of war. In her study of fathers and pregnancy loss, published in 2004, author Bernadette Susan McCreight wrote, the loss can be devastating for fathers yet, very often, the world that surrounds them tends to discount their loss, and emotional support and cultural rituals that are normally available to other bereaved individuals are often absent for this group of men.

Newman agrees. At the funeral of a Special Forces veteran recently, she saw a heartbreaking example of how people dont seem to know how to respond to mens grief. The manwas buried with full military honors, which can be a long affair.Kids clustered in a group poking one another and laughing, Newman says, while adults stood around together, somber and chatting. Then she saw the adult son,who was on his knees at the coffin sobbing entirely alone.

The only person who came to comfort him was his young son, Newman says. There is something about grief that can be frightening and is difficult for others to accept.

Human beings will do anything to avoid discomfort. As it makes them think of their own mortality and lack of control, death is at the top of the list of things that make people uncomfortable, she says. Additionally, traditional gendered expectations might influence how couples deal with grief. Klow says he has counseled women who say they want their male partners to be more in touch with their feelings but dont actually like seeing them cry or express emotions.

Some men might feel isolated in their grief not because they dont know how to feel emotions but because they dont feel its okay to express them.

A web content strategist in the UK, Kevin lost his father last year, shortly before he and his partner found out they were having a baby. He now lives in his fathers house with his family and thinks of his dad often, such as when hes dancing around the kitchen to The Beatles to entertain his son and get him to stop crying. Kevin says he often apologizes for talking about his father even though his partner says she doesnt mind.

It feels wrong that hes not here to enjoy the newborn, Kevin says. It will always feel socially unacceptable for me to express my grief no matter how hard people try to make me feel comfortable.

Cultural background and upbringing have a huge impact on how much men might adhere to stereotypical male tendencies, such as stoicism, that might make them feel less comfortable feeling and expressing grief. And it might be doing men a disservice to expect them to grieve more like women tend to, with outward shows of emotion, according to J. Scott Janssen, MSW, LCSW. Janssen says men who grieve more quietly and keep their emotions in check around others might simply have a more masculine style of grieving that isnt necessarily unhealthy and shouldnt be dismissed.

Of course, caveats exist. You have to be careful with the terms masculine and feminine, which are bound by culture and tradition, and in the age of gender neutrality, this distinction may even be meaningless, Newman says. It comes down to whether a man feels free to express his emotions without judgment and is simply choosing not to versus not expressing emotions because thats not what a man should do.

The latter situation a man feeling like a bad person because theyre experiencing normal, painful emotions is harmful.

There are signs that the walls around male grief are coming down. Recently, comedian Michael Cruz Kayne tweeted on the 10th anniversary of his son Fishers death and received an outpouring of support, as did James Van Der Beekwhen hewrote about the grief he and his wife felt about losing a baby to miscarriage in a heartfelt Instagram post. Comedian Patton Oswalt also has talked openlyabout grieving the death of his first wife, author Michelle McNamara, the mother of his daughter, Alice.

Many men (and women) need time to grieve privately, which is not the same thing as isolating.Although he also talked about his loss with others, Turner says he also needed alone time to process Colbys death.

For quite a few years, two hours into any car ride by myself I would be in tears having that much time alone with my thoughts, Turner says. But if I didnt get that time regularly, my emotions were more likely to come out sideways, in non-preferred ways.

Theres no timeline to it, Klow says. Ten years later, a long solo drive or the dog getting sick can trigger grief all over again. Healthy grieving changes from person to person.It can take a lot of different forms. To help process the loss, it can help to have a social gathering with friends and family to say goodbye and celebrate the life of the person who has died, says Elgin, Illinois, funeral home owner and director, US Army Reserve First Sergeant and father of two Dan Symonds.

Symonds was stationed in Afghanistan when his family told him his father was dying. He lost it for about 15 seconds in front of his Commander, he says, but didnt cry again for a while after his fathers death. He returned home and busied himself arranging military honors for his dad, an example of instrumental grieving that includes task like tending to the estate and cleaning out the house of the person who died. Those tasks shouldnt be dismissed as avoidance they can help people process the loss, Klow says.

Being alone with grief for stretches of time, however, isnt necessarily unhealthy. It can help to put thoughts and feelings into words, Klow says. Humans are social creatures; reaching out to social networks and naming the person theyre grieving and talking about memories and what theyre feeling tends to help.

What helps me is talking about my dad with my children, telling them what he was like and how he would have loved them so much, Symonds says. We keep his memory alive every day.

Klow suggests finding several people to listen to about grief; that can maximize someones avenues of support and alleviate the worry that theyre overburdening one person. That network can include a partner, family members, friends, or a therapist. Klow holds group therapy sessions for men and says many seem relieved to have a safe space in which to express themselves.

Its important not to be alone in grief, Klow says.

Someones partner can be a life-saving source of support, but they might have to work on making the relationship as egalitarian as possible, he adds: You dont have to be perfect, but both partners need to hold space for each other so that there isnt just one person whos the designated feeler of feelings, he says.

It can be difficult to do, but the Turners were able to give each other permission to be in different places in their grief.

We were okay if one of us was sad and the other was not. We werent afraid to give each other space, Turner says. We did see other couples that would get upset with one another with out-of-sync feelings of They need to move on or Why arent they still sad? Im not sure why, but we didnt fall into that trap.

A therapeutic retreat for bereaved parents, if it can fit into the budget, also might be helpful. Turner and his wife went to one after friends suggested it.

I had never been in any therapy session at all, and although it was emotionally and physically exhausting, we found it helpful, he says, but adds, The next year they even invited us back to help lead the retreat as we were the only couple in the group still married. The divorce rate among bereaved parents is really high.

The Turners also found a fulfilling way to process their grief through charity work with the American Heart Association. His daughter, Ella, got involved, too, raising more than $60,000 for the ACS after an event she participated in received media attention.

It gave us the opportunity to talk about Colby and use her story in a positive way, Turner says.

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For Men, Dealing With Grief Is Lonely and Isolating. This Needs to Change - Fatherly

A fathers diet can have a significant effect on the future health of his offspring, affecting everything from blood pressure to heart function and putting them at greater risk of cardiovascular disease, according to research.

The lead author of a British study says the findings show that men who want to start a family should have a healthy, balanced diet from at least three months before conception.

A study from researchers at the University of Nottingham published in the Journal of Physiology shows that poor paternal diet, specifically one that is low in protein, may impact the heart health of the offspring by changing sperm, and the seminal fluid, which bathes sperm.

We have known for a very long time that what a mother eats during pregnancy can influence how her child develops, and whether or not it will develop obesity, type two diabetes and heart disease, explains senior author of the study, and lead researcher, Prof Adam Watkins, assistant professor in reproductive biology at the universitys faculty of medicine and health sciences. However, the importance of the fathers diet on the health of the offspring has been largely ignored or overlooked. We were interested in investigating whether a fathers poor-quality diet at the time of conception might affect the long-term health of its offspring.

Researchers carried out their study on male mice on a poor, low-protein diet, monitoring the cardiovascular health of their offspring. The way mice produce sperm, the way the embryo develops, the way the foetus develops and the way a mouses blood and heart function are all very similar to humans. This means we can use mice to identify important biological processes which we can then look at in human patients.

What his research found, he reports, was both that the way the mices blood vessels worked, and the level of certain important factors in their blood, which regulate heart and blood vessel function, were significantly altered in response to the poor diet of the father: The blood vessels in the offspring did not work as well as they should do. This can ultimately affect blood pressure.

The normal proteins in the blood which would regulate blood vessels and heart function were altered, says Prof Watkins, adding that essentially what this meant was that the young mice were at increased risk of developing cardiovascular ill-health or heart disease.

We know that a poor lifestyle in men does have negative influences on sperm quality and that being overweight or smoking, or consuming excessive alcohol is not good for reproductive health. What we dont know yet is what the long-term implications of a fathers poor diet or lifestyle might be, he says.

We know that the sperm provides genetic information from a father to the egg it fertilises, and we know that poor diet in males can change that. We also know that the seminal fluid in which sperm is carried, interacts with the uterus and initiates a range of responses in the maternal immune system. These responses prime the uterus for the embryo.

We know that the sperm provides genetic information and that the seminal fluid primes the uterus for the embryo, so here are two possible ways that a fathers diet could influence how the offspring might develop.

Essentially, Prof Watkins explains, the Nottingham research shows that the health of mice offspring is influenced by sperm and fluid and that both of them have an equal influence on offspring health.

However, he says, while the research has to date only been carried out on mice, it has significant implications for human fertility in fact the researchers hope to run clinical trials on humans within the next two or three years.

We know that it can take about 75 days to make a sperm, and that seminal fluid is reproduced every 24-48 hours, says Prof Watkins.

If a man goes on a crash diet a week before getting his partner pregnant, he explains, the sperm will continue to reflect the old, poor quality diet,while the seminal fluid will reflect the newer, better-quality diet.

Therefore there may be a situation where the sperm and the fluid are not compatible to each other, so we are saying that if the sperm and the fluid are different, we see the biggest effect on offspring health.

The potential message is this, he warns: If men and women are thinking about changing their lifestyle and becoming parents, we would say that ideally they begin the changes three months before trying to start a family. That is an ideal time frame to change over from a poor diet and lifestyle to a healthier one in terms of its implications for the mans reproductive health.

The Nottingham research findings have interesting implications for what we know about the role of seminal fluid and sperm DNA fragmentation (a term used for the presence of abnormal genetic material within the sperm, which may lead to male subfertility, in-vitro fertilisation failure and miscarriage) believes Dr Bart Kuczera, consultant gynaecologist and fertility expert at Beacon Care Fertility:

What we know is that men with a poor lifestyle in terms of diet, smoking and drinking can have a condition called sperm DNA fragmentation.

Men are advised to live a healthy lifestyle in order to keep their sperm in the best condition, because, he explains: Sperm DNA fragmentation can be affected by poor diet, stress and overeating, for example. This study would make the case for a good diet and lifestyle for men; that is, a normal balanced protein diet.

Sperm quality of men in the western world, he warned, has been shown to have deteriorated in the last 40 years: We believe this is very linked to lifestyle and the environment, to the sedentary lifestyle and a poor diet which reaches the recommended carbohydrate level but would not include a diversity of food.

In the greater picture you could potentially have a population of children who would be affected in terms of physical health problems and weight gain as a result of the paternal diet at conception. It is important to spread the responsibility between the man and the woman at the time of conception, he says, adding that this study suggests that the father may have an equally significant impact on his offsprings health problems.

This study has implications for our knowledge about diet and lifestyle in terms of fertility and men should be made aware of it, believes Dr Hans Arce, fertility consultant and medical director of ReproMed, a leading Irish fertility and IVF clinic network. The majority of our knowledge in relation to diet and lifestyle in terms of fertility comes because we studied women. Women were the ones who got pregnant and they were the focus. We saw, for example, that women with obesity had children with a higher risk of obesity and diabetes.

However this study showed the offspring of male mice with poor diets ended up having the expression of inflammation, and more of a tendency to high blood pressure, for example.

Men should be made aware of this. Its something the schools, the public health service and the GP should be telling men about that our diets can affect their future childrens health. Studies like these have implication for human beings, he says, adding that the results point in the direction of the fact that the health of a man may have implications for the health of his offspring.

What this study says, he observes, is that a mans diet will not just affect his own health, but potentially has implications for the health of his offspring: We dont have proper human studies yet this is mice but it is pointing in that direction!

Lifestyle is the single biggest issue when it comes to fertility, believes consultant nutritionist Gaye Godkin.

Godkin believes the University of Nottingham study is a further endorsement of what she says, is the role of epigenetics in health outcomes from pre-conception health across the life course.

There is a growing body of evidence showing just how much the fathers diet impacts on the pre-conception phase, in terms of its impact on sperm and seminal fluid and from there on to the long-term health of his offspring.

Epigenetics, she explains, is the environment in which the sperm lives prior to penetrating the egg. Sperm is produced around every 75 days or so but new seminal fluid is produced every 24 to 48 hours.

If the man has a long-term poor diet, it will affect his sperm, she says, adding however, that a man can have healthy sperm, while at the same time his seminal fluid could be of much lower quality because of a poor diet just before conception.

Normal sperm carries DNA. A poor diet has a negative effect on the DNA and the DNA enzymes which in turn are crucial to the formation of a healthy foetus.

In fertility clinics, they measure the level of a condition called DNA fragmentation in the male sperm. This test shows the quality of the sperm. For years I have worked with men who have high levels of DNA fragmentation in their sperm. I believe that it is strongly linked to diet, as well as to lifestyle factors such as smoking, alcohol consumption, excess weight and the effect of pesticides.

While the Nottingham study was based on a mouse model, she says, its findings were moving in the right direction in terms of our understanding of the volatility of sperm quality and what affects it, as well as its relationship with the internal environment of the male body.

While there is no medical treatment available for DNA fragmentation, says Godkin, she has found that 90 days on a good-quality diet which also features a reversal of poor lifestyle factors can lead to fragmentation levels being significantly reduced to the extent that a couple are in a position to use their own sperm to achieve conception.

Excerpt from:
Diets of fathers can affect future health of offspring, study finds - The Irish Times

This image shows Channelrhodopsin-eYFP neurons (green) expressed in the central amygdala (CeA) neurotensin (NTS) containing neurons. The magenta is antibody staining for the neuropeptide NTS. Credit: McElligott Lab

The UNC School of Medicine lab of Zoe McElligott, PhD, found that alcohol consumption is regulated by the activity of a particular set of neurons in a specific brain region, a discovery that could lead to a better understanding of why some casual drinkers develop an alcohol use disorder.

Scientists have known that a region of the brain called the central nucleus of the amygdala (CeA) plays a role in behaviors related to alcohol use and consumption in general. Its been less known which precise populations of brain cells and their projections to other brain regions mediate these behaviors. Now, UNC School of Medicine scientists discovered that specific neurons in the CeA contribute to reward-like behaviors, alcohol consumption in particular.

Published in the Journal of Neuroscience, this research pinpoints a specific neural circuit that when altered caused animal models to drink less alcohol.

Zoe McElligott, Ph.D. Credit: University of North Carolina Health Care

The fact that these neurons promote reward-like behavior, that extremely low levels of alcohol consumption activate these cells, and that activation of these neurons drive alcohol drinking in animals without extensive prior drinking experience suggests that they may be important for early alcohol use and reward, said senior author Zoe McElligott, Ph.D., assistant professor of psychiatry and pharmacology. Its our hope that by understanding the function of this circuit, we can better predict what happens in the brains of people who transition from casual alcohol use to subsequent abuse of alcohol, and the development of alcohol use disorders.

McElligott, who is also a member of the UNC Bowles Center for Alcohol Studies, set out to investigate if a population of neurons that express a specific neuropeptide (neurotensin or NTS) contributes to reward-like behaviors and alcohol drinking. She was especially interested in these neurons in the context of inexperienced alcohol use, such as when a person first begins to drink alcohol. Also, NTS neurons are a subpopulation of other neurons in this CeA brain region that have been implicated in anxiety and fear known as the somatostatin and corticotropin releasing factor neurons.

Using modern genetic and viral technologies in male mice, McElligott and colleagues found that selectively lesioning or ablating the NTS neurons in the CeA, while maintaining other types of CeA neurons, would cause the animals to drink less alcohol. This manipulation did not alter anxiety-like behavior. It also did not affect the consumption of other palatable liquids such as sucrose, saccharin, and bitter quinine solutions.

We found that these NTS neurons in the CeA send a strong projection to the hindbrain, where they inhibit the parabrachial nucleus, near the brainstem, McElligott said.

Mara Luisa Torruella Suarez. Credit: University of North Carolina Health Care

Using optogenetics a technique where light activates these neurons the researchers stimulated the terminal projections of the CeA-NTS neurons in the parabrachial and found that this stimulation inhibited the neurons in the parabrachial. When the scientists stimulated this projection with a laser in one half of the animals box, animals would spend more time where the stimulation would occur.

Animals also learned to perform a task to get the laser stimulation to turn on, and they would do this repeatedly, suggesting that they found this stimulation to be rewarding.

Furthermore, when we stimulated this projection, animals would drink more alcohol as compared to when they had an opportunity to drink alcohol without laser stimulation, McElligott said. In contrast to our study where we ablated the NTS neurons, laser stimulation of this parabrachial pathway also caused the animals to consume caloric and non-caloric sweetened beverages. When the animals were presented with regular food and a sweet food, however, laser stimulation did not enhance the consumption regardless of the mouses hunger state. This suggests that different circuits may regulate the consumption of rewarding fluids and solids.

McElligott and her graduate student Mara Luisa Torruella Suarez, the first author of this study, hope to explore how alcohol experience may change these neurons over time.

Would these cells respond differently after animals have been drinking high quantities of alcohol over time? McElligott said. We also want to discover which populations of neurons in the parabrachial are receiving inputs from these neurons. Fully understanding this circuit could be the key to developing therapeutics to help people with alcohol use disorders.###

Reference: Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice by Mara Luisa Torruella-Surez, Jessica R. Vandenberg, Elizabeth S. Cogan, Gregory J. Tipton, Adonay Teklezghi, Kedar Dange, Gunjan K. Patel, Jenna A. McHenry, J. Andrew Hardaway, Pranish A. Kantak, Nicole A. Crowley, Jeffrey F. DiBerto, Sara P. Faccidomo, Clyde W. Hodge, Garret D. Stuber and Zo A. McElligott, 19 November 2019, Journal of Neuroscience.DOI: 10.1523/JNEUROSCI.1466-19.2019

The National Institutes of Health, The North Carolina Translational Clinical Science (NC TraCS) Institute, the Alcohol Beverage Medical Research Foundation, and The UNC Bowles Center for Alcohol Studies funded this research.

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Alcohol Consumption Is Regulated by Particular Set of Neurons in Specific Brain Region - SciTechDaily

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Interferon Insight

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

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

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

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

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

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

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

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

HLH, hemophagocytic lymphohistiocytosis; EEG, electroencephalogram.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Materials and Methods

Supplementary case summary

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

Fig. S2. Longitudinal series of laboratory parameters.

Fig. S3. Multiple sequence alignment of STAT2.

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

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

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

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

Fig. S8. Prolonged STAT2 phosphorylation in PBMCs.

Fig. S9. STAT2 immunofluorescence image analysis.

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

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

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

Fig. S13. Phosflow gating strategy.

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

Table S2. Rare variants segregating with disease.

Table S3. Digital ELISA detection of IFN protein concentration.

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

Table S5. RT-PCR primers and probes.

Table S6. Antibodies.

Data file S1. Raw data (Excel).

References (5159)

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

YAKUTSK, Russia Russian scientists have shown off a prehistoric dog or wolf puppy, thought to be 18,000 years old, found in permafrost in the country's Far East.

Discovered last year in a lump of frozen mud near the city of Yakutsk, the puppy is unusually well-preserved, with its hair, teeth, whiskers and eyelashes still intact.

"This puppy has all its limbs, pelage fur, even whiskers. The nose is visible. There are teeth. We can determine due to some data that it is a male," Nikolai Androsov, director of the Northern World private museum where the remains are stored, said Monday at Yakutsk's Mammoth Museum, which specializes in ancient specimens.

Love Daln, a professor of evolutionary genetics at the Stockholm-based Center for Palaeogenetics, which took a piece of the puppy's bone to study its DNA, said it still couldn't be determined whether the puppy was that of a dog or a wolf.

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"That makes it even more interesting," Daln said.

In recent years, Russia's Far East has provided many riches for scientists studying the remains of ancient animals. As the permafrost melts, affected by climate change, more and more parts of woolly mammoths, canines and other prehistoric animals are being discovered. Often it is mammoth tusk hunters who discover them.

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"Why has Yakutia come through a real spate of such unique findings over the last decade? First, it's global warming," Sergei Fyodorov, a scientist at North Eastern Federal University, told The Associated Press. "It really exists, we feel it, and local people feel it strongly. Winter comes later. Spring comes earlier."

The Center for Palaeogenetics has been studying the puppy's DNA for more than year. Further tests have left scientists with more questions than answers.

"The first step was, of course, to send the sample to radiocarbon dating to see how old it was, and when we got the results back, it turned out that it was roughly 18,000 years old," Daln said in an online interview.

"We have now generated a nearly complete genome sequence from it, and normally when you have a two-fold coverage genome, which is what we have, you should be able to relatively easily say whether it's a dog or a wolf, but we still can't say and that makes it even more interesting," Daln said.

He said scientists planned to conduct a third round of genome sequencing, which might solve the mystery.

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18,000-year-old puppy found remarkably preserved in permafrost - NBCNews.com

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Female hair loss can happen for a variety of reasons, such as genetics, changing hormone levels, or as part of the natural aging process.

There are various treatment options for female hair loss, including topical medications, such as Rogaine. Other options include light therapy, hormone therapy, or in some cases, hair transplants.

Eating a nutritious diet and maintaining a healthy lifestyle can also help keep hair healthy.

The Food and Drug Administration (FDA) approves Minoxidil to treat hair loss. Sold under the name Rogaine, as well as other generic brands, people can purchase topical Minoxidil over-the-counter (OTC). Minoxidil is safe for both males and females, and people report a high satisfaction rate after using it.

Minoxidil stimulates growth in the hairs and may increase their growth cycle. It can cause hairs to thicken and reduce the appearance of patchiness or a widening hair parting.

Minoxidil treatments are available in two concentrations: the 2% solution requires twice daily application for the best results, while the 5% solution or foam requires daily use.

While the instinct may be to choose the stronger solution, this is not necessary. Studies posted to the International Journal of Women's Dermatology and the Journal of the American Academy of Dermatology found that 2% minoxidil was effective for females with androgenetic alopecia, or pattern baldness.

If a person finds success with minoxidil, they should continue using it indefinitely. When a person stops using minoxidil, the hairs that depended on the drug to grow will likely fall out within 6 months.

Side effects from minoxidil are uncommon and generally mild. Some females may experience irritation or an allergic reaction to ingredients in the product, such as alcohol or propylene glycol. Switching formulas or trying different brands may alleviate symptoms.

Some females may also experience increased hair loss at first when using minoxidil. This typically stops after the first few months of treatment as the hair gets stronger.

Additionally, misapplying minoxidil or applying it to the forehead or too much of the neck may cause hair growth in these areas. Only apply minoxidil to the scalp to avoid these side effects.

Minoxidil is available to purchase in stores and online.

Low-level light therapy may not be sufficient treatment for hair loss on its own, but it may act to amplify the effects of other hair loss treatments, such as minoxidil.

A trial posted to the Indian Journal of Dermatology, Venereology, and Leprology found that compared to control groups, adding low light therapy to regular 5% minoxidil treatment for androgenetic alopecia helped improve the recovery of the hairs and the participants' overall satisfaction with their treatment.

Researchers will need to carry out further research to help strengthen these results.

The drug ketoconazole may help treat hair loss in some cases, such as androgenetic alopecia, where inflammation of the hair follicles often contributes to hair loss.

One review posted to the International Journal of Women's Dermatology noted that topical ketoconazole might help reduce inflammation and improve the strength and look of the hair.

Ketoconazole is available as a shampoo. Nizoral is the best known brand and is available for purchase over the counter and online. Nizoral contains a low concentration of ketoconazole, but stronger concentrations will require a prescription from a doctor.

Some females may also respond to corticosteroid injections. Doctors use this treatment only when necessary, for conditions such as alopecia areata. Alopecia areata results in a person's hair falling out in random patches.

According to the National Alopecia Areata Foundation, injecting corticosteroids directly into the hairless patch may encourage new hair growth. However, this not may prevent other hair from falling out. Topical corticosteroids, which are available as creams, lotions, and other preparations, may also reduce hair loss.

Early evidence suggests that injections of platelet-rich plasma may also help reduce hair loss. A plasma-rich injection involves a doctor drawing the person's blood, separating the platelet-rich plasma from the blood, and injecting it back into the scalp at the affected areas. This helps speed up tissue repair.

A recent review posted to Aesthetic Plastic Surgery noted that most studies suggest that this therapy reduces hair loss, increases hair density, and increases the diameter of each hair.

However, because most studies up until now have been very small, the review calls for more research using platelet-rich plasma for androgenic alopecia.

If hormone imbalances due to menopause, for example, cause hair loss, doctors may recommend some form of hormone therapy to correct them.

Some possible treatments include birth control pills and hormone replacement therapy for either estrogen or progesterone.

Other possibilities include antiandrogen medications, such as spironolactone. Androgens are hormones that can speed up hair loss in some women, particularly those with polycystic ovary syndrome, who typically produce more androgens.

Antiandrogens can stop the production of androgens and prevent hair loss. These medications may cause side effects, so always talk to the doctor about what to expect and whether antiandrogens are suitable.

In some cases where the person does not respond well to treatments, doctors may recommend hair transplantation. This involves taking small pieces of the scalp and adding them to the areas of baldness to increase the hair in the area naturally. Hair transplant therapy can be more costly than other treatments and is not suitable for everybody.

Some minor hair loss may happen due to clogged pores on the scalp. Using medicated shampoos designed to clear the pores from dead skin cells may help promote healthy hair. This may help clear minor signs of hair loss.

Massaging the scalp may increase circulation in the area and help clean away dandruff. This helps keep the scalp and hair follicles healthy.

The most common cause of hair loss in females is androgenetic alopecia, which has strong links to genetics and can run in families.

According to the International Journal of Women's Dermatology, hair loss from androgenetic alopecia may start at a young age. Some females may begin losing their hair in their late teens or early twenties, though most females may not begin to lose their hair until their 40s or older.

Both males and females can develop androgenetic alopecia, but they experience it in different ways. Males tend to experience a receding hairline or bald spot on top of their head, while females tend to present different symptoms.

In females, the parting at the center of the hair often becomes more defined or wider. Females may also experience thinning hairs, and hair may appear more thin or patchy overall.

These symptoms are due to a thinning of each hair strand. The hairs also have a shorter life cycle, and hairs only stay on the head for a shorter period.

Female pattern hair loss is a progressive condition. Females may only notice a slightly wider parting in their hair at first, but as symptoms progress, this can become more noticeable.

Other forms of alopecia, such as alopecia areata, may cause one or more patches of complete baldness.

Other factors may play a role in hair loss, such as inflammatory conditions that affect the scalp and hormone imbalances. Doctors may want to investigate these possible causes if the person does not respond to typical treatments.

While losing hair at a young age may be concerning, hair loss is a reality for many people as they age. One study posted to the Indian Journal of Dermatology, Venereology, and Leprology noted that up to 75% of females would experience hair loss from androgenetic alopecia by the time they are 65 years old.

While many females look for ways to treat hair loss while they are young, at some point, most people accept hair loss as a natural part of the aging process.

Some people may choose to wear head garments or wigs as a workaround to hair loss. Others work with their aging hair by wearing a shorter haircut that may make thin hair less apparent.

Hair loss can affect both males and females. Hair loss in females may have a range of causes, though the most common is androgenetic alopecia.

There are a variety of treatments for hair loss for females, including OTC hair loss treatments, which are generally effective. Anyone experiencing hair loss should visit their doctor who can diagnose any underlying factors.

If a doctor suspects there is another underlying cause or the person does not respond well to OTC treatments, they will look into other treatment options.

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10 ways of treating female hair loss - Medical News Today

An 18,000-year-old puppy buried for centuries in a lump of frozen mud was unveiled on Monday by scientists who hope it can help bridge the connection between dogs and wolves.

The puppy, which was male, was discovered 18 months ago, preserved in a layer of permafrost in Siberias Far Eastern reaches, according to Dave Stanton, a research fellow at the Center for Palaeogenetics in Stockholm and one of the scientists who examined its DNA.

The fur, skeleton, teeth, head, lashes and whiskers of the pup, named Dogor, are still intact, he said. But scientists dont know whether it is a dog or wolf. Stanton said more DNA research would be conducted in the coming months. We need to put this information into context, he said in an interview.

Many scientists say dogs evolved about 15,000 years ago from a species of extinct wolves. Others suggest it could have happened much earlier, perhaps 30,000 years ago or more. These wolves evolved after generations of exposure to humans, were domesticated and became the canine companions we know today.

The puppy, which was found by locals, is being studied at North-Eastern Federal University in Yakutsk, the capital of Yakutia, a sprawling region in eastern Siberia that constitutes 20 per cent of Russia. (The puppy remains were found near Yakutsk.) Nikolai Androsov, director of the Northern World museum where the remains will be kept, presented the discovery on Monday, according to The Associated Press. Yakutia is known for its oil and gas reserves and abundance of diamond mines.

Several extinct animals have been found in the thick permafrost, in part because of the melting of ice resulting from climate change. They include a male steppe bison, a woolly rhinoceros, a mummified pony and several mammoths. Stanton said treasure seekers sometimes used water cannons to break through the permafrost to extract mammoth ivory tusks, which are later sold. It must have frozen quickly before scavengers could get to it, Stanton said of the puppy. We also found a lot of samples that were not well preserved. There seems to be natural traps in the landscape where animals are frozen before they decomposed.

He said the DNA used to date the puppy and figure out its gender was extracted from a rib bone. He said he was not sure if a necropsy was performed to see if its organs, including the heart and liver, were intact.

The body is well preserved, which is rare, Stanton said. Its the best Ive seen.

Modern dogs are not like modern wolves. Wolves are reticent to eat in front of people, for example, while domesticated dogs beg for dinner table scraps. Their physiology is different, with dogs having shorter snouts and wider skulls. And male wolves participate in pup raising, while male dogs generally avoid it.

Stanton said the dating of the dog was done at Oxford University, and he and his colleagues will continue to collaborate with scientists at North-Eastern Federal University. We need to look at more samples from that time period, he said. Then we will be able to understand if it was a dog or a wolf. New York Times

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Dog or wolf? Frozen 18,000-year-old puppy gives scientists pause - The Irish Times

The title metaphor of my new novel, The Stone Boys, is of a boy who must become hard like stone to survive childhood sexual abuse. As an adult, he may function well for large chunks of time, even marrying, being intimate, raising children; but his internal resources are thin, and he rarely has any choice, if untreated, but to resort to hardening up against relationships, especially those that become close.

I was one of the stone boys. At ten years old, in 1968, my psychiatrist molested me over a period of six months, first grooming me, then moving to abuse. After I escaped him, my confusion, shame and terror had no outlet except into signs of trauma that adults at the time did not recognize as abuse-trauma for two reasons: I did not disclose the abuse until I was 18, and in 1968, the signs were not public enough for people to know about them.

My client, Tom, had some of the same signs I had. In my office, he said, Ive never been very good at relationships, and reading your Stone Boys book, I think I finally understand why. Its so obvious, but I missed it.

Whats obvious?

Tom had been married and divorced twice, had difficulty holding down jobs, and had been in and out of rehab.

Well now, antsy, he stood up out of the chair; I asked if we should go take a walk together, to which he agreed. At a local park, we sat down on a bench.

Did the story trigger memories? I asked. He nodded his head but didnt speak.

You can tell me, I said. Im safe, were confidential, and you know I will get what youre saying. You know Ive been there, in my own way.

I know, he acknowledged, standing back up again. We walked again in silence for a while, returning to my office where, once the door was closed, he told me his story. His abuse had been even more brutal than mine.

***

By now, most or all therapists are familiar with the ACEs (Adverse Childhood Experiences) survey, a very useful tool for trauma-informed counseling. I have also developed my own relationship-based checklist for my clients. Tom had eight of these Signs of Unresolved Childhood Abuse Trauma in Adult Relationships.

Treating Abused Boys and Men

A first step in treating males especially is Personal Storytelling. Even if a therapist has never experienced sexual abuse trauma, all of us have experienced trauma of some kind: some form of storytelling about trauma in your own life can help males to open themselves up.

A second step is recognition that sexual abuse for males is indeed different than for females (in most cases), not only in the myriad ways males and females are neurobiologically different but in the specific male confusion over pleasure. Most sexual abuse of males, though not all, involves male ejaculation, something that gives pleasure. Much less often does the abused girl experience an orgasm. With Tom, talking about this helped him sort through guilt and shame at deep levels.

More Best Practices for the Abuse Survivors and Their Therapists

For abused males, these are best practices I have relied upon and will likely be needed as ongoing mechanisms for healing.

Therapy, Medication, Brain-Direct Modalities EMDR (Eye Movement Desensitization Reprocessing), Neurofeedback, mindfulness, meditation, prayer, spiritual dialogue (talking directly with God), and ongoing talk therapy.

Ongoing Support Groups Getting men involved in support groups, mentoring/counseling by and with males, and groups and counseling with people from their own milieu (racial, sexual orientation, culture, similar religious background) who have also been traumatized.

Couples Therapy Because nearly everyone who has been sexually traumatized has relational difficulties of some kind, these men often need couples/relational therapy as soon as possible.

Addiction Work Many abuse victims also possess addiction genetics which get triggered by the abuse. Recovery groups and addiction therapy can be crucial.

Choice Theory Because an abuse survivor has felt out-of-control during the months or years of trauma, it is important to give him choices and control now, years later.

Help Him Avoid Rumination Loops Negative rumination loops may be precursors to severe depression and actions taken (What should I do!), especially in a mans islands of competence, can help.

Journaling Writing or video journaling can lead to more rumination, so it can backfire, but often it is a good tool for boys and men who lean already toward reading, tech, and/or verbal processing.

Organizations That Can Provide Support

National Sexual Assault Helpline. 800.656.HOPE (4673).Department of Defense Helpline. (877) 995-5247.SAMHSA (Substance Abuse and Mental Health Services Administration).

Additional Reading

The Stone Boys, Michael Gurian, Latah Books, 2019.Saving Our Sons, Michael Gurian, GI Press, 2017Victims No Longer, Mike Lew, HarperPerennial, 2004.Abused Boys, Mic Hunter, Ballantine, 1991Beyond Betrayal, Richard Gartner, John Wiley, 2005.

File under:The Art of Psychotherapy,Child & Adolescent Therapy

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Counseling the Stone Boys: Helping Boys and Men Who Have Been Sexually Abused - Psychotherapy.net

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Amazon kept up its tradition on Cyber Monday.

The online giant said that Cyber Monday was the single biggest shopping day in its history, based on the number of items ordered worldwide. Cyber Monday has been Amazon's top sales day for several years, outpacing the previous Prime Day and Black Friday. Amazons best-selling products on Cyber Monday in the U.S. included Echo Dot, Fire TV Stick with Alexa Voice Remote, Play-Doh Sweet Shoppe Cookie Creations, Keurig K-Cafe Coffee Maker and Lego City Ambulance Helicopter 60179 Building Kit.

In keeping with its policy of rarely (if ever) revealing exact numbers, Amazon said that hundreds of millions of products were ordered worldwide between Thanksgiving and Cyber Monday. Shoppers purchased millions more Amazon devices over the holiday period compared to the same period last year, the said, with Echo Dot and Fire TV Stick 4K with Alexa Voice Remote ranking as the top-selling items.

In other holiday weekend highlights from Amazon:

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Amazon set a record of its own on Cyber Monday - Chain Store Age

Male babiesborn to older mothers have a higher risk of heart problems because the placenta doesn't work as well,according to a study on rats.

The study was conducted by the University of Cambridgeandpublished in the journalScientific Reports. Itfound that changes in the placentas of older mothers could damage the health of male babies, according to Science Daily. Older mothers in the research were the rat equivalent of a pregnant woman aged 35 or older, which is considered a geriatric pregnancy. Rats are usedsince their biology is similar to humans'.

PREVIOUSLY:Study Finds Older Mothers Are More Likely To Birth Multiples

The research showed that male babies suffered negative consequences of the late birth, while females did not. In fact, in certain cases, the females even appeared to benefit. The researchers said placentas became less efficient at transporting nutrients and oxygen to foetuses as the mothers got older.

"With the average age of first pregnancy in women becoming higher and higher, it is very important to understand how the age of the mother and the sex of the baby interact to determine pregnancy and later-life health of the child," said Dr. Amanda Sferruzzi-Perri.

According to the researchers, the placenta, which connects mother to baby in the womb, is 'highly dynamic'. They added that genetic changes in a woman as she ages could affect how the placenta functions. It was also found that babies of either sex did not grow as large in the placentas of older women. And the males were more likely to have high blood pressure or heart problems as they grew older because the mother's had a different internal shape and became less efficient. However, female babies did not suffer the same risk.

The scientistsrevealed that, in the combination of older mother and female baby, the placenta actually "showed beneficial changes in structure and function that would maximise the support of fetal growth". Similar discoveries about males have been made before but it was not well understood why they were at a particular disadvantage. The new research shows the genes involved in the older mother-male baby mix make the placenta less able to do its job.

According to Cambridge's Dr. Tina Napso: "A pregnancy at an older age is a costly proposition for the mother, whose body has to decide how nutrients are shared with the fetus. That's why, overall, fetuses do not grow sufficiently during pregnancy when the mother is older compared to when she is young. We now know that growth, as well as gene expression in the placenta is affected in older mothers in a manner that partially depends on sex: changes in the placentas of male fetuses are generally detrimental."

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Placenta Changes May Mean Male Babies Of Older Women Likely To Have Heart Problems - BabyGaga