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Neurons lack the ability to replicate their DNA, so they’re constantly working to repair damage to their genome. Now, a new study by Salk scientists finds that these repairs are not random, but instead focus on protecting certain genetic “hot spots” that appear to play a critical role in neural identity and function.
The findings, published in the April 2, 2021, issue of Science, give novel insights into the genetic structures involved in aging and neurodegeneration, and could point to the development of potential new therapies for diseases such Alzheimer’s, Parkinson’s and other age-related dementia disorders.
“This research shows for the first time that there are sections of genome that neurons prioritize when it comes to repair,” says Professor and Salk President Rusty Gage, the paper’s co-corresponding author. “We’re excited about the potential of these findings to change the way we view many age-related diseases of the nervous system and potentially explore DNA repair as a therapeutic approach.”
Unlike other cells, neurons generally don’t replace themselves over time, making them among the longest-living cells in the human body. Their longevity makes it even more important that they repair lesions in their DNA as they age, in order to maintain their function over the decades of a human life span. As they get older, neurons’ ability to make these genetic repairs declines, which could explain why people develop age-related neurodegenerative diseases like Alzheimer’s and Parkinson’s.
To investigate how neurons maintain genome health, the study authors developed a new technique they term Repair-seq. The team produced neurons from stem cells and fed them synthetic nucleosides — molecules that serve as building blocks for DNA. These artificial nucleosides could be found via DNA sequencing and imaged, showing where the neurons used them to make repairs to DNA that was damaged by normal cellular processes. While the scientists expected to see some prioritization, they were surprised by just how focused the neurons were on protecting certain sections of the genome.
“What we saw was incredibly sharp, well-defined regions of repair; very focused areas that were substantially higher than background levels,” says co-first and co-corresponding author Dylan Reid, a former Salk postdoctoral scholar and now a fellow at Vertex Pharmaceutics. “The proteins that sit on these ‘hot spots’ are implicated in neurodegenerative disease, and the sites are also linked to aging.”
The authors found approximately 65,000 hot spots that covered around 2 percent of the neuronal genome. They then used proteomics approaches to detect what proteins were found at these hot spots, implicating many splicing-related proteins. (These are involved in the eventual production of other proteins.) Many of these sites appeared to be quite stable when the cells were treated with DNA-damaging agents, and the most stable DNA repair hot spots were found to be strongly associated with sites where chemical tags attach (“methylation”) that are best at predicting neuronal age.
Previous research has focused on identifying the sections of DNA that suffer genetic damage, but this is the first time researchers have looked for where the genome is being heavily repaired.
“We flipped the paradigm from looking for damage to looking for repair, and that’s why we were able to find these hot spots,” Reid says. “This is really new biology that might eventually change how we understand neurons in the nervous system, and the more we understand that, the more we can look to develop therapies addressing age-related diseases.”
Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, adds, “Understanding which areas within the genome are vulnerable to damage is a very exciting topic for our lab. We think Repair-seq will be a powerful tool for research, and we continue to explore additional new methods to study genome integrity, particularly in relation to aging and disease.”
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The state is wrestling with most of the issues and trade-offs that come with such a giant undertaking.UPPER MARLBORO, Md. — The path to quickly vaccinating the nation’s 250 million adults will be paved with pharmacy chains, hospitals and hulking stadiums where uniformed troops help inoculate thousands of people a day.But it will also rely on the recreation center at the First Baptist Church of Glenarden here, along with tiny storefront service organizations and vaccine-stocked vans that scour neighborhoods for the unprotected.Maryland offers a microcosm of the issues states face as they rush to open enough vaccination sites to meet President Biden’s goal of making every adult eligible for Covid-19 shots by May 1. It has encountered nearly all the geographic, demographic and human behavioral challenges that come with a public health task of this scale: poor urban neighborhoods where many lack access to regular care; wealthy Washington suburbs whose residents have proved adept at vacuuming up shots meant for other ZIP codes; isolated rural areas; and a sign-up system that has so vexed the citizenry that vaccine hunting has become for many a part-time job.“We are going to push, but we’re also going to have to pull,” said Dennis Schrader, the acting health secretary in Maryland, describing the state’s plan to not only ramp up capacity at mega-sites and pharmacies, but to “pull people in” with smaller, more targeted efforts.Nearly every state in the nation now finds itself in a perilous race between vaccinating its residents and succumbing to an onerous wave of cases fueled partly by the emergence of new variants of the coronavirus. As states rush to expand eligibility for the shot, many are also loosening rules on dining, gathering and masks.It will take extensive group efforts across competing interests to push states closer to herd immunity. Efforts to track who is getting vaccinated, and where, will become all the more important so that health officials can quickly identify who is being left behind, and shift their strategies and resources accordingly.Many states have already opened vaccination to all adults, including more than a dozen this week alone. To push the process along, Mr. Biden announced a new promotional campaign Thursday aimed at communities where vaccine hesitancy remains high.“It really is going to be the start of much more surveillance and analysis being needed to make sure that this was both a fast and a fair rollout of the largest vaccination campaign in human history,” said Alison M. Buttenheim, an associate professor at the University of Pennsylvania School of Nursing.Here in Maryland, the pent-up demand for the vaccine is huge: only people 65 and older, some types of essential workers and a few other narrow categories were eligible until late March, leaving two-thirds of the population still unprotected.On Tuesday, Gov. Larry Hogan, a Republican, opened up vaccination to all who are 16 and older and have certain medical conditions; by April 27, everyone 16 and older will be eligible regardless of medical status.Maryland officials are working with local health departments and community partners, particularly churches, to open “pop-up” vaccination sites aimed at populations that may be geographically or socially isolated.Erin Schaff/The New York TimesBut while Mr. Hogan has faced stark criticism from local leaders about the state’s middle-of-the-road pace, now some people worry it is speeding up too quickly. Mr. Hogan has already been criticized for not doing enough to reach Black and Latino residents, who make up more than 40 percent of the state’s population, but only 28 percent of those who have received at least one shot.The Hogan administration is planning to open four more mass vaccination sites by the end of April, bringing the total to 12, and has 320 pharmacies administering shots; a federally operated site will open at a suburban metro station next week. Mr. Hogan’s goal is to administer 100,000 shots per day by May, up from an average of 57,000 a day now.The state has started adding primary care doctors to the effort, with the goal of having 400 practices administering shots by May. It is also working with local health departments and community partners, particularly churches, to open “pop-up” vaccination sites aimed at populations that may be geographically or socially isolated, or distrustful of government and large institutions.Pastor John Jenkins at the First Baptist Church of Glenarden understood the role his church could play as he drove down a main drag in Prince George’s County — a majority-Black area that has had high Covid infection rates, but low vaccine rates — past the snaking line of cars leading to a mass vaccination site at the Six Flags amusement park.The vaccination site at the First Baptist Church of Glenarden planned to vaccinate a few hundred people a day, but quickly got closer to 1,000.Erin Schaff/The New York TimesA man received his shot at the church vaccination site.Erin Schaff/The New York TimesPastor John Jenkins of First Baptist Church of Glenarden. “I am grateful the governor reallocated resources here,” he said.Erin Schaff/The New York Times“The people in those cars didn’t look like people in the county,” Pastor Jenkins said. “The people in this community could not get appointments.”With the help of his church’s long-term partner, the University of Maryland Capital Region Health, he quickly created pop-up vaccine sites with his army of church volunteers. State officials, who were providing contract workers, came to see his sprawling indoor recreation center and quickly agreed to greatly expand on his initial dreams of several hundreds shots a week.The site, which functions like a medical center, planned to vaccinate a few hundred people a day, but quickly got closer to 1,000 with residents like Denise Evans, who said she felt “more comfortable” at her church than at the stadium down the road. The church will soon ramp up to provide shots daily. “I am grateful the governor reallocated resources here,” Pastor Jenkins said.Targeting smaller populations can also take special efforts. A group of Latino residents in Baltimore, who were given 25 slots at a state convention center, were often unable to reach the site, and those who got there could not find anyone who spoke Spanish. The Esperanza Center in Baltimore, a unit of Catholic Charities of Baltimore, was approached in February by the National Guard to set up a clinic for that group with Johns Hopkins at Sacred Heart of Jesus church.“The thing that was really important to us was that they not be in uniform,” said Katherine Phillips, the center’s medical director. (Many of those who attend the church are undocumented immigrants.)The site uses a hotline to help residents get appointments and offers shots at its church on Friday nights, when more area residents who could not otherwise leave work can get there.Another focus of criticism in Maryland, as in many other states, has been the system for scheduling vaccine appointments. Instead of a single online portal where people can view available appointments across the state, every provider has its own online appointment system, which means people often have to look through multiple sites to find a slot. The state recently created a single online platform where residents can preregister for an appointment at any of its mass vaccination sites, but Mr. Schrader, the acting health secretary, said that the hospital systems and pharmacy chains running most sites “want to use their own system.”Dr. Josh Sharfstein, a vice dean at the Johns Hopkins Bloomberg School of Public Health in Baltimore and a former Maryland health secretary, said he expected that approach to prove more problematic as more and more people seek appointments.“This chaotic system where people have to go to 15 websites, it really does discriminate against people who don’t have computers or can’t spend all day doing this,” Dr. Sharfstein said.Mr. Biden said recently that his administration would help make it easier to find vaccine appointments, including by creating a federally supported website that will show people the locations near them where shots are being given and a toll-free hotline that people can call for help finding a vaccine, both by May 1. He also promised to deploy “technology teams” to states that need help improving their vaccine appointment portals.To date, Maryland has been sending about 30 percent of its weekly vaccine allocation to its mass sites, 30 percent to local health departments, which share with community groups and other small providers, and the rest to hospital systems, pharmacies and independent doctors’ offices.Moving forward, Mr. Schrader said the state would rely heavily on local health departments and community health centers, which provide primary care to low-income and uninsured people at 126 locations around the state and are getting their own allocation directly from the federal government. Among other things, they will be able to compare their patient lists with the state’s vaccine registry to figure out who still needs a shot.Alvin and Tesha Adams took a selfie in front of an “I got vaccinated” sign after she got her first Covid-19 shot.Erin Schaff/The New York TimesIn Baltimore, where 21 percent of residents live below the poverty level, local hospitals, pharmacies and a nursing school have partnered with the city health department to send teams at least six times a week to public housing for the elderly, vaccinating more than 2,300 people there so far. The city will expand the program to other high-risk populations soon, said Dr. Letitia Dzirasa, the city’s health commissioner.“It is a little nerve-racking to think a month from now it will be completely open,” Dr. Dzirasa said.Still, she and other local officials around the state said they did not expect to have any shortage of vaccinators or sites where people could come for shots. In Washington County, where large rural swaths border Pennsylvania, Virginia and West Virginia, Maulik S. Joshi, the president and chief executive of Meritus Health, the local hospital system, said that between the county health department, the local aging commission and his own work force of nearly 3,000, he was not worried about staffing as the number of vaccine-eligible balloons.“We’ve deployed people like you wouldn’t believe,” Dr. Joshi said as he prepared to open a mass vaccination site at an outlet mall off a highway in Hagerstown, once an outpost of cut-rate merino wool sweaters and Orange Julius, now part medical center. “People from finance and outpatient rehab care are running our vaccination sites. We’re hiring. We’re ready to go. It’s not a cost issue or a people issue for us, it’s just a vaccine issue.”

We tend to think of childhood as a time of innocence and joy, but as many as 2 to 3 percent of children from ages 6 to 12 can have serious depression.When parents bring their children in for medical care these days, there is no such thing as a casual, “Hey, how’s it going?” We doctors walk into every exam room prepared to hear a story of sadness and stress, or at the very least, of coping and keeping it together in this very hard year, full of isolation, loss, tragedy and hardship, with routines disrupted and comfort hard to come by.Parents have carried heavy burdens of stress and responsibility, worrying about themselves but also watching their children struggle, and there is worldwide concern about depression and suicidality among young people. But it isn’t only the adults and the young adults and teenagers who are suffering and sad; young children can also experience depression, but it can look very different, which makes it challenging for parents — or doctors — to recognize it and provide help.Rachel Busman, a clinical psychologist at the Child Mind Institute in New York City, said that it can be hard to think about depression in younger children because we picture childhood as a time of innocence and joy. But as many as 2 to 3 percent of children ages 6 to 12 can have serious depression, she said. And children with anxiety disorders, which are present in more than 7 percent of children aged 3 to 17, are also at risk for depression.Dr. Helen Egger, until recently the chair of child and adolescent psychiatry at N.Y.U. Langone Health, said that according to her epidemiologic research, between 1 and 2 percent of young children — as young as 3 — are depressedDepression was originally conceived of as an adult problem. Maria Kovacs, professor of psychiatry at the University of Pittsburgh School of Medicine, said that in the 1950s and ’60s, there were child psychiatrists who believed that children did not have sufficient ego development to feel depression, but that research that she and other colleagues did in the ’70s showed that “school age children can suffer from diagnosable depression.”Before adolescence, depression is equally common in girls and boys, though among adolescents, it is twice as common in girls, and that predominance then lasts across most of adult life, until old age, when it again appears to equalize.What does depression look like in younger children?When young children are depressed, Dr. Kovacs said, it’s not unusual for “the primary mood to be irritability, not sadness — it comes across as being very cranky.” And children are much less likely to understand that what they’re feeling is depression, or identify it that way. “It almost never happens that they say, ‘something’s wrong because I’m sad,’” Dr. Kovacs said. It’s up to adults to look for signs that something is not right, she said.The best way for parents to recognize depression in young children is not so much by what a child says as by what the child does — or stops doing. Look for “significant changes in functioning,” Dr. Kovacs said, “if a child stops playing with favorite things, stops responding to what he used to respond to.”This might mean a child loses interest in the toys or games or jokes or rituals that used to be reliably fun or entertaining, or doesn’t seem interested in the usual back and forth of family life.“You’ve had a kid who was one way and then you see that they’re more irritable and sad,” said Dr. Egger, who is now the chief medical and scientific officer at Little Otter, a new online mental health care company for children. Children may seem flattened, have less energy or tire easily. And they may start complaining about physical symptoms, especially stomach aches and headaches. They may sleep more — or less — or lose their appetites.A preschool-aged child might be depressed if she is having daily tantrums, with behaviors that risk hurting herself or other people. Depression “may look like a behavior problem but is really being driven by what the kid is feeling inside,” Dr. Egger said.“It’s like walking through the world with dark-colored glasses,” Dr. Busman said. “It’s about myself, about the other person, and the world — I suck, this sucks, everything sucks.”Should I ask about suicidal thoughts?The irritability and the anger — or the flatness and the shutting down — can be signs of profound sadness. And while suicide attempts by elementary school-aged children are rare, they do happen and have increased in recent years. Suicide was the second leading cause of death in children 10 to 14 in 2018, and a 2019 JAMA study showed increasing emergency room visits by children for suicidal thoughts or actions from 2007 to 2015 — 41 percent in children under 11 years old. The presence of suicidal thoughts should be seen as a call for help.The most problematic myth about suicide is the fear “that if you ask about suicide you’re putting the idea in their heads,” said Dr. Kovacs, who developed the Children’s Depression Inventory which is used all over the world.“If you’re dealing with a child for whom this is not an issue, they’re just going to stare at you like you’re out of your head,” Dr. Kovacs said. “You cannot harm somebody by asking them.”But what if children say they have thought of suicide? As with adults, this suggests the child is living with pain and perhaps thinking about a way out. Dr. Kovacs said, children may imagine death as “a release, a surcease, a relief.”Dr. Busman said that she works with children who may say, “I don’t want to kill myself but I feel so bad I don’t know what else to do and say.”If a child talks about wanting to die, ask what that child means, and get help from a therapist if you’re concerned. A statement like this can be a real signal that a child is in distress, so don’t dismiss it or write it off as something the child is just saying for attention, she said.How can treatment help?“Parents should take child symptoms very seriously,” said Jonathan Comer, professor of psychology and psychiatry at Florida International University. “In serious forms it snowballs with time, and earlier onset is associated with worse outcomes across the life span.”In a 2016 longitudinal study, Dr. Kovacs and her colleagues traced the course of depression starting in childhood, and found recurrent episodes in later life.So if you see changes like withdrawal from activities, irritability or sadness, fatigue, or sleep disturbances that persist for two weeks, consider having the child evaluated by someone who is familiar with mental health issues in children of that age. Start with your pediatrician, who will know about resources available in your area.Parents should insist on a comprehensive mental health evaluation, Dr. Busman said, including gathering history from the parent, spending time with the child and talking to the school. An evaluation should include questions about symptoms of depression as well as looking for other problems, like attention deficit hyperactivity disorder or anxiety, which may be at the root of the child’s distress.Early treatment is effective, Dr. Comer said, “There’s terrific evidence for family-focused treatment for child depression — it focuses on family interactions and their impact on mood.” With children from 3 to 7, he said, versions of parent-child interaction therapy, known as PCIT, are often used — essentially coaching parents, and helping them emphasize and praise what is positive about their children’s behavior.As much as possible, parents should try to keep children going outside, taking walks, even playing outdoor games, even if they are less enthusiastic about their usual activities. As with adults, physical exercise has both mental and biological benefits — as do fresh air and sunshine.Depression does not necessarily lend itself to simple cause-and-effect explanations, but Dr. Kovacs emphasized that with a first episode in a child, there is almost always a particular stressor that has set off the problem. It could be a change in the family constellation — a parental divorce, a death — or it could be something more subtle, like an anxiety that has spiraled out of control. If a child does begin therapy, part of the treatment will be to identify — and talk about — that stressor.How can I find help for my child?If you’re concerned that your child might be depressed, start with your pediatrician or other primary care provider. Some clinics and health centers will have in-house mental health services, and you may be able to have your child seen there. Some doctors will have links to local therapists with experience with young children. Mental health specialists can be in short supply (and there’s a lot of need right now), so be open to the possibility of care being delivered remotely, through telehealth. Dr. Kovacs also suggested that parents who are looking for treatment consider clinical psychology department clinics at a local university, where students in psychology and counseling are supervised by licensed psychologists; she said such clinics often have good availability.[The Society of Clinical Child and Adolescent Psychology has advice on how to know if treatment is evidence-based.]“Parents should see children’s struggles as opportunities to intervene,” Dr. Comer said. “The majority of early child mood problems will go away with time, sensitive parenting and supportive environments.”

A highly contagious SARS-CoV-2 variant was unknowingly spreading for months in the United States by October 2020, according to a new study from researchers with The University of Texas at Austin COVID-19 Modeling Consortium. Scientists first discovered it in early December in the United Kingdom, where the highly contagious and more lethal variant is thought to have originated. The journal Emerging Infectious Diseases, which has published an early-release version of the study, provides evidence that the coronavirus variant B117 (501Y) had spread across the globe undetected for months when scientists discovered it.
“By the time we learned about the U.K. variant in December, it was already silently spreading across the globe,” said Lauren Ancel Meyers, the director of the COVID-19 Modeling Consortium at The University of Texas at Austin and a professor of integrative biology. “We estimate that the B117 variant probably arrived in the U.S. by October of 2020, two months before we knew it existed.”
Analyzing data from 15 countries, researchers estimated the chance that travelers from the U.K. introduced the variant into 15 countries between Sept. 22 and Dec. 7, 2020. They found that the virus variant had almost certainly arrived in all 15 countries by mid-November. In the U.S., the variant probably had arrived by mid-October.
“This study highlights the importance of laboratory surveillance,” Meyers said. “Rapid and extensive sequencing of virus samples is critical for early detection and tracking of new variants of concern.”
In conjunction with the paper’s publication, consortium members developed a new tool that decision-makers anywhere in the United States can use in planning for genetic sequencing that helps to detect the presence of variants. To help the U.S. expand national surveillance of variants, the new online calculator indicates the number of virus samples that must be sequenced in order to detect new variants when they first emerge. For example, if the goal is to detect an emerging variant by the time it is causing 1 out of every 1,000 new COVID-19 infections, approximately 3,000 SARS-CoV-2 positive specimens per week need to be sequenced.
“Health officials are looking for better ways to manage the unpredictability of this virus and future variants,” said Spencer Woody, a postdoctoral fellow at the UT COVID-19 Modeling Consortium. “Our new calculator determines how many positive SARS-CoV-2 specimens must be sequenced to ensure that new threats are identified as soon as they start spreading.”
He explained that the calculator has a second feature. “It also helps labs figure out how quickly they will detect new variants, given their current sequencing capacity.”
“We created this tool to support federal, state and local health officials in building credible early warning systems for this and future pandemic threats,” Meyers said.
In addition to Meyers, authors of the Emerging Infectious Disease paper are Zhanwei Du, Bingyi Yang, Sheikh Taslim Ali, Tim K. Tsang, Songwei Shan, Peng Wu, Eric H.Y. Lau and Benjamin J. Cowling of the WHO Collaborating Centre for Infectious Disease Epidemiology and Control in Hong Kong and Lin Wang of the University of Cambridge.
The research was funded by Hong Kong’s Health and Medical Research Fund, the National Institutes of Health and the Centers for Disease Control and Prevention.
Meyers holds the Denton A. Cooley Centennial Professorship at The University of Texas at Austin.
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Materials provided by University of Texas at Austin. Note: Content may be edited for style and length.

In the 1960s, a national focus on hunger was essential to address major problems of undernutrition after World War II. In the 1990s, the nation shifted away from hunger toward “food insecurity” to better capture and address the challenges of food access and affordability.
Now, a new Viewpoint article argues that today’s health and equity challenges call for the U.S. to shift from “food insecurity” to “nutrition insecurity” in order to catalyze appropriate focus and policies on access not just to food but to healthy, nourishing food.
The Viewpoint, by Dariush Mozaffarian of the Friedman School of Nutrition Science & Policy at Tufts University, Sheila Fleischhacker of Georgetown Law School, and José Andrés of World Central Kitchen, was published online in JAMA this week.
The concept of food security focuses on access to and affordability of food that is safe, nutritious, and consistent with personal preferences. In reality, however, the “nutritious” part often has been overlooked or lost in national policies and solutions, with resulting emphasis on quantity, rather than quality, of food, say the authors.
“Food is essential both for life and human dignity. Every day, I see hunger, but the hunger I see is not only for calories but for nourishing meals. With a new focus on nutrition security, we embrace a solution that nourishes people, instead of filling them with food but leaving them hungry,” said Chef José Andrés, founder of World Central Kitchen.
The authors define nutrition security as having consistent access to and availability and affordability of foods and beverages that promote well-being, while preventing — and, if needed, treating — disease. Nutrition security provides a more inclusive view that recognizes that foods must nourish all people.
“‘Nutrition security’ incorporates all the aims of food security but with additional emphasis on the need for wholesome, healthful foods and drinks for all. COVID-19 has made clear that Americans who are most likely to be hungry are also at highest risk of diet-related diseases including obesity, diabetes, heart disease, and many cancers — a harsh legacy of inequities and structural racism in our nation. A new focus on nutrition security for all Americans will help crystallize and catalyze real solutions that provide not only food but also well-being for everyone,” said first author Dariush Mozaffarian, dean of the Friedman School of Nutrition Science & Policy at Tufts University.
“It’s the right time for this evolution,” said Sheila Fleischhacker, adjunct professor at Georgetown Law School, who has drafted food, nutrition and health legislation and campaign positions at the local, state, tribal and federal levels. “By prioritizing nutrition security, we bring together historically siloed areas — hunger and nutrition — which must be tackled together to effectively address our modern challenges of diet-related diseases and disparities in clinical care, government food and food assistance policies, public health investments, and national research.”
“The current approach is not sufficient,” the authors write, and “traditionally marginalized minority groups as well as people living in rural and lower-income counties are most likely to experience disparities in nutrition quality, food insecurity, and corresponding diet-related diseases.”

A team of researchers at the University of Alberta has uncovered a long-sought link in the battle to control cholesterol and heart disease.
The protein that interferes with low-density lipoprotein (LDL) receptors that clear “bad” cholesterol from the blood was identified in findings recently published in Nature Communications by Dawei Zhang, associate professor of pediatrics in the Faculty of Medicine & Dentistry. Excess LDL cholesterol can lead to atherosclerosis — a narrowing and hardening of arteries — and ultimately, heart attack.
“We have known for many years that these receptors could be cleaved, but nobody knew which protein was responsible,” said Zhang. “There had been several attempts around the world but nobody else was successful.”
Now that the culprit has been identified, Zhang’s lab is already at work to find a drug to target the protein, allowing the receptors to clear more LDL.
A cholesterol-reducing class of drugs called statins — Lipitor and Crestor are two well-known brand names — has been shown to reduce cardiac events by 20 to 40 per cent, but they have side-effects that mean they can’t be given in high enough doses to work for everyone. The new drug would be used in combination with statins to boost their effect, Zhang said.
Zhang’s team stumbled upon the role of the protein — membrane type 1 matrix metalloproteinase — by accident while studying another protein involved in heart function. They then set out to repeat and confirm their findings in mouse, rat and human cells, working in collaboration with researchers in China and other faculty members at the U of A. Their study was funded by the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. Zhang is also a member of the Women and Children’s Health Research Institute.
The protein has other critical physiological functions, Zhang explained, so his lab will work to identify and focus on the specific region within the protein that acts on the LDL receptor. They are also working with a new technique to further target their potential drug so it will work only within the liver, further reducing the likelihood of unwanted side-effects. Their early results are encouraging, Zhang said.
Zhang noted the protein is also critical for cancer tumour invasion, so the team will collaborate with U of A oncology experts to learn more.
“The one protein is a shared risk factor for the two most common diseases in humans — cancer and cardiovascular disease,” he said. “We will explore whether we can target one protein to reduce the incidence of the two most common human diseases.”
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Materials provided by University of Alberta Faculty of Medicine & Dentistry. Note: Content may be edited for style and length.

Bipolar disorder affects millions of Americans, causing dramatic swings in mood and, in some people, additional effects such as memory problems.
While bipolar disorder is linked to many genes, each one making small contributions to the disease, scientists don’t know just how those genes ultimately give rise to the disorder’s effects.
However, in new research, scientists at the University of Wisconsin-Madison have found for the first time that disruptions to a particular protein called Akt can lead to the brain changes characteristic of bipolar disorder. The results offer a foundation for research into treating the often-overlooked cognitive impairments of bipolar disorder, such as memory loss, and add to a growing understanding of how the biochemistry of the brain affects health and disease.
The Cahill lab and their colleagues at Michigan State University published their findings March 24 in Neuron.
Akt is a kinase, a type of protein that adds tags of the molecule phosphate to other proteins. These phosphate tags can act as on or off switches, changing how other proteins work, ultimately influencing vital functions. In neurons, those functions can include how cells signal to one another, which can affect thinking and mood. When the Akt pathway is revved up, a lot of other proteins get phosphate tags. When it’s quieter, those phosphate tags are absent.
The researchers discovered that men with bipolar disorder have reduced activity of this pathway, known at Akt-mTOR, in a brain region crucial for attention and memory. And when the researchers disrupted the pathway in mice, the rodents developed memory problems and crucial brain connections withered away, simulating changes in humans with bipolar disorder.

A possible explanation for why many cancer drugs that kill tumor cells in mouse models won’t work in human trials has been found by researchers with The University of Texas Health Science Center at Houston (UTHealth) School of Biomedical Informatics and McGovern Medical School.
The research was published today in Nature Communications.
In the study, investigators reported the extensive presence of mouse viruses in patient-derived xenografts (PDX). PDX models are developed by implanting human tumor tissues in immune-deficient mice, and are commonly used to help test and develop cancer drugs.
“What we found is that when you put a human tumor in a mouse, that tumor is not the same as the tumor that was in the cancer patient,” said W. Jim Zheng, PhD, professor at the School of Biomedical Informatics and senior author on the study. “The majority of tumors we tested were compromised by mouse viruses.”
Using a data-driven approach, researchers analyzed 184 data sets generated from sequencing PDX samples. Of the 184 samples, 170 showed the presence of mouse viruses.
The infection is associated with significant changes in tumors, and Zheng says that could affect PDX as a drug testing model for humans.
“When scientists are looking for a way to kill a tumor using the PDX model, they assume the tumor in the mouse is the same as cancer patients, but they are not. It makes the results of a cancer drug look promising when you think the medication kills the tumor — but in reality, it will not work in human trial, as the medication kills the virus-compromised tumor in mouse,” Zheng said.
He hopes his findings will change researchers’ approach to find a way to kill tumor cells.
“We all share the common goal of hoping to find a cure for cancer. There are 210 ongoing NIH-funded projects relevant to PDX models, with a combined annual fiscal year budget of over $116 million. We need to tighten up quality control and use models that are not compromised so that the treatments we give to future patients are effective,” Zheng said.
This work is a collaboration between the Texas Therapeutics Institute, Institute of Molecular Medicine (IMM) at McGovern Medical School, and the Data Science and Informatics Core for Cancer Research at the School of Biomedical Informatics.
“As a team, we synergized the strengths of McGovern Medical School’s virology research and School of Biomedical Informatics’ data analysis expertise, and it has led to the success of this project,” said Zhiqiang An, PhD, co-senior author of the study, professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School.
The study is partly supported by the Cancer Prevention and Research Institute of Texas through grant RP170668, RP150551, and RP190561; the National Institutes of Health through grants 1UL1TR003167 and R01AG066749; and the Welch Foundation AU-0042-20030616.
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Materials provided by University of Texas Health Science Center at Houston. Original written by Jeannette Sanchez. Note: Content may be edited for style and length.

Type I Diabetes Mellitus (T1D) is an autoimmune disorder leading to permanent loss of insulin-producing beta-cells in the pancreas. In a new study, researchers from The University of Tokyo developed a novel device for the long-term transplantation of iPSC-derived human pancreatic beta-cells.
T1D develops when autoimmune antibodies destroy pancreatic beta-cells that are responsible for the production of insulin. Insulin regulates blood glucose levels, and in the absence of it high levels of blood glucose slowly damage the kidneys, eyes and peripheral nerves. Because the body loses the ability to produce insulin over time, the current mainstay of treatment for T1D is to inject insulin. An exciting research endeavor over the past decade has been to find ways to replace lost beta-cells by means of cell therapy.
“Cell therapy is an exciting, but challenging, approach to treat type I diabetes mellitus,” says lead author of the study Professor Shoji Takeuchi. “The challenge arises from the difficulty to make large amounts of human beta-cells in a dish, and more importantly, to achieve safe and effective transplantation. In this study, we wanted to develop a novel construct that enables successful transplantation of beta-cells in the long-term.”
To achieve their goal, the researchers developed a lotus-root-shaped cell-encapsulated construct (LENCON) and packaged it with human iPSC-derived pancreatic beta-cells, which are a limitless cell source and allow for the production of any number of beta-cells. The necessity for such an encapsulation technique arises from the fact that immune cells of the recipient could destroy the newly transplanted cells. To prevent this from happening, the researchers constructed the LENCON graft with millimeter thickness. The millimeter-thick graft diameters have previously been shown to mitigate the body’s immune response to a foreign body. At millimeter thickness, oxygen and nutrients could not be supplied to the center of the cells, but by using a lotus root shape, the cells were placed only near the edge of the graft where oxygen and nutrients can diffuse sufficiently, creating an environment in which the cells could survive, even in the millimeter-thick graft.
Having designed the LENCON, the question was if it would effectively control blood glucose levels in the long-term without provoking an immune response. To address this question, the researchers transplanted the construct in immunodeficient and immunocompetent diabetic mice. The former helped investigate the efficacy of the graft on controlling blood glucose levels in the absence of an immune response, while the latter approach tackled both goals. The researchers found that LENCON was able to maintain normal blood glucose levels for more than 180 days in the former mice, and was able to be removed without adhesion after more than one year of transplantation in the latter mice.
“These are striking results that show how LENCON can successfully and safely be used in the setting of type I diabetes mellitus. Our results suggest that LENCON could offer a novel option for cell therapy for type I diabetes mellitus,” says the first author of the study Dr. Fumisato Ozawa.
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Materials provided by Institute of Industrial Science, The University of Tokyo. Note: Content may be edited for style and length.

UConn researcher Paulo Verardi, associate professor of pathobiology and veterinary science in the College of Agriculture, Health and Natural Resources, has demonstrated the success of a vaccine against Zika virus and recently published his findings in Scientific Reports, a Nature Research publication. He has also filed provisional patent for the novel vaccine platform technology used to generate the vaccine, as well as genetic modifications made to the vaccine that significantly enhance expression of the vaccine antigen.
Verardi, a Brazilian native, was in Brazil visiting family in the summer of 2015 when the Zika outbreak first began to make waves and soon reached epidemic status.
Back in the United States, Verardi kept tabs on the Zika epidemic and its emerging connection to microcephaly, a serious birth defect that causes babies to be born with small heads and underdeveloped brains.
In October of that year, Verardi called then-Ph.D.-student Brittany Jasperse (CAHNR ’19) into his office and told her he wanted to apply their newly developed vaccine platform and start developing a vaccine for Zika virus.
Verardi and Jasperse were among the first researchers in the US to receive NIH funding to generate a vaccine against Zika virus, thanks to Verardi recognizing the significance of Zika virus early.
Modern advancements in genomic technology have expediated the vaccine development process. In the past, researchers needed to have access to the actual virus. Now just obtaining the genetic sequence of the virus can be sufficient to develop a vaccine, as was the case for the Zika vaccine Verardi and Jasperse developed, and the COVID-19 vaccines currently approved for emergency use in the United States and abroad.