Publisher Health

Telehealth has become a critical way for doctors to still provide health care while minimizing in-person contact during COVID-19. But with phone or Zoom appointments, it’s harder for doctors to get important vital signs from a patient, such as their pulse or respiration rate, in real time.
A University of Washington-led team has developed a method that uses the camera on a person’s smartphone or computer to take their pulse and respiration signal from a real-time video of their face. The researchers presented this state-of-the-art system in December at the Neural Information Processing Systems conference.
Now the team is proposing a better system to measure these physiological signals. This system is less likely to be tripped up by different cameras, lighting conditions or facial features, such as skin color. The researchers will present these findings April 8 at the ACM Conference on Health, Interference, and Learning.
“Machine learning is pretty good at classifying images. If you give it a series of photos of cats and then tell it to find cats in other images, it can do it. But for machine learning to be helpful in remote health sensing, we need a system that can identify the region of interest in a video that holds the strongest source of physiological information — pulse, for example — and then measure that over time,” said lead author Xin Liu, a UW doctoral student in the Paul G. Allen School of Computer Science & Engineering.
“Every person is different,” Liu said. “So this system needs to be able to quickly adapt to each person’s unique physiological signature, and separate this from other variations, such as what they look like and what environment they are in.”
The team’s system is privacy preserving — it runs on the device instead of in the cloud — and uses machine learning to capture subtle changes in how light reflects off a person’s face, which is correlated with changing blood flow. Then it converts these changes into both pulse and respiration rate.

In the first study to use whole genome sequencing (WGS) to discover rare genomic variants associated with Alzheimer’s disease (AD), researchers have identified 13 such variants (or mutations). In another novel finding, this study establishes new genetic links between AD and the function of synapses, which are the junctions that transmit information between neurons, and neuroplasticity, or the ability of neurons to reorganize the brain’s neural network. These discoveries could help guide development of new therapies for this devastating neurological condition. Researchers at Massachusetts General Hospital (MGH), the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center report these findings in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Over the last four decades, MGH has pioneered research on the genetic origins of AD, led by Rudolph Tanzi, PhD, vice chair of Neurology and director of the hospital’s Genetics and Aging Research Unit. Notably, Tanzi and colleagues co-discovered genes that cause early onset (prior to age 60) familial AD (that is, a form that runs in families), including the amyloid protein (A4) precursor (APP), and the presenilin genes (PSEN1 and PSEN2). Mutations in these genes lead to accumulation of amyloid plaques in the brain, a hallmark of AD.
The next 30 AD gene variants that were discovered are primarily linked to chronic inflammation in the brain (or neuroinflammation), which also increases the risk for this cognitive disease. However, loss of synapses is the neurological change that is most closely correlated with the severity of dementia in Alzheimer’s disease, yet no clear genetic links between the disease and these vital connections had previously been identified. “It was always kind of surprising that whole-genome screens had not identified Alzheimer’s genes that are directly involved with synapses and neuroplasticity,” says Tanzi.
Prior to this paper, the genome-wide association study (GWAS) was the primary tool used for identifying AD genes. In a GWAS, the genomes of many individuals are scanned in search of common gene variants that occur more frequently in people who have a given disease, such as AD. But to date, common Alzheimer’s-associated gene variants have accounted for less than half of the heritability of AD. A standard GWAS misses the rare gene variants (those occurring in less than 1% of the population), a problem solved by the WGS, which scans every bit of DNA in a genome.
“This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn’t do before,” says Dmitry Prokopenko, PhD, of MGH’s McCance Center for Brain Health, who is lead author of the study.
Identifying less-common gene mutations that increase the risk for AD is important because they may hold critical information about the biology of the disease, says Tanzi. “Rare gene variants are the dark matter of the human genome,” he says, and there are lots of them: Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants — and 77% are rare.
In their quest to find rare AD gene variants, Tanzi, Prokopenko and their colleagues performed WGS analyses on the genomes of 2,247 individuals from 605 families that include multiple members who have been diagnosed with AD. They also analyzed WGS datasets on 1,669 unrelated individuals. The study identified 13 previously unknown rare gene variants associated with AD. Strikingly, these gene variants were associated with functioning of synapses, development of neurons, and neuroplasticity.
“With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease,” says Tanzi, who sees potential for their methods to be used to study the genetics of many other conditions. Moreover, he plans to use “Alzheimer’s in a dish” — three-dimensional cell culture models and brain organoids he and his colleagues have developed over the past decade — to explore what happens when the rare mutations this paper identified are inserted in neurons. “That could help guide us in novel drug discovery,” says Tanzi.
This study was supported by the Cure Alzheimer’s Fund and grants from the National Institutes of Health.
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Kidney development is a balancing act between the self-renewal of stem and progenitor cells to maintain and expand their numbers, and the differentiation of these cells into more specialized cell types. In a new study in the journal eLife from Andy McMahon’s laboratory in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, former graduate student Alex Quiyu Guo and a team of scientists demonstrate the importance of a molecule called β-catenin in striking this balance.
β-catenin is a key driver at the end of a complex signaling cascade known as the Wnt pathway. Wnt signaling plays critical roles in the embryonic development of multiple organs including the kidneys. By partnering with other Wnt pathway molecules, β-catenin controls the activity of hundreds to thousands of genes within the cell.
The new study builds on the McMahon Lab’s previous discovery that Wnt/β-catenin can initiate progenitor cells to execute a lengthy and highly orchestrated program of forming structures in the kidney called nephrons. A healthy human kidney contains a million nephrons that balance body fluids and remove soluble waste products. Too few nephrons results in kidney disease.
Previous studies from the UT Southwestern Medical Center laboratory of Thomas Carroll, a former postdoctoral trainee in the McMahon Lab, suggested that Wnt/β-catenin signaling plays opposing roles in ensuring the proper number of nephrons: promoting progenitor maintenance and self-renewal, and stimulating progenitor cell differentiation.
“It sounded like Wnt/β-catenin is doing two things — both maintenance and differentiation — that seem to be opposite operations,” said Guo. “Therefore, the hypothesis was that different levels of Wnt/β-catenin can dictate different fates of the nephron progenitors: when it’s low, it works on maintenance; when it’s high, it directs differentiation.”
In 2015, it became more possible to test this hypothesis when Leif Oxburgh, a scientist at the Rogosin Institute in New York and a co-author of the eLife study, developed a system for growing large numbers of nephron progenitor cells, or NPCs, in a Petri dish.

Researchers pushed back after the C.D.C. director asserted that vaccinated people “do not carry the virus.”The Centers for Disease Control and Prevention on Thursday walked back controversial comments made by its director, Dr. Rochelle P. Walensky, suggesting that people who are vaccinated against the coronavirus never become infected or transmit the virus to others.The assertion called into question the precautions that the agency had urged vaccinated people to take just last month, like wearing masks and gathering only under limited circumstances with unvaccinated people.“Dr. Walensky spoke broadly during this interview,” an agency spokesman told The Times. “It’s possible that some people who are fully vaccinated could get Covid-19. The evidence isn’t clear whether they can spread the virus to others. We are continuing to evaluate the evidence.”The agency was responding in part to criticism from scientists who noted that current research was far from sufficient to claim that vaccinated people cannot spread the virus.The data suggest that “it’s much harder for vaccinated people to get infected, but don’t think for one second that they cannot get infected,” said Paul Duprex, director of the Center for Vaccine Research at the University of Pittsburgh.In a television interview with MSNBC’s Rachel Maddow, Dr. Walensky referred to data published by the C.D.C. showing that one dose of the Moderna or Pfizer-BioNTech vaccine was 80 percent effective at preventing infection, and two doses were 90 percent effective.That certainly suggested that transmission from vaccinated people might be unlikely, but Dr. Walensky’s comments hinted that protection was complete. “Our data from the C.D.C. today suggests that vaccinated people do not carry the virus, don’t get sick,” she said. “And that it’s not just in the clinical trials, it’s also in real-world data.”Dr. Walensky went on to emphasize the importance of continuing to wear masks and maintain precautions, even for vaccinated people. Still, the brief comment was widely interpreted as saying that the vaccines offered complete protection against infection or transmission.In a pandemic that regularly spawns scientific misunderstanding, experts said they were sympathetic to Dr. Walensky and her obvious desire for Americans to continue to take precautions. It was only Monday that she said rising caseloads had left her with a sense of “impending doom.”“If Dr. Walensky had said most vaccinated people do not carry virus, we would not be having this discussion,” said John Moore, a virologist at Weill Cornell Medicine in New York.“What we know is the vaccines are very substantially effective against infection — there’s more and more data on that — but nothing is 100 percent,” he added. “It is an important public health message that needs to be gotten right.”Misinterpretation could disrupt the agency’s urgent pleas for immunization, some experts said. As of Wednesday, 30 percent of Americans had received at least one dose of a vaccine and 17 percent were fully immunized.“There cannot be any daylight between what the research shows — really impressive but incomplete protection — and how it is described,” said Dr. Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center in New York.“This opens the door to the skeptics who think the government is sugarcoating the science,” Dr. Bach said, “and completely undermines any remaining argument why people should keep wearing masks after being vaccinated.”All of the coronavirus vaccines are spectacularly successful at preventing serious disease and death from Covid-19, but how well they prevent infection has been less clear.Clinical trials of the vaccines were designed only to assess whether the vaccines prevent serious illness and death. The research from the C.D.C. on Monday brought the welcome conclusion that the vaccines are also extremely effective at preventing infection.The study enrolled 3,950 health care workers, emergency responders and others at high risk of infection. The participants swabbed their noses each week and sent the samples in for testing, which allowed federal researchers to track all infections, symptomatic or not. Two weeks after vaccination, the vast majority of vaccinated people remained virus-free, the study found.Follow-up data from clinical trials support that finding. In results released by Pfizer and BioNTech on Wednesday, for example, 77 people who received the vaccine had a coronavirus infection, compared with 850 people who got a placebo.“Clearly, some vaccinated people do get infected,” Dr. Duprex said. “We’re stopping symptoms, we’re keeping people out of hospitals. But we’re not making them completely resistant to an infection.”The number of vaccinated people who become infected is likely to be higher among those receiving vaccines made by Johnson & Johnson and AstraZeneca, which have a lower efficacy, experts said. (Still, those vaccines are worth taking, because they uniformly prevent serious illness and death.)Infection rates may also be higher among people exposed to a virus variant that can sidestep the immune system.Cases across the country are once again on the upswing, threatening a new surge. Dr. Walensky’s comment came just a day after she made an emotional appeal to the American public to continue taking precautions.“I am asking you to just hold on a little longer, to get vaccinated when you can, so that all of those people that we all love will still be here when this pandemic ends,” she said.Given the rising numbers, it’s especially important that immunized people continue to protect those who have not yet been immunized against the virus, experts said.“Vaccinated people should not be throwing away their masks at this point,” Dr. Moore said. “This pandemic is not over.”

A multistate group of anesthesiologists filed cases in Texas and Colorado, accusing the insurance giant of squeezing them like a “boa constrictor.”UnitedHealthcare, one of the nation’s largest health insurers, is being sued in two states by a large group of anesthesiologists who are accusing the company of stifling competition by forcing the doctors out of its network and by using its enormous clout to pressure hospitals and surgeons to stop referring patients to them.The lawsuits, filed Wednesday in Colorado and Texas, were brought by U.S. Anesthesia Partners, a sizable physician-owned practice backed by private-equity investors. The practice claims in the Texas lawsuit that United engaged in “unlawful tactics and pressure campaigns,” including “bribing” surgeons with contracts that paid them much more if they steered patients away from the group’s anesthesiologists.The doctors make similar claims in the lawsuit they filed in Colorado, where they say United orchestrated a “group boycott.” They describe United as “like a boa constrictor,” squeezing the group “from all angles.”In an emailed statement, United said the lawsuits were “just the latest example of the group’s efforts to pressure us into agreeing to its rate demands and to distract from the real reason that it no longer participates in our network.” The company said it had not yet been served with either complaint.United added that many of the private-equity-backed physician groups “expect to be paid double or even triple the median rate we pay other physicians providing the same services,” driving up the cost of care. The company says these groups have been using their increasing presence in a given regional market to demand higher rates. It says that its goal has been to keep the groups in network but that it is rethinking its approach.While insurers and the hospitals and doctors have long had ugly standoffs during contract negotiations, the parties typically come to a last-minute agreement. But United has become increasingly aggressive in its stance toward large physician groups like U.S. Anesthesia, dropping a number of them from its network, according to analysts.“United has a lot of market power and they want to use it to their advantage,” said Dean Ungar, who follows the insurance behemoth for Moody’s Investors Service, which evaluates the company’s debt. “They are willing to play hardball with some of these companies.”U.S. Anesthesia, which operates in nine states, said it had a long relationship with United and was part of the carrier’s networks in Texas and Colorado until last year.But the doctors also raise questions about the insurer’s potential conflicts of interest as its parent company, UnitedHealth Group, also offers medical services. UnitedHealth, which had $257 billion in sales last year, has become a sprawling conglomerate that includes more than 50,000 physicians, a chain of surgery centers, a pharmacy benefit manager and other assorted health care businesses in addition to its traditional insurance business.UnitedHealth directly competes with U.S. Anesthesia, according to the Texas lawsuit, through an ownership interest in Sound Physicians, a large medical practice that provides emergency and anesthesiology services. Sound Physicians is looking to expand in markets like Fort Worth and Houston, and U.S. Anesthesia claims in the lawsuit that its doctors were contacted by Sound Physicians “to induce them to leave” and challenge the noncompete provisions in their contracts to work with the United group.The major insurer throws its weight around in other ways, the lawsuit claims. While the company’s Optum unit, which operates the surgery centers and clinics, is technically separate from the health insurer, the doctors accuse United of forcing its OptumCare facilities to sever their relationships with the anesthesiology group and pushing in-network surgeons to move their operations to hospitals or facilities that do not have contracts with U.S. Anesthesia.“United and its affiliates have extended their tentacles into virtually every aspect of health care, allowing United to squeeze, choke and crush any market participant that stands in the way of United’s increased profits,” the doctors claim in their lawsuit.It is standard practice, United said, for an insurer to encourage the use of hospitals and doctors within its network.In contrast to many smaller physician groups that are struggling because of the pandemic, United has maintained a strong financial position, shoring up profits while elective surgeries and other procedures were shut down, resulting in fewer medical claims. So it has continued to expand, hiring more doctors and buying up additional practices. The company says it plans to add more than 10,000 employed or affiliated doctors this year.The relationship between insurers and providers has become more complicated as more insurance carriers own doctors’ groups or clinics. “They want to be the referee and play on the other team,” said Michael Turpin, a former United executive who is now an executive vice president at USI, an insurance brokerage.Employers that rely on UnitedHealthcare to cover their workers have a difficult time judging who benefits when insurers fail to reach an agreement to keep a provider in network. “This is just as much about profit as it is about principle,” Mr. Turpin said.United has defended its actions in the past by pointing to the role many of these doctors’ groups, financed by private equity, played in creating surprise medical bills that overwhelmed and burdened Americans around the country. Because the groups’ doctors specialize in areas like emergency care or anesthesia, patients are often shocked to find out that they are not in network even if the hospital where they received care is.Some of the doctors’ groups, like Envision Healthcare, whose doctors provide emergency-room care, pursued a strategy of keeping their doctors out of network to make more money. Patients were caught in the middle as insurers and doctors fought over out-of-network bills, and many people ended up owing large sums not covered by their health plans.When criticism of these tactics pressured Congress to consider remedies, the private-equity firms backing groups like Envision and TeamHealth spent large sums trying to block federal legislation. Lawmakers finally took action at the end of last year to protect patients from surprise bills by requiring parties to reach a fair price.But doctors say United is increasingly unwilling to come to an agreement they can accept. Envision, which eventually agreed to lower its payments and be included in the health plan’s network, said United dropped it this year because it would not agree to “drastic cuts to clinician pay.”“United turned down multiple proposals that would reduce the total cost of care for patients,” Envision said in an emailed statement. “We are left to wonder why it appears United does not want our 25,000 clinicians in their network.”The insurer has also dropped other groups. Last year, Mednax, which employed specialists in neonatology and anesthesiology, announced it had been dropped by United in four states. The company has since sold both its radiology and anesthesiology practices.

A multistate group of anesthesiologists filed cases in Texas and Colorado, accusing the insurance giant of squeezing them like a “boa constrictor.”UnitedHealthcare, one of the nation’s largest health insurers, is being sued in two states by a large group of anesthesiologists who are accusing the company of stifling competition by forcing the doctors out of its network and by using its enormous clout to pressure hospitals and surgeons to stop referring patients to them.The lawsuits, filed Wednesday in Colorado and Texas, were brought by U.S. Anesthesia Partners, a sizable physician-owned practice backed by private-equity investors. The practice claims in the Texas lawsuit that United engaged in “unlawful tactics and pressure campaigns,” including “bribing” surgeons with contracts that paid them much more if they steered patients away from the group’s anesthesiologists.The doctors make similar claims in the lawsuit they filed in Colorado, where they say United orchestrated a “group boycott.” They describe United as “like a boa constrictor,” squeezing the group “from all angles.”In an emailed statement, United said the lawsuits were “just the latest example of the group’s efforts to pressure us into agreeing to its rate demands and to distract from the real reason that it no longer participates in our network.” The company said it had not yet been served with either complaint.United added that many of the private-equity-backed physician groups “expect to be paid double or even triple the median rate we pay other physicians providing the same services,” driving up the cost of care. The company says these groups have been using their increasing presence in a given regional market to demand higher rates. It says that its goal has been to keep the groups in network but that it is rethinking its approach.While insurers and the hospitals and doctors have long had ugly standoffs during contract negotiations, the parties typically come to a last-minute agreement. But United has become increasingly aggressive in its stance toward large physician groups like U.S. Anesthesia, dropping a number of them from its network, according to analysts.“United has a lot of market power and they want to use it to their advantage,” said Dean Ungar, who follows the insurance behemoth for Moody’s Investors Service, which evaluates the company’s debt. “They are willing to play hardball with some of these companies.”U.S. Anesthesia, which operates in nine states, said it had a long relationship with United and was part of the carrier’s networks in Texas and Colorado until last year.But the doctors also raise questions about the insurer’s potential conflicts of interest as its parent company, UnitedHealth Group, also offers medical services. UnitedHealth, which had $257 billion in sales last year, has become a sprawling conglomerate that includes more than 50,000 physicians, a chain of surgery centers, a pharmacy benefit manager and other assorted health care businesses in addition to its traditional insurance business.UnitedHealth directly competes with U.S. Anesthesia, according to the Texas lawsuit, through an ownership interest in Sound Physicians, a large medical practice that provides emergency and anesthesiology services. Sound Physicians is looking to expand in markets like Fort Worth and Houston, and U.S. Anesthesia claims in the lawsuit that its doctors were contacted by Sound Physicians “to induce them to leave” and challenge the noncompete provisions in their contracts to work with the United group.The major insurer throws its weight around in other ways, the lawsuit claims. While the company’s Optum unit, which operates the surgery centers and clinics, is technically separate from the health insurer, the doctors accuse United of forcing its OptumCare facilities to sever their relationships with the anesthesiology group and pushing in-network surgeons to move their operations to hospitals or facilities that do not have contracts with U.S. Anesthesia.“United and its affiliates have extended their tentacles into virtually every aspect of health care, allowing United to squeeze, choke and crush any market participant that stands in the way of United’s increased profits,” the doctors claim in their lawsuit.It is standard practice, United said, for an insurer to encourage the use of hospitals and doctors within its network.In contrast to many smaller physician groups that are struggling because of the pandemic, United has maintained a strong financial position, shoring up profits while elective surgeries and other procedures were shut down, resulting in fewer medical claims. So it has continued to expand, hiring more doctors and buying up additional practices. The company says it plans to add more than 10,000 employed or affiliated doctors this year.The relationship between insurers and providers has become more complicated as more insurance carriers own doctors’ groups or clinics. “They want to be the referee and play on the other team,” said Michael Turpin, a former United executive who is now an executive vice president at USI, an insurance brokerage.Employers that rely on UnitedHealthcare to cover their workers have a difficult time judging who benefits when insurers fail to reach an agreement to keep a provider in network. “This is just as much about profit as it is about principle,” Mr. Turpin said.United has defended its actions in the past by pointing to the role many of these doctors’ groups, financed by private equity, played in creating surprise medical bills that overwhelmed and burdened Americans around the country. Because the groups’ doctors specialize in areas like emergency care or anesthesia, patients are often shocked to find out that they are not in network even if the hospital where they received care is.Some of the doctors’ groups, like Envision Healthcare, whose doctors provide emergency-room care, pursued a strategy of keeping their doctors out of network to make more money. Patients were caught in the middle as insurers and doctors fought over out-of-network bills, and many people ended up owing large sums not covered by their health plans.When criticism of these tactics pressured Congress to consider remedies, the private-equity firms backing groups like Envision and TeamHealth spent large sums trying to block federal legislation. Lawmakers finally took action at the end of last year to protect patients from surprise bills by requiring parties to reach a fair price.But doctors say United is increasingly unwilling to come to an agreement they can accept. Envision, which eventually agreed to lower its payments and be included in the health plan’s network, said United dropped it this year because it would not agree to “drastic cuts to clinician pay.”“United turned down multiple proposals that would reduce the total cost of care for patients,” Envision said in an emailed statement. “We are left to wonder why it appears United does not want our 25,000 clinicians in their network.”The insurer has also dropped other groups. Last year, Mednax, which employed specialists in neonatology and anesthesiology, announced it had been dropped by United in four states. The company has since sold both its radiology and anesthesiology practices.

A new, detailed model of the surface of the SARS-CoV-2 spike protein reveals previously unknown vulnerabilities that could inform development of vaccines. Mateusz Sikora of the Max Planck Institute of Biophysics in Frankfurt, Germany, and colleagues present these findings in the open-access journal PLOS Computational Biology.
SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. A key feature of SARS-CoV-2 is its spike protein, which extends from its surface and enables it to target and infect human cells. Extensive research has resulted in detailed static models of the spike protein, but these models do not capture the flexibility of the spike protein itself nor the movements of protective glycans — chains of sugar molecules — that coat it.
To support vaccine development, Sikora and colleagues aimed to identify novel potential target sites on the surface of the spike protein. To do so, they developed molecular dynamics simulations that capture the complete structure of the spike protein and its motions in a realistic environment.
These simulations show that glycans on the spike protein act as a dynamic shield that helps the virus evade the human immune system. Similar to car windshield wipers, the glycans cover nearly the entire spike surface by flopping back and forth, even though their coverage is minimal at any given instant.
By combining the dynamic spike protein simulations with bioinformatic analysis, the researchers identified spots on the surface of the spike proteins that are least protected by the glycan shields. Some of the detected sites have been identified in previous research, but some are novel. The vulnerability of many of these novel sites was confirmed by other research groups in subsequent lab experiments.
“We are in a phase of the pandemic driven by the emergence of new variants of SARS-CoV-2, with mutations concentrated in particular in the spike protein,” Sikora says. “Our approach can support the design of vaccines and therapeutic antibodies, especially when established methods struggle.”
The method developed for this study could also be applied to identify potential vulnerabilities of other viral proteins.
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The humble lab mouse has provided invaluable clues to understanding diseases ranging from cancer to diabetes to COVID-19. But when it comes to psychiatric conditions, the lab mouse has been sidelined, its rodent mind considered too different from that of humans to provide much insight into mental illness.
A new study, however, shows there are important links between human and mouse minds in how they function — and malfunction. Researchers at Washington University School of Medicine in St. Louis devised a rigorous approach to study how hallucinations are produced in the brain, providing a promising entry point to the development of much-needed new therapies for schizophrenia.
The study, published April 2 in the journal Science, lays out a way to probe the biological roots of a defining symptom of psychosis: hallucinations. The researchers trained people and mice to complete a computer-based task that induced them to hear imaginary sounds. By analyzing performance of the task, the researchers were able to objectively measure hallucination-like events in people and mice. This innovative approach allowed them to study the neural circuits underlying hallucinations, opening up mental symptoms to the kind of scientific studies that have been so fruitful for diseases of other parts of the body.
“It’s so easy to accept the argument that psychosis is a fundamentally human thing and say, ‘Forget about mice’,” said senior author Adam Kepecs, PhD, a professor of neuroscience and of psychiatry, and a BJC Investigator at the School of Medicine. “But right now, we’re failing people with serious psychiatric conditions. The prognosis for psychotic patients has not substantially improved over the past decades, and that’s because we don’t really understand the neurobiology of the disease. Animal models have driven advances in every other field of biomedicine. We’re not going to make progress in treating psychiatric illnesses until we have a good way to model them in animals.”
Psychosis occurs when a person loses touch with reality. During a psychotic episode, people may acquire false beliefs (delusions) or confidently believe that they are seeing or hearing things that are not occurring (hallucinations). A psychotic episode can be a sign of a serious mental illness such as schizophrenia or bipolar disorder, but people without mental illness also can experience symptoms such as hallucinations.
To study how hallucinations occur, Kepecs — with first author Katharina Schmack, MD, PhD, of Cold Spring Harbor Laboratory, and colleagues — set up a computer game that could be completed by both people and mice. The researchers played a particular sound, and subjects indicated that they’d heard it by clicking a button (people) or poking their noses into a port (mice). The task was made challenging by obscuring the sound with background noise. People in the study rated how confident they felt that they’d accurately identified a real sound by moving a slider on a scale; mice indicated their confidence by how long they waited for a reward. When a subject confidently reported that he or she had heard a sound that was not actually played, the researchers labeled that a hallucination-like event.

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.”