Publisher Health

UT Southwestern researchers have identified the structure of a key member of a family of proteins called nicotinic acetylcholine receptors in three different shapes. The work, published online today in Cell, could eventually lead to new pharmaceutical treatments for a large range of diseases or infections including schizophrenia, lung cancer, and even COVID-19.
Nicotinic acetylcholine receptors are members of a broader super-family of proteins called Cys-loop receptors that function as ion channels on cell surfaces and are found in the membranes of many cell types. When the right molecule settles on these receptors, it opens the gated channels, letting ions flood from the outside to the inside of cells to trigger other cellular processes. Nicotinic acetylcholine receptors respond to acetylcholine, a molecule that nerve cells use to communicate with each other. However, they also respond to other molecules found outside the body, such as nicotine, the essential nutrient choline, and a toxin found on the skin of poison dart frogs called epibatidine.
These receptors, which have been identified in nerve, lung, and immune cells, are connected to conditions such as mental illness, neurodegenerative diseases, lung cancers, and even the destructive immune reactions characteristic of COVID-19 and other infections.
Researchers had previously identified the structures of some members of the Cys-loop super-family, a significant step toward creating drugs that fit onto these ion channels to block or enhance their function. However, say study leaders Colleen M. Noviello, Ph.D., Senior Research Scientist at UTSW, and Ryan E. Hibbs, Ph.D., Associate Professor of Neuroscience and Biophysics at UTSW, the shape, or conformation, of these channels isn’t fixed. Cys-loop receptors cycle through three major states during their gating cycle that correspond to when they’re closed and waiting to respond to a ligand, or activating molecule (resting state); when they’ve responded to the ligand and opened for ion flow (open state); or when they are still holding the ligand but have closed again (desensitized state).
After striking out for years to characterize the structure of a key nicotinic acetylcholine receptor called a7, Noviello and Hibbs got a major boost in 2016 after UTSW purchased equipment for cryogenic electron microscopy, or cryo-EM. This technology allows scientists to take photos of biologic molecules at atomic level resolution. When the researchers and their colleagues added to a7 a chaperone protein — a protein that helps support and protect other proteins — it helped a7 retain its proper shape.
With these new tools, the researchers imaged a7 in its different conformations. Because a7’s structure is dynamic, allowing it to shift and wiggle, the researchers added different ligands to stabilize it so the cryo-EM images wouldn’t be blurry from motion.
When they analyzed these images, Noviello, Hibbs, and their colleagues found several interesting structural features that helped explain some of a7’s unusual properties. For example, a negatively charged amino acid in a7’s inner channel seems to draw in positively charged calcium from outside cells, explaining why a7 is so permeable to calcium. Also, a curved structure on a7 seems to function as a latch to open the gated channel.
The team says that these newly identified structures for a7 could eventually be used as a template for pharmaceutical companies to develop new medicines that target this and related nicotinic acetylcholine receptors. They plan to continue studying a7 in various cell types and how it interacts with other molecules and proteins.
“The more we know about this important receptor found on so many diverse cell types, the closer we’ll get to understanding how it functions in physiology and disease,” says Hibbs, an Effie Marie Cain Scholar in Medical Research and member of the Peter O’Donnell Jr. Brain Institute.
Other researchers who contributed to this study include Anant Gharpure, Rico Cabuco, Leah Baxter, and Dominika Borek, all of UTSW; and Nuriya Mukhtasimova and Steven M. Sine, of Mayo Clinic College of Medicine.
This research was funded by National Institutes of Health grants (U24GM129547, NS120496, NS077983, NS095899, NS94124), and by the Friends of the Alzheimer’s Disease Center.

A study led by researchers at the University of California San Diego Jacobs School of Engineering provides new insights for developing therapies for muscle disease, injury and atrophy. By studying how different pluripotent stem cell lines build muscle, researchers have for the first time discovered how epigenetic mechanisms can be triggered to accelerate muscle cell growth at different stages of stem cell differentiation.
The findings were published Mar. 17 in Science Advances.
“Stem cell-based approaches that have the potential to aid muscle regeneration and growth would improve the quality of life for many people, from children who are born with congenital muscle disease to people who are losing muscle mass and strength due to aging,” said Shankar Subramaniam, distinguished professor of bioengineering, computer science and engineering, and cellular and molecular medicine at UC San Diego and lead corresponding author on the study. “Here, we have discovered that specific factors and mechanisms can be triggered by external means to favor rapid growth.”
The researchers used three different human induced pluripotent stem cell lines and studied how they differentiate into muscle cells. Out of the three, one cell line grew into muscle the fastest. The researchers looked at what factors made this line different from the rest, and then induced these factors in the other lines to see if they could accelerate muscle growth.
They found that triggering several epigenetic mechanisms at different time points sped up muscle growth in the “slower” pluripotent stem cell lines. These include inhibiting a gene called ZIC3 at the outset of differentiation, followed by adding proteins called beta-catenin transcriptional cofactors later on in the growth process.
“A key takeaway here is that all pluripotent stem cells do not have the same capacity to regenerate,” Subramaniam said. “Identifying factors that will prime these cells for specific regeneration will go a long way in regenerative medicine.”
Next, the team will explore therapeutic intervention, such as drugs, that can stimulate and accelerate muscle growth at different stages of differentiation in human induced pluripotent stem cells. They will also see whether implanting specific pluripotent stem cells in dystrophic muscle can stimulate new muscle growth in animals. Ultimately, they would like to see if such a stem cell-based approach could regenerate muscle in aging humans.
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Materials provided by University of California – San Diego. Original written by Liezel Labios. Note: Content may be edited for style and length.

A new study shows that the proportion of gun violence relative to other forms of violence in TV dramas increased from 2000 to 2018, with statistical parallels to trends in actual gun homicides among U.S. youths. Patrick E. Jamieson and Daniel Romer of the University of Pennsylvania’s Annenberg Public Policy Center present these findings in the open-access journal PLOS ONE on March 17, 2021.
Firearm injuries and deaths are a major public health concern in the U.S. A long-standing hypothesis suggests that increases in gun violence in popular media result in increases real-life gun violence among youths. However, homicide rates among youths have declined in recent decades, challenging this view.
In the new study, Jamieson and colleagues assert that overall homicide rates are not actually appropriate for exploring the potential influence of entertainment on gun violence. Instead, they say, research should focus on trends in the proportion of gun violence compared to other forms of violence. In line with that assertion, the researchers examined trends in the proportion of gun violence compared to other forms of violence in 33 popular TV dramas from 2000 to 2018. Over the same period, they also examined trends in real-life homicides attributable to firearms in different age groups in the U.S.
The analysis showed that TV gun use increased over the study period, both in absolute terms and in proportion to other forms of violence. The proportional increase of TV gun violence paralleled trends in rates of homicides attributable to firearms — as opposed to other types of homicides — among all age groups, with the strongest statistical relationship seen for youths aged 15 to 24.
This kind of correlational study cannot prove causal conclusions about the relationship between TV gun violence and real-life gun violence. Nonetheless, the findings appear consistent with the hypothesis that gun violence in popular media may contribute to real-life use of guns for violent purposes.
The authors note that, whether or not that hypothesis holds true, TV gun violence is probably not the main cause of the longstanding higher rate of gun homicides among U.S. youth. But the findings do suggest that further research is necessary to better understand the role of media gun violence and other potential contributors.
The authors add: “Our research found that gun use has substantially increased over the past 20 years on primetime TV dramas in the US, a trend that paralleled the use of firearms in homicides. Just as the entertainment media contributed to the uptake of cigarettes among youth, our findings suggest that it may be doing the same for guns.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

A bit of seaweed in cattle feed could reduce methane emissions from beef cattle as much as 82 percent, according to new findings from researchers at the University of California, Davis. The results, published today (March 17) in the journal PLOS ONE, could pave the way for the sustainable production of livestock throughout the world.
“We now have sound evidence that seaweed in cattle diet is effective at reducing greenhouse gases and that the efficacy does not diminish over time,” said Ermias Kebreab, professor and Sesnon Endowed Chair of the Department of Animal Science and director of the World Food Center. Kebreab conducted the study along with his Ph.D. graduate student Breanna Roque.
“This could help farmers sustainably produce the beef and dairy products we need to feed the world,” Roque added.
Over the course of five months last summer, Kebreab and Roque added scant amounts of seaweed to the diet of 21 beef cattle and tracked their weight gain and methane emissions. Cattle that consumed doses of about 80 grams (3 ounces) of seaweed gained as much weight as their herd mates while burping out 82 percent less methane into the atmosphere. Kebreab and Roque are building on their earlier work with dairy cattle, which was the world’s first experiment reported that used seaweed in cattle.
Less gassy, more sustainable
Greenhouse gases are a major cause of climate change, and methane is a potent greenhouse gas. Agriculture is responsible for 10 percent of greenhouse gas emissions in the U.S., and half of those come from cows and other ruminant animals that belch methane and other gases throughout the day as they digest forages like grass and hay.

An international collaboration between Great Ormond Street Hospital, the UCL GOS Institute for Child Health and Harvard Medical School has shown that the beneficial effects of gene therapy can be seen decades after the transplanted blood stem cells has been cleared by the body.
The research team monitored five patients who were successfully cured of SCID-X1 using gene therapy at GOSH. For 3-18 years patients’ blood was regularly analysed to detect which cell types and biomarker chemicals were present in their blood. The results showed that even though the stem cells transplanted as part of gene therapy had been cleared by the patients, the all-important corrected immune cells, called T-cells, were still forming.
Gene therapy works by first removing some of the patients’ blood-forming stem cells, which create all types of blood and immune cells. Next, a viral vector is used to deliver a new copy of the faulty gene into the DNA of the patients’ cells in a laboratory. These corrected stem cells are then returned to patients in a so-called ‘autologous transplant’, where they go on to produce a continual supply of healthy immune cells capable of fighting infection.
In the gene therapy for SCID-X1 the corrected stem cells have been eventually cleared by the body but the patients remained cured of their condition. This team of researchers suggested that the ‘cure’ was down to the fact that the body was still able to continually produce newly-engineered T cells — an important part of the body’s immune system.
They used state-of-the-art gene tracking technology and numerous tests to give unprecedented details of the T cells in SCID-X1 patients decades after gene therapy.
The team believe that this gene therapy has created the ideal conditions for the human thymus (the part of the body where T cells develop) to host a long-term store of the correct type of progenitor cells that can form new T cells. Further investigation of how this happens and how it can be exploited could be crucial for the development of next generation gene therapy and cancer immunotherapy approaches.
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Materials provided by University College London. Note: Content may be edited for style and length.

It is too soon to tell whether the shots have a broad beneficial effect on patients with continuing issues, but scientists are intrigued and beginning to study the phenomenon.Judy Dodd began struggling with long Covid symptoms last spring — shortness of breath, headaches, exhaustion. Then she got the vaccine.After her first Pfizer-BioNTech shot in late January, she felt so physically miserable that she had to be persuaded to get the second. For three days after that one, she also felt awful. But the fourth day, everything changed.“I woke up and it was like ‘Oh what a beautiful morning,’” said Ms. Dodd, a middle-school teacher who is also an actor and director. “It was like I’d been directing ‘Sweeney Todd’ for months, and now I’m directing Oklahoma.”Ms. Dodd, who continues to feel good, is among a number of people who are reporting that the post-Covid symptoms they’ve experienced for months have begun improving, sometimes significantly, after they got the vaccine. It’s a phenomenon that doctors and scientists are watching closely, but as with much about the yearlong coronavirus pandemic, there are many uncertainties.Scientists are only beginning to study any potential effect of vaccines on long Covid symptoms. Anecdotes run the gamut: Besides those who report feeling better after the shots, many people say they have experienced no change and a small number say they feel worse.Reports from doctors vary too. Dr. Daniel Griffin, an infectious disease physician at Columbia University, said about 40 percent of the long Covid patients he’s been treating cite symptom improvement after the vaccine. “They notice, ‘Hey, over the days, I’m feeling better. The fatigue isn’t so bad, maybe smell is coming back,’” Dr. Griffin said.Other doctors say it is too early to know.“Too few of our participants have been vaccinated so far to really be able to provide insight into this question,” said Dr. Michael Peluso, an infectious disease specialist working on a study of long-term Covid patients at University of California, San Francisco. “I’ve heard anecdotes as well, but I’ve seen too little data so far.”This month, a small study by British researchers that has not yet been peer reviewed found that eight months after people were hospitalized for Covid-19, those who were vaccinated experienced improvement in more long Covid symptoms than those who weren’t yet vaccinated. The 44 vaccinated patients in the study were older and had more underlying medical conditions, since people with those characteristics qualified for vaccines earlier.One month after vaccination, those patients reported improvement in 23 percent of their long Covid symptoms like joint pain and breathing, while 5.6 percent of their symptoms had worsened. The 22 unvaccinated people questioned at that time said 15 percent of their symptoms were better, while 14 percent of their symptoms were worse. There was no difference in response between people who received the Pfizer-BioNTech and Oxford-AstraZeneca vaccines.Additional information comes from two surveys of several hundred people with long Covid symptoms, many of whom were never hospitalized for the disease.Jim Golen, a former hospice nurse in Saginaw, Minn. He said his long Covid symptoms have gotten worse since his vaccination, but he’s still glad he got the vaccine.Tim Gruber for The New York TimesOne survey of 345 people, mostly women and mostly in the U.K., found that two weeks or more after their second vaccine dose, 93 felt slightly better and 18 felt back to normal — a total of 32 percent reporting improved long Covid symptoms.In that survey, by Gez Medinger, a London-based filmmaker who has experienced post-Covid symptoms, 61 people, just under 18 percent, felt worse, most of them reporting only a slight decline in their condition. Nearly half — 172 people — reported feeling no different.Another survey, by Survivor Corps, a group of over 150,000 Covid survivors, found that as of March 17, 225 of 577 respondents reported some improvement, while 270 felt no change and 82 felt worse.Jim Golen, 55, of Saginaw, Minn., feels some long Covid symptoms have worsened since his vaccination. Mr. Golen, a former hospice nurse who also has a small farm, had experienced months of difficulty, including blood clots in his lungs, chest pain, brain fog, insomnia and shortness of breath with any exertion. Late last year, after seeing several doctors, “I was finally starting to get better,” he said.Since receiving the second dose of the Pfizer vaccine in mid-January, he said, his chest burning and shortness of breath have returned with a vengeance, especially if he taxes himself with activities like collecting sap from the maple trees on his farm. Nonetheless, Mr. Golen said he was “very happy” to be vaccinated, emphasizing that the effects of Covid were worse and preventing it is crucial.Some people shared stories of stark symptom improvements that took them by surprise.Laura Gross, 72, of Fort Lee, N.J. rattled off a lengthy list of debilitating long Covid symptoms she’d experienced since April, including exhaustion, joint pain, muscle aches and a “zizzy-dizzy-weaky thing that was like an internal headachy all-over-body vibration.”Her cognitive fuzziness and forgetfulness were so intense that “brain fog barely describes it,” she said. “It’s more like brain cyclone.”She also felt uncharacteristically “hopeless, sad, lonely, unmotivated,” she said.Three days after her first Moderna shot in late January, everything changed. “It was like a revelation,” she said. The brain fog cleared completely, muscle aches were gone, joint pains were less intense and she suddenly had much more energy. It felt, she said, “like the old me.”That continued after the second dose. “It’s like my cells went kerflooey last year when they met Covid,” she said, and the “vaccine said, ‘Wait, you dopes, that isn’t how you fight this, do it this way.’”Recently, she walked briskly for 23 minutes and even “ran a little bit because I was so happy,” she said. “I’m a very happy little chappy.”Laura Gross of Fort Lee, N.J., said brain fog is inadequate in describing her symptoms: “It’s more like brain cyclone,” she said. She reports feeling much better since being vaccinated.Nancy Borowick for The New York TimesScientists say that understanding whether vaccines help some long Covid patients but not others could help unravel the underlying causes of different symptoms and potential ways to treat them.“They might be different disease processes and you manage them differently,” said Dr. Adam Lauring, a virologist and infectious disease physician at the University of Michigan. “It might be that there’s a subset of people who have a certain type of long Covid, who respond well to vaccines, but there might be other people who have a different subtype that we haven’t quite defined yet.”Akiko Iwasaki, an immunologist at Yale, said that a vaccine, by generating antibodies to the coronavirus’s spike protein, could potentially eliminate vestiges of the virus or remnants of viral RNA that may linger in some patients.If this is occurring, she said, it could suggest that the vaccine “might be like a permanent cure” for those patients.Dr. Iwasaki said the vaccine might also help people whose long Covid symptoms may be caused by a post-viral response resembling an autoimmune disease if “the vaccine stimulates innate immune responses that dampen these kinds of autoreactive responses,” she said. But based on experiences of people with other autoimmune diseases, that relief would “not be very long-lasting and they would kind of revert back” to having symptoms like fatigue, she said.Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Institute in San Diego, said he is starting a study to measure physiological information like heart rate, respiratory rate, temperature and markers of immune system response in people with long Covid before they receive a vaccine and weeks afterward.It’s plausible that “you have your immune system revved up when you’re fighting a reservoir” of virus or RNA remnants, he said, “and that could be an explanation of why you’re in overdrive with your heart rate.” He wants to see if these biological indicators improve post-vaccine.“We’d really like objective metrics that show that you not just feel better,” Dr. Topol said. “You could feel better from the placebo effect, but it’s unlikely your heart rate’s going to go from 100 to 60 because of a placebo effect. And if we keep seeing that pattern, that would be like Eureka.”He added, “I think there’s probably something there, but I just don’t know what is the magnitude, how many people are going to benefit.”There are many other questions: Are there specific characteristics, like age, gender, type or duration of symptoms, that might make some long Covid patients more likely to feel better? Would a vaccine be less effective for people with more complex conditions: people whose symptoms are driven by multiple biological pathways (perhaps both an RNA remnant and autoimmune activation) or whose symptoms have changed or fluctuated over time? Are certain types of vaccines more likely to produce benefit?“It was awful thinking it may never get better, like ‘Is this my new normal, am I now damaged this way?’” recalled Bridget Hayward of her symptoms, which she says have eased since her vaccination.Alyssa Schukar for The New York TimesBridget Hayward, 51, an operating room nurse in Alexandria, Va., said that after contracting Covid a year ago, her body ached from her hands to her hips and she became so brain-fogged that instead of asking for a scalpel, she would say “Give me that sharp thing we cut with.”Almost daily, she would briefly pass out while bending down to fix a patient’s intravenous line or plug in the cord of a hospital bed.“It was horrifying,” she said. “It was awful thinking it may never get better, like ‘Is this my new normal, am I now damaged this way?’”After several months, her worst symptoms improved, but she still tired easily, felt hot even in cool weather, and found it too taxing to do some ordinary tasks, she said.One day after her first dose of the Pfizer vaccine in late December, “it was like click, everything is fine,” she said. Her body temperature has normalized and “it felt like a darkness lifted.”While “it’s not 100 percent every day,” she said she has so much energy now that “I’m not just getting from A to B, I’m like leaping up.”One recent day, she did several long-overdue errands. “This may not sound like much but it is a 180-turnaround from three months ago,” she said. “I’m back!”Kim Leighton, 64, of Vancouver, Wash., has had a similar experience. She was hospitalized last March and had long Covid symptoms that included mini blackouts, shortness of breath, getting lost in her own neighborhood, depression and fatigue.“It really has been hell,” she said.When she started feeling better in late January, she didn’t even think to connect it to the vaccine, but later realized her stark improvement had started four days after receiving her first Moderna shot. She is delighted that she can now take walks in downtown Portland and has the desire to reconnect with friends.“Every day, I feel like I’m feeling stronger,” Ms. Leighton said. “All the stuff I had to let go of, I’m trying to get it back.”Ms. Dodd, like several others, said she wasn’t taking her improvement for granted. “I’m still sort of wary of what’s around the corner, this disease is so unpredictable,” she said.But, she added, “even if, God forbid, I have a relapse, to have this time now when I feel better, it’s really amazing.”

It is too soon to tell whether the shots have a broad beneficial effect on patients with continuing issues, but scientists are intrigued and beginning to study the phenomenon.Judy Dodd began struggling with long Covid symptoms last spring — shortness of breath, headaches, exhaustion. Then she got the vaccine.After her first Pfizer-BioNTech shot in late January, she felt so physically miserable that she had to be persuaded to get the second. For three days after that one, she also felt awful. But the fourth day, everything changed.“I woke up and it was like ‘Oh what a beautiful morning,’” said Ms. Dodd, a middle-school teacher who is also an actor and director. “It was like I’d been directing ‘Sweeney Todd’ for months, and now I’m directing Oklahoma.”Ms. Dodd, who continues to feel good, is among a number of people who are reporting that the post-Covid symptoms they’ve experienced for months have begun improving, sometimes significantly, after they got the vaccine. It’s a phenomenon that doctors and scientists are watching closely, but as with much about the yearlong coronavirus pandemic, there are many uncertainties.Scientists are only beginning to study any potential effect of vaccines on long Covid symptoms. Anecdotes run the gamut: Besides those who report feeling better after the shots, many people say they have experienced no change and a small number say they feel worse.Reports from doctors vary too. Dr. Daniel Griffin, an infectious disease physician at Columbia University, said about 40 percent of the long Covid patients he’s been treating cite symptom improvement after the vaccine. “They notice, ‘Hey, over the days, I’m feeling better. The fatigue isn’t so bad, maybe smell is coming back,’” Dr. Griffin said.Other doctors say it is too early to know.“Too few of our participants have been vaccinated so far to really be able to provide insight into this question,” said Dr. Michael Peluso, an infectious disease specialist working on a study of long-term Covid patients at University of California, San Francisco. “I’ve heard anecdotes as well, but I’ve seen too little data so far.”This month, a small study by British researchers that has not yet been peer reviewed found that eight months after people were hospitalized for Covid-19, those who were vaccinated experienced improvement in more long Covid symptoms than those who weren’t yet vaccinated. The 44 vaccinated patients in the study were older and had more underlying medical conditions, since people with those characteristics qualified for vaccines earlier.One month after vaccination, those patients reported improvement in 23 percent of their long Covid symptoms like joint pain and breathing, while 5.6 percent of their symptoms had worsened. The 22 unvaccinated people questioned at that time said 15 percent of their symptoms were better, while 14 percent of their symptoms were worse. There was no difference in response between people who received the Pfizer-BioNTech and Oxford-AstraZeneca vaccines.Additional information comes from two surveys of several hundred people with long Covid symptoms, many of whom were never hospitalized for the disease.Jim Golen, a former hospice nurse in Saginaw, Minn. He said his long Covid symptoms have gotten worse since his vaccination, but he’s still glad he got the vaccine.Tim Gruber for The New York TimesOne survey of 345 people, mostly women and mostly in the U.K., found that two weeks or more after their second vaccine dose, 93 felt slightly better and 18 felt back to normal — a total of 32 percent reporting improved long Covid symptoms.In that survey, by Gez Medinger, a London-based filmmaker who has experienced post-Covid symptoms, 61 people, just under 18 percent, felt worse, most of them reporting only a slight decline in their condition. Nearly half — 172 people — reported feeling no different.Another survey, by Survivor Corps, a group of over 150,000 Covid survivors, found that as of March 16, 207 of 508 respondents reported some improvement, while 231 felt no change and 70 felt worse.Jim Golen, 55, of Saginaw, Minn., feels some long Covid symptoms have worsened since his vaccination. Mr. Golen, a former hospice nurse who also has a small farm, had experienced months of difficulty, including blood clots in his lungs, chest pain, brain fog, insomnia and shortness of breath with any exertion. Late last year, after seeing several doctors, “I was finally starting to get better,” he said.Since receiving the second dose of the Pfizer vaccine in mid-January, he said, his chest burning and shortness of breath have returned with a vengeance, especially if he taxes himself with activities like collecting sap from the maple trees on his farm. Nonetheless, Mr. Golen said he was “very happy” to be vaccinated, emphasizing that the effects of Covid were worse and preventing it is crucial.Some people shared stories of stark symptom improvements that took them by surprise.Laura Gross, 72, of Fort Lee, N.J. rattled off a lengthy list of debilitating long Covid symptoms she’d experienced since April, including exhaustion, joint pain, muscle aches and a “zizzy-dizzy-weaky thing that was like an internal headachy all-over-body vibration.”Her cognitive fuzziness and forgetfulness were so intense that “brain fog barely describes it,” she said. “It’s more like brain cyclone.”She also felt uncharacteristically “hopeless, sad, lonely, unmotivated,” she said.Three days after her first Moderna shot in late January, everything changed. “It was like a revelation,” she said. The brain fog cleared completely, muscle aches were gone, joint pains were less intense and she suddenly had much more energy. It felt, she said, “like the old me.”That continued after the second dose. “It’s like my cells went kerflooey last year when they met Covid,” she said, and the “vaccine said, ‘Wait, you dopes, that isn’t how you fight this, do it this way.’”Recently, she walked briskly for 23 minutes and even “ran a little bit because I was so happy,” she said. “I’m a very happy little chappy.”Laura Gross of Fort Lee, N.J., said brain fog is inadequate in describing her symptoms: “It’s more like brain cyclone,” she said. She reports feeling much better since being vaccinated.Nancy Borowick for The New York TimesScientists say that understanding whether vaccines help some long Covid patients but not others could help unravel the underlying causes of different symptoms and potential ways to treat them.“They might be different disease processes and you manage them differently,” said Dr. Adam Lauring, a virologist and infectious disease physician at the University of Michigan. “It might be that there’s a subset of people who have a certain type of long Covid, who respond well to vaccines, but there might be other people who have a different subtype that we haven’t quite defined yet.”Akiko Iwasaki, an immunologist at Yale, said that a vaccine, by generating antibodies to the coronavirus’s spike protein, could potentially eliminate vestiges of the virus or remnants of viral RNA that may linger in some patients.If this is occurring, she said, it could suggest that the vaccine “might be like a permanent cure” for those patients.Dr. Iwasaki said the vaccine might also help people whose long Covid symptoms may be caused by a post-viral response resembling an autoimmune disease if “the vaccine stimulates innate immune responses that dampen these kinds of autoreactive responses,” she said. But based on experiences of people with other autoimmune diseases, that relief would “not be very long-lasting and they would kind of revert back” to having symptoms like fatigue, she said.Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Institute in San Diego, said he is starting a study to measure physiological information like heart rate, respiratory rate, temperature and markers of immune system response in people with long Covid before they receive a vaccine and weeks afterward.It’s plausible that “you have your immune system revved up when you’re fighting a reservoir” of virus or RNA remnants, he said, “and that could be an explanation of why you’re in overdrive with your heart rate.” He wants to see if these biological indicators improve post-vaccine.“We’d really like objective metrics that show that you not just feel better,” Dr. Topol said. “You could feel better from the placebo effect, but it’s unlikely your heart rate’s going to go from 100 to 60 because of a placebo effect. And if we keep seeing that pattern, that would be like Eureka.”He added, “I think there’s probably something there, but I just don’t know what is the magnitude, how many people are going to benefit.”There are many other questions: Are there specific characteristics, like age, gender, type or duration of symptoms, that might make some long Covid patients more likely to feel better? Would a vaccine be less effective for people with more complex conditions: people whose symptoms are driven by multiple biological pathways (perhaps both an RNA remnant and autoimmune activation) or whose symptoms have changed or fluctuated over time? Are certain types of vaccines more likely to produce benefit?“It was awful thinking it may never get better, like ‘Is this my new normal, am I now damaged this way?’” recalled Bridget Hayward of her symptoms, which she says have eased since her vaccination.Alyssa Schukar for The New York TimesBridget Hayward, 51, an operating room nurse in Alexandria, Va., said that after contracting Covid a year ago, her body ached from her hands to her hips and she became so brain-fogged that instead of asking for a scalpel, she would say “Give me that sharp thing we cut with.”Almost daily, she would briefly pass out while bending down to fix a patient’s intravenous line or plug in the cord of a hospital bed.“It was horrifying,” she said. “It was awful thinking it may never get better, like ‘Is this my new normal, am I now damaged this way?’”After several months, her worst symptoms improved, but she still tired easily, felt hot even in cool weather, and found it too taxing to do some ordinary tasks, she said.One day after her first dose of the Pfizer vaccine in late December, “it was like click, everything is fine,” she said. Her body temperature has normalized and “it felt like a darkness lifted.”While “it’s not 100 percent every day,” she said she has so much energy now that “I’m not just getting from A to B, I’m like leaping up.”One recent day, she did several long-overdue errands. “This may not sound like much but it is a 180-turnaround from three months ago,” she said. “I’m back!”Kim Leighton, 64, of Vancouver, Wash., has had a similar experience. She was hospitalized last March and had long Covid symptoms that included mini blackouts, shortness of breath, getting lost in her own neighborhood, depression and fatigue.“It really has been hell,” she said.When she started feeling better in late January, she didn’t even think to connect it to the vaccine, but later realized her stark improvement had started four days after receiving her first Moderna shot. She is delighted that she can now take walks in downtown Portland and has the desire to reconnect with friends.“Every day, I feel like I’m feeling stronger,” Ms. Leighton said. “All the stuff I had to let go of, I’m trying to get it back.”Ms. Dodd, like several others, said she wasn’t taking her improvement for granted. “I’m still sort of wary of what’s around the corner, this disease is so unpredictable,” she said.But, she added, “even if, God forbid, I have a relapse, to have this time now when I feel better, it’s really amazing.”

Biologists have long held that a fetus needs a living uterus to develop. Maybe not anymore.Mouse embryos, their beating hearts visible, grown outside the womb after four days. Video by A. Aguilera-Castrejon et al., Nature 2021The mouse embryos looked perfectly normal. All their organs were developing as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute.But these embryos were not growing in a mother mouse. They were developed inside an artificial uterus, the first time such a feat has been accomplished, scientists reported on Wednesday.The experiments, at the Weizmann Institute of Science in Israel, were meant to help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.In a study published in the journal Nature, Dr. Jacob Hanna described removing embryos from the uteruses of mice at five days of gestation and growing them for six more days in artificial wombs.At that point, the embryos were about halfway through their development; full gestation is about 20 days. A human at this stage of development would be called a fetus. To date, Dr. Hanna and his colleagues have grown more than 1,000 embryos in this way.“It really is a remarkable achievement,” said Paul Tesar, a developmental biologist at Case Western Reserve University School of Medicine.Alexander Meissner, director of genome regulation at the Max Planck Institute for Molecular Genetics in Berlin, said that “getting this far is amazing” and that the study was “a major milestone.”But the research has already progressed beyond what the investigators described in the paper. In an interview, Dr. Hanna said he and his colleagues had taken fertilized eggs from the oviducts of female mice just after fertilization — at Day 0 of development — and had grown them in the artificial uterus for 11 days.Until now, researchers were able to fertilize eggs from mammals in the laboratory and grow them for only a short time. The embryos needed a living womb. “Placental mammals develop locked away in the uterus,” Dr. Tesar said.That prevented scientists from answering fundamental questions about the earliest stages of development.“The holy grail of developmental biology is to understand how a single cell, a fertilized egg, can make all of the specific cell types in the human body and grow into 40 trillion cells,” Dr. Tesar said. “Since the beginning of time, researchers have been trying to develop ways to answer this question.”The only way to study the development of tissues and organs was to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like snapshots than video.What was needed was a way to get inside the uterus, watching and tweaking development in mammals as it happened. For Dr. Hanna, that meant developing an artificial uterus.He spent seven years developing a two-part system that includes incubators, nutrients and a ventilation system. The mice embryos are placed in glass vials inside incubators, where they float in a special nutrient fluid.Viable embryos spinning in vials in a mechanical womb.A. Aguilera-Castrejon et al., Nature 2021Development of a mouse embryo over a five-day period.A. Aguilera-Castrejon et al., Nature 2021The vials are attached to a wheel that slowly spins so the embryos do not attach to the wall, where they would become deformed and die. The incubators are connected to a ventilation machine that provides oxygen and carbon dioxide to the embryos, controlling the concentration of those gasses, as well as the gas pressure and flow rate.At Day 11 of development — more than halfway through a mouse pregnancy — Dr. Hanna and his colleagues examined the embryos, only the size of apple seeds, and compared them to those developing in the uteruses of living mice. The lab embryos were identical, the scientists found.By that time, though, the lab-grown embryos had become too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient.Getting past that hurdle is the next goal, Dr. Hanna said in an interview. He is considering using an enriched nutrient solution or an artificial blood supply that connects to the embryos’ placentas.In the meantime, experiments beckon. The ability to keep embryos alive and developing halfway through pregnancy “is a gold mine for us,” Dr. Hanna said.The artificial womb may allow researchers to learn more about why pregnancies end in miscarriages or why fertilized eggs fail to implant. It opens a new window onto how gene mutations or deletions affect fetal development. Researchers may be able to watch individual cells migrate to their ultimate destinations.The work is “a breakthrough,” said Magdalena Zernicka-Goetz, professor of biology and biological engineering at Caltech. It “opens the door to a new age of studying development in the experimental mouse model.”A developing mouse embryo inside its glass vial. Video by A. Aguilera-Castrejon et al., Nature 2021A recent development provides another opportunity. Researchers have directly created mouse embryos from mouse fibroblasts — connective tissue cells — making early embryos without starting with a fertilized egg.Combine that development with Dr. Hanna’s work, and “now you don’t need mice to study mouse embryo development,” Dr. Meissner said. Scientists may be able to make all the embryos they need from connective tissue.If scientists could make embryos without fertilizing eggs and could study their development without a uterus, Dr. Meissner said, “you can get away from embryo destruction.” There would be no need to fertilize mouse eggs only to destroy them in the course of study.But the work might eventually extend beyond mice. Two other papers published in Nature on Wednesday report on attempts that edge near creating early human embryos in this way. Of course, Dr. Meissner said, creation of human embryos is years away — if it is permitted at all. And for now, international regulations prohibit studying human embryos beyond 14 days of fertilization.In the future, Dr. Tesar said, “it is not unreasonable that we might have the capacity to develop a human embryo from fertilization to birth entirely outside the uterus.”Of course, even the suggestion of this science fiction scenario is bound to horrify many. But it is early days, with no assurance human fetuses could ever develop entirely outside the womb.Even assuming they could, Dr. Tesar noted, “whether that is appropriate is a question for ethicists, regulators and society.”

Hepatitis B virus (HBV) infections are among the major global health problems. Particularly problematic is the high number of chronic courses of the disease, causing the deaths of more than 800,000 people globally every year. So far, there is no therapy to cure the condition. “With the discovery of a new hepatitis B virus in donkeys and zebras capable of causing prolonged infections, we now have the opportunity for a better understanding of the chronic course of the disease and thus also for mitigation or prevention of severe clinical consequences,” explains Prof. Dr. Jan Felix Drexler, DZIF researcher at the Charité — University Medicine Berlin. In the German Center for Infection Research (DZIF), he identifies and characterizes emerging viruses that could be dangerous for humans.
“Five years ago we were able to show for the first time that donkeys harbor viruses that are genetically related to the human hepatitis C virus,” explains Andrea Rasche, lead author of the study and DZIF scientist at the Charité — University Medicine Berlin. Since HBV and the hepatitis C virus (HCV) often occur together in humans, the researchers have also searched for HBV worldwide in donkeys. In addition to field work, extensive molecular, serological, histopathological and evolutionary biology methods were used. “We have studied nearly 3000 samples from equids, i.e. from donkeys, zebras and horses in five continents, and we found that donkeys are global carriers of the new hepatitis B virus,” explains Drexler.
The origins of the new HBV could be linked to the domestication of donkeys in Africa a few thousand years ago. Donkeys are naturally infected with HBV as well as with HCV. Zebras are also infected with HBV; horses are also likely to be receptive, but in initial studies, the scientists could not confirm any naturally infected horses. In naturally infected donkeys, the course of the infection is similar to chronic hepatitis B in humans.
“The new hepatitis B virus appears to use an unknown receptor for entry into the host cell,” explains Felix Lehmann, second lead author of the study and DZIF scientist at Giessen University (JLU) where he studied the molecular biology of virus binding and entry in cell culture. The emergence of human HBV and the development of its receptor use remain unclear and are jointly investigated by the researchers from Berlin and Giessen.
“Since the virus is unable to infect human liver cells, human infection with this virus can be ruled out with a high degree of probability,” emphasises Prof. Dr. Dieter Glebe, Head of the National Reference Centre for Hepatitis B and D viruses at JLU and DZIF scientist in the “hepatitis” research unit. The scientists are convinced that with the virus in donkeys and zebras, they can develop a better understanding of the pathogenesis of chronic hepatitis B and of HBV/HCV co-infection to lay a foundation for new therapies.
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A new study uncovers which cell types can be infected by SARS-CoV-2 due to their viral entry factors. The study also suggests that increased gene expression of these viral entry factors in some individuals partially explains the differences of COVID-19 severity reported in relation to age, gender and smoking status. The study evolved from the Human Cell Atlas Lung Biological Network with main contributions from Helmholtz Zentrum München, the Broad Institute of MIT and Harvard, the Wellcome Sanger Institute and University Medical Center Groningen.
COVID-19 does not affect everyone in the same way. While the coronavirus SARS-CoV-2 primarily manifests in the lung, it can infect other organs, too. Clinical observations throughout the pandemic also suggest that some population groups — such as elderly people, men and smokers — tend to be more severely affected by the disease. So far, the molecular reasons for this have not been described.
Previous studies had shown that in order to infect human cells, SARS-CoV-2 needs the cell to contain specific genetic viral entry factors — namely an ACE2 receptor and a protease (TMPRSS2 or CTSL). Knowing which cell types express both ACE2 and a protease would therefore give us information about which cells can potentially be infected with SARS-CoV-2.
The Human Cell Atlas (HCA) consortium is aiming to map every cell type in the human body, transforming our understanding of biology and disease. Within this, researchers from the HCA Lung Biological Network joined forces to contribute and analyse gene expression data from individual cells. Together, they analysed more than 100 datasets of single-cell gene expression of healthy people, to see which cell types express both ACE2 and a protease.
The analysis showed that specific cell types in the epithelium of the lung and airways, but also in the liver, the colon, and the eye are rich in genetic viral entry factors (=high expression of ACE2 receptor and a protease) — and therefore contain the necessary molecules to allow SARS-CoV-2 infection.
Moreover, the researchers found that the expression of genes underlying the viral entry factors is increased in the cells of elderly people and slightly in men compared to women. In addition, cells from smokers (in particular airway cells) express more SARS-CoV-2 entry factors than from non-smokers. These findings match differences in disease severity that have been reported for COVID-19 patients in those population groups and thus offer a molecular explanation for this difference (next to other factors which were not investigated in this study such as a weaker immune system).
Big data for biomedical research
“Fighting the pandemic, we cannot rely on conclusions that are limited to a few observations only. Instead, we must rely on robust analysis of big data. For example, to assess whether the ACE2 receptor required for virus entry is more abundant in cells of the elderly population, we need a strong representation of many diverse individuals in our dataset. Using data from the Human Cell Atlas, we could model how genetic viral entry factors in cells are expressed across the population,” says Malte Lücken, computational biologist at Helmholtz Zentrum München and co-first author of the study.
“A key aspect of this large-scale study was the age range of samples we were able to analyse. This study included data from human developmental stages, samples from children and young adults, as well as samples from elderly people. This gave us unique power to assess changes occurring over the human lifetime. The sheer scale of the data allowed us to see molecular differences with age, sex and smoking status,” said Kerstin Meyer, an author on the paper from the Wellcome Sanger Institute.
“This study was the epitome of a whole field coming together. Within the Human Cell Atlas consortium everyone who generated data on the healthy human lung contributed their data, both published and unpublished, to enable our analysis. When we then reached out beyond the consortium, more labs also contributed data to the effort. Only through these contributions was our analysis made possible,” adds Fabian Theis, Director of the Institute of Computational Biology at Helmholtz Zentrum München.
Strengths and limitations
The study investigated which cells are most likely to be infected by SARS-CoV-2. The results partially explain how disease severity might differ between population groups because of the molecular profile of cells. This provides a target for further intervention research. Moving forward, the findings may also help to better understand the spread of the corona virus across the body. The connection between viral entry factor expression and increased ease of infection or disease severity has been shown in mice and in the lab, but requires further validation in humans.