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In half of the couples that are unable to conceive a child, the infertility is due to the man. A new study identifies the defective function of ‘CatSper’, an ion channel controlling calcium levels in sperm, as a common cause of seemingly unexplained male infertility. CatSper-deficient human sperm fail to fertilize the egg, because they cannot penetrate its protective vestments. Thus far, this sperm channelopathy has remained undetectable. Scientists from Münster, Germany, have unravelled CatSper´s role in infertility using a novel laboratory test that identifies affected men. Based on the results of the study, which has been published in The Journal of Clinical Investigation, diagnostics and care of infertile couples can be improved.
One in six couples fail to conceive a child. The underlying cause often remains unresolved. In fact, in about one third of infertile couples, the man´s semen analysis yields no abnormalities in the number, motility, or morphology of the sperm. This poses a problem: the lack of a clear diagnosis prevents an evidence-based selection of a therapy option. As a result, affected couples often experience unsuccessful treatments.
How do men fail to conceive a child despite normal semen parameters? An interdisciplinary team of scientists from the University of Münster in Germany, set out to answer this question. ‘For quite a while, we have considered CatSper a prime suspect’ says Prof. Timo Strünker from the Centre of Reproductive Medicine and Andrology (CeRA). Some years ago, Strünker and colleagues revealed that sperm use CatSper as a sensor to detect messenger molecules released by the egg. These molecules activate CatSper, which leads to an influx of calcium into the flagellum, changing its beating pattern.
To scrutinize whether this is essential for fertilization, the researchers developed a simple laboratory test that enabled them to determine the activity of CatSper in sperm from almost 2300 men. This revealed that about one in a hundred infertile men with unremarkable semen parameters indeed features a loss of CatSper function. ‘The most common cause is genetic variants in genes encoding one of CatSper’s components’, adds the Reproductive Geneticist Prof. Frank Tüttelmann, Münster.
Sperm require the changes in flagellar beating mediated by CatSper to break through the egg´s protective coat. Another important finding of the study: CatSper-related male infertility also involves failure of medically assisted reproduction via intrauterine insemination, involving the application of sperm via a catheter into the uterus right before ovulation, or classical in-vitro fertilization (fertilization in the petri dish). This is not surprising, considering that these treatments still require the sperm to break through the egg coat. Affected men/couples could only conceive a child via the ICSI method, which involves the manual injection of a sperm cell into the egg.
‘Thanks to this comprehensive research endeavour, we can now identify and diagnose this channelopathy, enabling evidence-based treatment of affected couples’, summarizes Prof. Sabine Kliesch, Head of the Department of Clinical and Surgical Andrology at the CeRA. ‘Thereby, we minimize the medical risk for the couples and maximize the chances of success’.
The function of sperm is not only controlled by CatSper but also various other proteins. These are also in the focus of the Clinical Research Unit (CRU326) ‘Male Germ Cells’, which, funded by the German Research Council, provided the collaborative framework for the current study. The overarching aim of the researchers in Münster is to systematically elucidate the role of these proteins in (in)fertility, improving diagnostics and care of affected couples.

New research shows that the recently emerged BA.2.86 omicron subvariant of the virus that causes COVID-19 can be neutralized by bivalent mRNA vaccine-induced antibodies in the blood, which explains why this variant did not cause a widespread surge as previously feared.
However, the study in cell cultures showed this SARS-CoV-2 variant can infect human cells that line the lower lung and engage in virus-host cell membrane fusion more efficiently, two features linked to severe disease symptoms.
The study is published today (Jan. 8, 2024) in the journal Cell.
The BA.2.86 variant of omicron is the ancestor of the currently dominating JN.1 and has about 60 more spike protein mutations than the original, or parent, coronavirus, including over 30 more than its close omicron relatives — the early BA.2 variant and the recently dominant XBB.1.5 variant among them. These mutations led scientists to worry that so many changes would make the variant as tough to contain as the initial omicron outbreak in 2021-22.
“We found that, surprisingly, despite all those 60 mutations combined together, BA.2.86 is not as immune-evasive as the XBB.1.5 variant, which until recently had been dominating the pandemic for months. That’s good news,” said Shan-Lu Liu, senior author the study and a virology professor in the Department of Veterinary Biosciences at The Ohio State University.
“But BA.2.86 appears to have increased infectivity of human lung epithelial cells compared to all omicron variants, so that’s a little worrisome. And, consistent with infectivity, it also has increased fusion activity with human lung epithelial cells,” said Liu, also a professor in the Department of Microbial Infection and Immunity. “That raises a potential concern about whether or not this virus is more pathogenic compared to recent omicron variants.”
The published findings coincide with reports from the Centers for Disease Control and Prevention that after a brief increase in BA.2.86 infections, its derived sublineage JN.1 rapidly gained ground in the United States, responsible for an estimated 44% of COVID-19 cases as of Dec. 23, 2023.

First detected in July in Europe and the Middle East, BA.2.86 and its sublineages have since been spreading with increasing frequency in different parts of the world. On Nov. 22, the World Health Organization classified BA.2.86 and sublineages as “variants of interest.”
The Ohio State researchers analyzed neutralizing antibodies in blood serum samples from health care professionals who had received three monovalent vaccine doses or two monovalent vaccines followed by one bivalent vaccine booster, and from first responders who had COVID-19 infections during the wave dominated by the XBB.1.5 variant. They compared the ability of neutralizing antibodies to block infection by BA.2.86, an XBB-derived variant known as FLip, the parent virus and several omicron variants.
Overall, antibodies produced by serum from the bivalent vaccine-dosed health care professionals were more efficient at neutralizing BA.2.86 than they were at neutralizing other omicron variants, including XBB.1.5. In contrast, the three monovalent vaccines and previous XBB.1.5 infection were barely effective in blocking infection by BA.2.86.
“People who have had a COVID-19 infection should remember that omicron variants are less virulent compared to prior variants such as delta, meaning they don’t make most people very sick,” Liu said. “If you have less severe disease, the antibodies generated by infection are low — almost 10-fold lower than vaccine-induced antibodies. That is why you cannot rely on natural infection alone for immunity.
“While bivalent vaccine can still neutralize BA.2.86, the efficiency is clearly reduced. Therefore, it is important to get the newest booster vaccine, which is formulated with only XBB.1.5 and has been shown to be effective against BA.2.86,” Liu added.
However, the researchers were surprised to find that a monoclonal antibody known as S309, which has been shown to inhibit almost all other major omicron variants, does not neutralize BA.2.86. Molecular modeling revealed that some of the BA.2.86 mutations in the spike protein might have changed the conformation and rendered S309 unable to neutralize the new variant, Liu said.

Additional experiments pointed to the potential for BA.2.86 to be more likely to cause severe disease than its omicron relatives. Researchers found BA.2.86 was more efficient at infecting a cell line derived from the human lower airway epithelium in the lung. Infection of these cells is greatly facilitated through a cell surface protein, known as TMPRSS2, to promote membrane fusion, and this protein is a known contributor to SARS-CoV-2 infection and disease symptoms in the respiratory tract.
First author Panke Qu, a graduate student in Liu’s lab, conducted the cell-culture studies using pseudoviruses — a non-infectious viral core surrounded by different SARS-CoV-2 spike proteins on the surface structured to match known variants.
“Because we used a pseudovirus, we need to confirm these findings using the real virus,” said Liu, also associate director of Ohio State’s Center for Retrovirus Research and a program co-director of the Viruses and Emerging Pathogens Program in Ohio State’s Infectious Diseases Institute. “But from our past experience, we know that the infectivity in human epithelial cell lines provides very important information. The concern is whether or not this variant, as well as its descendants including JN.1, will have an increased tendency to infect human lung epithelial cells similar to the parental virus that launched the pandemic in 2020.”
Liu noted that other labs have recently suggested that JN.1, one of fastest-growing descendants of BA.2.86, is much more resistant to neutralizing antibodies that are effective against BA.2.86.
“We know that coronaviruses are prone to viral recombination, which can lead to new variants with huge numbers of mutations that could have increased immune evasion but also disease severity,” he said. “That’s why surveillance of the variants is still very important, even though we are in the end of year four of the pandemic.”
This work was supported by anonymous donor funds, the National Institutes of Health, the National Center for Advancing Translational Sciences, the Glenn Barber Fellowship from Ohio State’s College of Veterinary Medicine, the Robert J. Anthony Fund for Cardiovascular Research, and Ohio State’s Comprehensive Cancer Center and Center for Clinical and Translational Science.
Additional co-authors, all from Ohio State, are Kai Xu, Julia Faraone, Negin Goodarzi, Yi-Min Zheng, Claire Carlin, Joseph Bednash, Jeffrey Horowitz, Rama Mallampalli, Linda Saif, Eugene Oltz, Daniel Jones and Richard Gumina.

Published24 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Marie-Louise ConnollyBBC News NI health correspondentJunior doctors in Northern Ireland are to be balloted about strike action for the first time.The ballot will run for six weeks and could result in a 24-hour walk out.A newly qualified doctor in Northern Ireland earns £26,000 per year; in England the starting rate is over £33,000, and in Scotland it is £32,000. The Republic of Ireland’s pay grades operate differently, but junior doctors are paid a higher rate than their colleagues in Northern Ireland. In England, junior doctors started six days of strike action at 07:00 GMT on Wednesday in their dispute over pay.Northern Ireland’s Department of Health has said there is “no scope for a pay offer to be tabled for this year”.Dr Steven Montgomery, a paediatric junior doctor in the Southern Trust, called for “pay parity, better working conditions and to save the NHS”.”The main reason we need pay parity is so we stop haemorrhaging staff. We are losing staff to multiple countries, and these are highly skilled, qualified staff that we can’t afford to lose,” he said.”As a junior doctor you just feel burnt out. The feeling among staff is that morale is low the lowest I have ever seen since I have been working in the health care system.”‘Unprecedented action’Northern Ireland Junior Doctor Chair (NIJDC) Dr Fiona Griffin said the ballot is unprecedented among junior doctors in Northern Ireland.”Our health service cannot afford to lose these doctors, which is why we need to address the issues around pay urgently. This can be done with an immediate above-inflation pay rise and a commitment to full pay restoration in Northern Ireland,” she said.Dr Griffin called for the government to engage with NIJDC as a “matter of urgency”. She said failure to address pay in Northern Ireland now equates to a 30% reduction in 15 years. Image source, Getty ImagesDr Montgomery, who works as a senior registrar at Craigavon Area Hospital, said Northern Ireland has lost too many doctors to other countries which means wards are struggling every day to meet demand, and not just at winter time. Originally from Limavady, he qualified in 2017. He said he was reluctant to leave Northern Ireland but wants a better work-life balance with his partner who also works in the health service. On average, he works 48 hours a week but realistically it works out at approximately 55 hours.”Too few doctors mean it is a lot harder to get time off for annual leave even for things like weddings. “I have friends who struggled to get their own wedding day off even though they let the department know 18-24 months before their wedding,” Dr Montgomery said. Each year, Northern Ireland employs about 270 newly qualified doctors. Image source, Dr Steven MontgomeryIn 2023 there were 20 jobs that became vacant because the doctors chose to work outside Northern Ireland. Hospitals call on junior doctors to return to workAccording to health unions, the ongoing negativity is having an impact on attracting younger people to the profession. A potential walk-out would impact on waiting lists and patients waiting to be seen on wards with consultants expected to cover junior doctor roles. ‘Pressure on services’The BMA has stressed that strike action is a last resort and it would welcome any approach from the Northern Ireland secretary to talk to them. The union warned that if there is no progress they would have to escalate action to longer strikes. In a statement, the Department of Health said it “fully understands the scale of the frustration among health and care staff about pay”.”Unfortunately, the 2023/24 health budget provided no scope for a pay offer to be tabled for this year,” it added.”We recognise that this is not a sustainable position and remain committed to pursuing all avenues to help achieve a resolution.”The department respects the right of every individual to take industrial action. However, doing so at this time – with no route to a successful resolution currently available – would only further add to already severe pressures on services.”On Friday the Royal College of Nursing announced it would be taking strike action, along with unions representing some other health sectors, on 18 January.More on this storyWhat are junior doctors paid – and how much to settle?Published4 days ago

Published46 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Izzy JuddBy Charlie JonesBBC News, HertfordshireRupert Johnston had been in a coma for two months after a horrific car crash in February 1997 and was showing no signs of brain activity.Doctors advised turning off the 18-year-old musician’s life support machine. But his father brought his son’s beloved French horn to his bedside. Rupert, who grew up in Harpenden, Hertfordshire, began slowly moving his fingers along the valves in time to a Mozart recording. “That was our first moment of hope that there was something there,” recalls his younger sister, violinist Izzy Judd, who was 12 at the time.Image source, Family handoutRupert’s skull needed to be rebuilt. He had 13 hours of brain surgery, where they removed his front left lobe, with his right lobe left in place but permanently damaged. “The muscles around his lips, which he used to play the horn, were the only part of his face that wasn’t severely damaged,” Izzy says.Rupert was studying at the Guildhall School of Music at the time of the accident, having left home at the age of eight to become a chorister at King’s College, Cambridge. He and Izzy, and their two brothers, grew up surrounded by music. Their parents ran a music school in Hertfordshire.”Rupert was an exceptionally gifted musician and he was so charismatic, full of life and vibrant,” Izzy recalls.”His ambition was to be a professional horn musician and I have no doubt he would have achieved that.”Image source, Family handoutRupert gradually began to physically recover and he was discharged from hospital. But the family soon realised he would always need 24-hour care.The now 45-year-old has problems with his memory and spatial awareness. He has no inhibitions and needs help doing basic tasks like washing and laundry, Izzy says.It feels like there is always someone missing, Izzy says, even though he is still here and the family is “still grieving the loss of who he might have been”.Yet Rupert can still play his French horn to an exceptional standard, which Izzy describes as “a miracle”. “As a child he had this extraordinary gift, and that still lives on. If there was going to be anything that would allow him to connect with us, it would be music. It is in his bones, it pours out of him and it has ever since he was a little boy.”Image source, Family handoutRupert has spent the last 21 years living in a home in Aylesbury, Buckinghamshire, run by The Brain Injury Rehabilitation Trust – a charity that cares for people with acquired brain injuries. He regularly performs with the Aylesbury concert band and still has the same brilliant technical ability, Izzy says.”He can sometimes be disruptive during rehearsals, but they are so accepting of him and he is a really valued member of the group.”When he plays there is such familiarity, so you can slip into a bit of normality for a moment and you almost forget what has happened.”Image source, Kyle GavinIzzy went on to study at The Royal Academy of Music in London. She and her other two brothers became professional musicians. Izzy joined the electric string quartet Escala, who found fame in 2008 on Britain’s Got Talent.She performed in the strings section for the band McFly on tour and began dating their drummer, Harry Judd.”Harry has always been phenomenal with Rupert and that was one of the reasons I knew I wanted to marry him. Harry did not know Rupert before the accident so he takes him for who he is,” she says.Image source, Izzy JuddOn their wedding day, Rupert performed a horn solo from John Williams’s Somewhere in My Memory, which features in the film Home Alone.”People were in awe. It takes your breath away when Rupert performs. I felt unbelievably proud, but also sad because he was on the path to such a huge career and he’s not likely to have his own wedding day.”Izzy and Harry went on to have three children, which Izzy says triggered a lot of emotions about her brother. “Rupert is very sweet with them and they are very close. My son Kit reminds me of Rupert as a young boy. He has the same zest for life and he pushes boundaries. It makes me think about the life that Rupert could be living.”Image source, PA MediaIzzy did not pick up her violin for some time after having children and says she was “a bit lost in early motherhood”.”We struggled to start a family and then after I had Lola, Kit came along quickly and unexpectedly and life became a bit chaotic. “When I had my youngest Lockie, I played the violin to soothe him one day and it really helped us both. I started to play different lullabies and my older two children started feeling calmer too.”When Izzy recently decided to go back in the studio to record a new album, which includes some of the lullabies she plays, she wanted to invite Rupert too. They recorded a new version of Somewhere In My Memory.This Instagram post cannot be displayed in your browser. Please enable Javascript or try a different browser.View original content on InstagramThe BBC is not responsible for the content of external sites.Skip instagram post by mrs_izzyjuddAllow Instagram content?This article contains content provided by Instagram. We ask for your permission before anything is loaded, as they may be using cookies and other technologies. You may want to read Meta’s Instagram cookie policy,

Published11 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesParents are being urged to take five simple steps to keep their children healthy as the new school term begins.Advice from health officials ranges from teaching good hygiene habits to stopping the spread of bugs and knowing when to keep your child at home.Winter often sees a rise in common viruses like chickenpox, norovirus and flu which can keep children off school.UK health officials say by following the advice parents can protect them as well as the wider community.Their advice comes as many children return to school for the spring term – but it is also when they are most likely to miss lessons.”The winter period can see an increase in some of the common seasonal viruses which disrupt children’s education and cause more serious illnesses,” says Dr Catherine Falconer from the UK Health Security Agency (UKHSA).The advice is to:1. Teach good hygiene habits, such as regular hand-washingIt is one of the most effective ways to stop the spread of viruses, the experts say, because they can live on our hands.Image source, Getty ImagesUse soap and warm water for 20 seconds or hand sanitiser to clean hands regularly.And to stop infections spreading, use tissues to catch coughs and sneezes, bin them afterwards and then wash hands (again).2. Stop the spread of stomach bugsSickness bugs such as norovirus and E. coli are on the up, and that means more children could have diarrhoea and vomiting.If affected, using bleach-based products to clean surfaces will help prevent bugs from spreading (along with washing hands with soap).The UKHSA says not to prepare food for others if you have symptoms, or for 48 hours after they stop.And it advises people to avoid visiting vulnerable relatives in care homes and hospitals to avoid passing anything on to them, and not to return to work, school or nursery until two days after symptoms end.3. Know when to keep your child at homeChildren should stay at home from school or nursery if they have a high temperature (fever) and are unwell, and wait until it has passed before going back.A child with diarrhoea and/or vomiting should also wait for 48 hours before going back, to stop the spread of stomach bugs.But if they have a runny nose, sore throat or slight cough – without a high temperature – children are encouraged to go to school, nursery or childcare.Image source, Getty ImagesScarlet fever and chickenpox can also spread at this time of year, and cases usually peak in late winter and early spring, health officials say.Scarlet fever symptoms include sore throat, fever, swollen neck glands, a bumpy rash on the tummy, flushed cheeks and “strawberry tongue” – so called because it means the tongue looks a bit like a strawberry. Contact your local GP if you see the signs and keep children away from school and nursery for 24 hours after the first dose of antibiotics.Chickenpox is highly contagious – the most common symptom is an itchy, spotty rash. Keep children off school until all the spots have crusted over.4. Get vaccinatedThere is a “quick and painless” nasal spray for children which offers the best protection against flu, UKHSA says. However, it says vaccine uptake among pre-school children is lower than other groups, despite the illness sometimes being more serious for this age group.Find out if your child is eligible for a flu vaccine in Wales, England, Scotland and Northern Ireland.There has also been a drop in uptake of other childhood vaccinations, which protect against diseases such as measles, mumps, rubella, diphtheria and polio. The advice is to make sure make sure your child is up to date with all their vaccinations. 5. Take online advice from NHS resourcesThe health service has plenty of advice for parents, such as:Is my child too ill for school?NHS vaccinations and when to have themHigh temperature (fever) in childrenCheck if it’s chickenpoxMore on this storyStrep A: What is strep A and what are the symptoms?Published9 December 2022Teenagers at risk after drop in vaccine take-upPublished24 April 2023Give toddlers chickenpox jab, advisers tell NHSPublished14 November 2023Related Internet LinksE-bug resourcesThe BBC is not responsible for the content of external sites.

Americans in the lower middle class are losing ground financially, researchers have found.Monique Louvigny, an event coordinator in the San Francisco Bay Area, economizes where she can. She drives a 10-year-old Prius, brings a thermos of coffee to work instead of patronizing a place with baristas, and takes advantage of a drive-through food pantry once a month.Laid off at 57, “I kind of reinvented myself,” she said. She rebuilt her career as a freelancer, overseeing receptions and conventions for many companies and institutions, including the local de Young and Legion of Honor art museums.But her income fell to less than $30,000 last year. “It’s erratic,” she said. “In January, I have 12 days of work.” In the summer, she might have only three or four.Ms. Louvigny, 64, feels fortunate on two fronts. For health insurance, she has qualified for Medi-Cal, California’s Medicaid program. And two years ago, she paid off the mortgage on her condo in relatively affordable Vallejo. A housemate pays rent, which helps cover maintenance costs and rising condo fees.“I think I can hang on for two years, workwise,” she said, and then she plans to begin receiving Social Security benefits at her full retirement age of 66.Ms. Louvigny’s earnings place her in a category defined in a recent study in the journal Health Affairs as lower middle class for Americans nearing retirement. It’s a group that has steadily lost ground financially over the past two decades, with stagnating earnings and fewer economic resources than it had in the early 1990s.Not only do such losses portend insecure retirement, but they also have disturbing implications for both health and life expectancy, the study and others have found.The upper middle class, on the other hand, has fared distinctly better.“There’s a lot of attention paid to the inequities between the very bottom and the top of income distribution,” said Jack Chapel, the lead author of the study, an economist and doctoral candidate at the University of Southern California. “We wanted to look at the middle class, where people are struggling.”Drawing on data from the national Health and Retirement Study between 1994 and 2018, the researchers found “a bifurcation” among Americans in their mid-50s, he said.In effect, they now divide into two middle classes: the more secure upper tier (which, in 2018, had on average more than $90,000 per person in annual resources, including income and the annualized value of home equity, retirement savings and pensions); and the increasingly precarious lower middle class. In 2018, people in that group had average annual resources of less than $32,000.In the early 1990s, by contrast, “our lower-middle-class group had pretty comparable outcomes to the upper middle class” in measures of health and economic well-being, Mr. Chapel said.No more. In two dozen years, the gap between them widened. Homeownership, for instance, declined by 5 percent in the upper middle class but declined by 31 percent in the lower middle class, only 54 percent of whom owned homes in 2018.For those still working, earnings rose 27 percent in the upper middle class and fell 5 percent for lower-middle-class workers, adjusted for inflation. “They’re making less because they’re working fewer hours or at lower wages, or both,” Mr. Chapel said. They were also far less likely to have employer-sponsored health insurance.Total financial resources projected over their lifetimes after age 60 — including earnings, savings, pensions, housing wealth and public benefits like Social Security — stagnated for lower-middle-class people, rising just 2 percent over 24 years to about $406,000.But total resources reached about $975,000 for the upper middle class, a 26 percent increase. (For the wealthiest group, the comparable figure was nearly $3 million.)Teresa Ghilarducci, an economist at the New School for Social Research whose studies have found similar results among middle-income Americans, pointed to one reason for the growing disparity. “The house has become a reservoir of debt,” she said. “Financial institutions have figured out how to extract wealth from homes with refinancing and second mortgages, and they’ve gotten more sophisticated.”For most middle-income people approaching retirement, she said, the primary source of wealth isn’t home equity or retirement savings. It’s Social Security benefits.One particularly stressed subset: older workers in physically demanding jobs. A report from the Older Workers Retirement Security Task Force, convened by the National Academy of Social Insurance, recently estimated that at least 10 million workers over age 50 belong in that category.Those jobs include “a lot of service-related work requiring you to be on your feet all day,” said Joel Eskovitz, a member of the task force and an AARP policy director. “People in retailing, home health aides, janitors. And a lot of jobs connected with Amazon and other tech companies — warehouse work, deliveries.” Workers in these jobs are disproportionately Black, Hispanic and Asian.Because “they’re not jobs that you can hold onto until deep into your 60s,” Mr. Eskovitz said, such workers often claim their Social Security retirement benefits early, at age 62. Doing so leads to “a significant reduction in monthly benefits and lifetime income” compared with waiting until full retirement age, now 67 for most beneficiaries.The gap between the two middle classes also shows up in measures of health. Among the lower middle class, “there’s almost no decline in smoking,” Mr. Chapel said. “But the upper middle has cut smoking roughly in half.”Those with lower income have more chronic health conditions and are far more likely to describe their health as fair or poor. (One exception: Obesity has risen dramatically for both income groups.)That translates to differences in life expectancy, too. “Everyone is living longer, but the upper middle class is getting much more of a gain, and a higher proportion of their remaining years are quality years,” without serious health problems, Mr. Chapel said.Between 1994 and 2018, life expectancy at age 60 increased twice as much for upper-middle-class men and women as for those in the lower middle class.Even those whose slightly higher incomes technically place them in the upper middle class can feel insecure. “I just pray I get to keep my job at least until I hit 65,” Patricia Thompson, who is 62, wrote in a Facebook message.She and her husband live in Hickory, N.C., where she earns $53,000 a year as an acquisitions editor for a small press and where her husband, 71 and retired, receives a $1,500 Social Security payment and draws $500 from retirement savings each month. That’s above the 45th percentile in total household income for a married couple.But they are still paying off a mortgage and a car loan, and “I have no pension,” Ms. Thompson wrote. “I barely have savings because of student loans late in life. Where’s the safety net for people like me?”“It really is a huge policy challenge, figuring out how to ensure different groups can live in dignity in retirement,” Mr. Eskovitz said.At a time of discussion about raising the Social Security retirement age, policymakers and advocates have suggested a number of measures to bolster financial stability for lower earners and those who are prematurely pushed out of the labor force.The Older Workers Retirement Security Task Force generated a long list of suggestions, including a “bridge benefit” for workers with physically arduous jobs, allowing them to receive partial Social Security payments early without locking them into reduced benefits for the rest of their lives.Raising the cap on the income subjected to payroll taxes could improve Social Security’s solvency for everyone.Mr. Chapel pointed to a new Labor Department program called RETAIN, which helps ill or injured workers return to their jobs and includes workplace accommodations, rehabilitation and retraining.Ms. Louvigny thinks she will be OK, as long as she can keep working for a few more years and remains careful about her spending. “I try not to worry,” she said. “I do not allow those thoughts.”

Published3 hours agoShareclose panelShare pageCopy linkAbout sharingBy Hugh PymHealth editorThe six-day junior doctors’ strike is the longest period of industrial action by NHS workers in its history.We were warned it would pose a “serious threat to patient safety”. One hospital even told staff the situation could become as difficult as it was during the first wave of Covid. How does a hospital cope when a large proportion of its medics heads out of the door and onto the picket line?On the first day of this strike, I went to a major teaching hospital to find out how it planned to cope in the days ahead. It was clear managers had planned well for the strike, with more consultants and other more senior medics drafted in to cover. The emergency department seemed to be running efficiently when I arrived, despite the strike and some staff sickness. But the general manager told me a “huge team effort” was under way to keep on top of demand for care, and manage “tight” capacity.It was to be a challenging week ahead, but senior doctors on the whole seemed to support the industrial action by their junior colleagues.That said, an obvious and growing sense of fatigue had set in. One consultant covering in the emergency department told me he expected to work 70 hours over the six days, by which time he would be “exhausted”.”The workload is heavy and it’s complex. And we can only sustain it in short bursts, doing this complete, perpetual day and night cover,” he said.As the ward and all its beds quickly filled up, he admitted the days ahead seemed “daunting”.After many months of covering strike days, hospital consultants are, like many others, keen to see a settlement. As well as covering the wards and dealing with medical emergencies, they are having to perform surgery, and even manage discharges. Delays in patients leaving hospital were likely to clog the system and create a shortage of beds for new arrivals, I was told.How much do junior doctors get paid and what will it take to settle?’Treading a tightrope’As most non-urgent operations are cancelled during doctors’ strikes, this hospital was prioritising cardiac and cancer surgery. But managers said they were “treading a tightrope” over decisions on whose operations should be postponed, as long waits for surgery could be life-threatening for some. The medical director told me the trust was “on track” with cancer operations, but “by the skin of our teeth”.Meanwhile, a matron running a post-surgery recovery ward told me her nurses were having to take on emergency cases during the strike. This, she said, was a “whole different kettle of fish” which required different skills and experience. Her already overstretched staff were worried about doing their best for patients, she said, which was “frustrating”.Some other hospitals are struggling with sheer demand. Historically, hospitals are under the greatest pressure at this time of year, and this time they’re having to cope without a significant proportion of their workforce.Many trusts have this week declared “critical incidents”, which means they are facing “extraordinary” pressures.More than 20 trusts have asked the doctors’ trade union, the British Medical Association (BMA), to call back striking doctors from the picket lines – requests which have largely been refused.An internal letter I have seen, sent to staff at another major hospital, reveals a heightened sense of concern about the junior doctor strikes. It refers to an incident response call-out plan to cover rota gaps and warned that “these are truly extraordinary measures which we have not had to implement since early pandemic times”.Image source, PA MediaWhen the strike ends early on Tuesday morning, there is likely to be renewed and intense focus on a solution. The BMA and the government have indicated a willingness to resume negotiations, but there may first have to be “talks about talks” to set out the terrain for discussion. The junior doctors’ committee of the BMA wants a more “credible” offer. Ministers may feel unwilling to add to the 3% extra suggested on top of the 8.8% already paid out.Patients, staff and NHS managers can only hope that a settlement can be reached, but the outcome is far from certain. There could still be more of this trouble ahead. Consultants in England are being balloted on a pay offer and it is possible they will reject it.Junior doctors in Wales are to stage a three-day strike from 15 January in a dispute over pay, and those in Northern Ireland are to be balloted. It is hard to rule out the possibility of continued walkouts and disruption for the NHS beyond the early weeks of 2024. More on this storyHospital declares critical incident amid pressurePublished5 January 2023What are junior doctors paid – and how much to settle?Published2 days agoGive us credible offer and we’ll end strikes – BMAPublished2 days agoNHS chief warns of tough new year as strike loomsPublished4 days agoDisruption warning as junior doctor strikes returnPublished20 December 2023Related Internet LinksBMA – Home – British Medical AssociationDepartment of Health and Social Care – GOV.UKNHS EnglandThe BBC is not responsible for the content of external sites.

Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment.
“This paper takes us from very fundamental cell biology in a fly, to explaining a human disease and harnessing that knowledge for a cancer therapy,” said UC Santa Barbara’s Denise Montell. “Each one of those steps feels like a major discovery, but here they are, all in one paper.”
Researchers in Montell’s lab published their findings in the Proceedings of the National Academy of Sciences and are now investigating the mechanisms and implications.
An ancient gene
The primary character in this story is a gene, Rac2, and the protein it encodes. Rac2 is one of three Rac genes in humans. “Rac is very ancient in evolution, so it must serve a fundamental function,” said senior author Montell, Duggan Professor and Distinguished Professor of Molecular, Cellular, and Developmental Biology.
Rac proteins help build a cell’s scaffolding, called the cytoskeleton. The cytoskeleton is made of dynamic filaments that allow cells to maintain their shape or deform, as needed. In 1996, while studying a small group of cells in the fruit fly ovary, Montell determined that Rac proteins are instrumental in cell movement. Since then, it has become clear that Rac is a nearly universal regulator of cell motility in animal cells.
Back in the ’90s, she noticed that a hyperactive form of the Rac1 protein, expressed in only a few cells in a fly’s egg chamber, destroyed the whole tissue. “Just expressing this active Rac in six to eight cells kills the entire tissue, which is composed of about 900 cells,” explained lead author Abhinava Mishra, a project scientist in Montell’s lab.

Why did this happen? How does it work? “This was our 25-year-old cold case,” Montell said.
A few years ago, evidence began to mount implicating cell eating, also known as cannibalism, in tissue destruction. There’s a step in normal fly egg development where certain cells similar to the border cells consume their neighbors because they are no longer needed. Indeed, cellular cannibalism is not as rare as you might expect: Millions of old red blood cells are eliminated from the human body this way every second.
Rac2 is one component of the complex eating process. Rac helps the eating cell to envelop its target. The team was curious if a hyperactive form of the protein was causing border cells to prematurely consume their neighbors.
For this to occur, the border cells need to recognize their targets, which requires a particular receptor. Indeed, when Mishra blocked this receptor, the border cells expressing activated Rac didn’t consume their neighbors, and the egg chamber remained alive and healthy.
“Our 25-year-old cold case was solved, and that was very satisfying for us,” Montell exclaimed. “But this is a fairly niche area of Drosophila egg development.” The implications would soon grow, though.
A mysterious immune condition
Around the time that her lab made their breakthrough, Montell caught wind of an intriguing study in the journal Blood. This paper found that three unrelated people suffering from recurrent infections had the exact same mutation, which hyperactivates Rac2, a Rac protein produced in blood cells. She suspected her lab’s recent revelation in fruit flies might shed light on this enigma.

The patients’ mutation was just mildly activating, and yet it was enough that they all suffered from multiple infections and ultimately needed bone marrow transplants. Blood tests revealed that these patients had nearly no T cells, a specialized kind of white blood cells crucial to the immune system. The team at the National Institutes of Health inserted the Rac2 mutation into mice and found the same mysterious loss of T cells. They also found that the T cells with hyperactive Rac developed normally in the animals’ bone marrow, and migrated to the thymus, where they continued to mature without incident. But then they just seemed to disappear. So, the paper ended with a mystery: what was causing the T cells to disappear?
The authors of that journal study had noticed that many of the patients’ neutrophils — another type of white blood cell — were enlarged. They seemed to be consuming quite a lot of material, unusual behavior in an otherwise healthy person.
Montell wondered if the patients’ T cells were disappearing because their innate immune cells like neutrophils with active Rac2 were eating them, much like the fruit fly border cells with active Rac were eating the egg chamber. Her team turned their attention to macrophages — the neutrophil’s more voracious counterpart — to investigate. Mishra cultured human macrophages with and without hyperactive Rac2 together with T cells. He observed that macrophages with hyperactive Rac consumed more cells, confirming the group’s hypothesis from their work with fruit flies.
To test whether this might cause the observed immunodeficiency, co-author Melanie Rodriguez (a graduate student in Montell’s lab) took bone marrow samples from mice with the same hyperactive Rac2 mutation found in the patients. She then grew the marrow stem cells into macrophages, and performed a similar experiment to Mishra, but this time mixing both macrophages and T cells with and without the Rac2 mutation.
She found that macrophages with active Rac2 consumed significantly more T-cells than their normal counterparts. However, T-cells with active Rac2 were also more vulnerable to consumption from either kind of macrophage. So the most likely explanation for the patients’ missing T cells was a combination of increased consumption by macrophages as well as increased vulnerability of the T cells themselves. A human medical mystery was solved based on fundamental observations in fruit flies.
Harnessing haywire cells
The implications of these insights expanded in January 2020, when co-author Meghan Morrissey interviewed for a faculty position at UCSB. In her talk she described programming macrophages to eat cancer cells as a novel treatment for the disease, an approach called CAR-M. Morrissey had found that adding a CAR receptor to macrophages promoted this behavior. But it was also clear that inducing the macrophages to eat more would make the approach more effective — especially if they would specifically consume, and kill, entire cancer cells .
Well, if there was one thing that Montell and her lab had learned, it was how to make macrophages eat and kill whole, living cells. So they collaborated with Morrissey, now an assistant professor of molecular, cellular and developmental biology, to determine if adding activated Rac2 would increase the effectiveness of the CAR-M approach.
Rodriguez grew macrophages from the bone marrow of normal and mutant mice with activated Rac2. In each of these groups, Morrissey expressed either a dummy receptor or the CAR receptor, which recognizes B cells (another type of white blood cell). They found that the normal and hyperactive Rac cells with the dummy receptors did not eat many B cell targets. The normal macrophages with CAR receptors consumed far more B cells, as Morrissey had previously shown. However the macrophages with both hyperactive Rac and the CAR receptors ate twice-again as many B cells as the CAR-only group. Activated Rac2 also seemed to increase the number of so-called “super eaters” — ravenous macrophages that eat and kill multiple cancer cells.
The results made it clear that activated Rac and the receptor were both necessary for the enhanced effect. “If you add active Rac without the right receptor, it doesn’t do anything,” Montell explained.
This level of control is good news for any potential treatments, because it would give doctors a way to focus the modified macrophages’ attack on cancerous cells. Clinicians hopefully won’t need to worry about the engineered cells eating the patient’s T-cells either, because the T-cells wouldn’t have the active Rac2 mutation making them more vulnerable to this, as Rodriguez had previously discovered.
There is a current cancer treatment called CAR-T, which uses the CAR receptor and a patient’s own T-cells to attack and destroy cancers. It is highly effective against some cancers, but there are many that do not respond. CAR-M,a newer cousin to CAR-T, has recently entered into clinical trials in humans and so far seems safe. Montell and her group are interested in harnessing Rac-enhanced CAR macrophages to increase the efficacy of CAR-M treatments. They’ve filed a provisional patent for the technique — which they call RaceCAR-M — and are inviting biotech companies to partner in further developing the approach.
This new multifaceted paper raises both basic science and practical questions, which the lab has begun to tackle. They’re investigating whether the technique, which is so effective in the lab, will also work in freshly collected human immune cells and in animal cancer models, in mice and zebrafish. The team is also exploring how Rac2 is making this all happen at the molecular level, deep inside the cells.
Further down the line, Montell wants to know how many kinds of cancer the RaceCAR-M treatment might successfully target. For comparison, CAR-T has been effective against cancers like leukemia and lymphoma, but not against solid-tumor cancers like breast, lung or colon.
The results have amazed Montell, an esteemed cell biologist with well over 100 papers to her name. “This is my favorite paper so far,” she said.
“We had this 25-year-old cold case in fruit flies, and we solved it,” Montell added. “And that helped us solve the mystery of an unexplained human immunodeficiency. And then we harnessed that knowledge to enhance a potential cancer immunotherapy.
“It was just one mystery after another, and Rac turned out to be the answer to each of them.”
You can hear more about the path from fruit flies to potential cancer treatment in Montell’s SNPets interview with the Genetics Society of America, episodes 4-6 (https://genetics-gsa.org/snpets/full-season-snpets/#montell).

Researchers at the University of Michigan Health Rogel Cancer Center have identified a mechanism that causes severe gastrointestinal problems with immune-based cancer treatment.
They also found a way to deliver immunotherapy’s cancer-killing impact without the unwelcome side effect.
The findings are published in Science.
“This is a good example of how understanding a mechanism helps you to develop an alternative therapy that’s more beneficial. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the anti-tumor effect,” said senior study author Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine.
Immunotherapy has emerged as a promising treatment for several types of cancer. But immune checkpoint inhibitors can also cause severe side effects, including colitis, which is inflammation in the digestive tract.
Colitis can cause severe gastrointestinal discomfort, and some patients will discontinue their cancer treatment because of it.
The problem facing researchers was that while patients were developing colitis, the laboratory mice were not. So researchers couldn’t study what was causing this side effect.

To get past this, the Rogel team, led by first author Bernard C. Lo, Ph.D., created a new mouse model, injecting microbiota from wild-caught mice into the traditional mouse model.
In this model, the mice did develop colitis after administration of antibodies used for tumor immunotherapy. Now, researchers could trace back the mechanism to see what was causing this reaction.
In fact, colitis developed because of the composition of the gut microbiota, which caused immune T cells to be hyper-activated while regulatory T cells that put the brakes on T cell activation were deleted in the gut.
This was happening within a specific domain of the immune checkpoint antibodies.
Researchers then removed that domain, which they found still resulted in a strong anti-tumor response but without inducing colitis.
“Previously, there were some data that suggested the presence of certain bacteria correlated with response to therapy. But it was not proven that microbiota were critical to develop colitis. This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition,” Nunez said.

To follow up what they saw in mice, researchers reanalyzed previously reported data from studies of human cells from patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis.
The antibody they used to stop the colitis was developed by Takeda Pharmaceuticals.
The Rogel team plans additional studies to further understand the mechanisms causing colitis and seeks clinical partners to move this knowledge to a clinical trial.
Additional authors are Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu Leo Lei and Weiping Zou.
Funding for this work is from National Institutes of Health grants R01 DK121504, R01 DK095782, R01 DE026728, R01 DE030691, P30 CA046592; Takeda Millennium Pharmaceuticals, Canadian Institutes of Health, Crohn’s and Colitis Foundation, National Science Foundation grant IOS-2107215.
This work was supported by these Rogel Cancer Center Shared Resources: Single Cell Spatial Analysis, Tissue and Molecular Pathology

Technological advancements have enabled scientists to comprehensively explore genetic control elements, unraveling the complexities of gene activation mechanisms in our genetic code. New evidence challenges the simplistic view that cis-regulatory elements (CREs) are mere on/off switches for genes, emphasizing their ability to exhibit complex behaviors, such as the simultaneous enhancement of gene activity and initiation of gene transcription, e.g., simultaneous enhancer and promoter activities. These switches aren’t only important for the enhancement of specific genes but are crucial for the basic functions that keep our cells healthy.
Now, a study conducted in Japan has revealed the existence of around 11,000 vital genetic switches active in every cell type — housekeeping cis-regulatory elements (HK-CREs) — that play a role in maintaining the stability and function of our cells, far beyond the regulation of housekeeping genes. This study was performed by scientists from the Laboratory of Functional Analysis in silico (Nakai-lab) at The Institute of Medical Science, The University of Tokyo, Japan: Professor Kenta Nakai, head of the laboratory, and Dr. Martin Loza, Assistant Professor, in collaboration with Dr. Alexis Vandenbon, Associate Professor, from the Institute of Life and Medical Sciences, Kyoto University, Japan. Their work was published in Nucleic Acids Research on December 12, 2023.

Discussing his motivation behind this study, Dr. Loza states, “Given the significant association between cancer and mutations in epigenetic components, every small insight we gain could be key in the ongoing battle against this disease, which has tragically claimed innumerable lives. Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.” The research team found that HK-CREs were not solely confined to regulating the well-studied housekeeping genes (HKGs), which only constituted less than 20% of the genes associated with these elements. Instead, these elements predominantly resided within core promoter regions of many more genes (around 8,000), indicating a broader regulatory role beyond typical housekeeping gene functions. By employing bioinformatics analyses and levering diverse public datasets, the team validated the robustness of HK-CREs across 50 randomly selected healthy cell types, confirming the location of HK-CREs within the genome. These elements were highly conserved, residing in unmethylated CpG-rich regions, a trait strongly associated with their housekeeping regulatory function.
Sharing his concerns about the analysis, Dr. Lozastates, “By leveraging bioinformatics analyses of multiomics data, we offer an approach to harnessing publicly available datasets for exploring diverse biological mechanisms. We anticipate that employing similar workflows can significantly streamline analyses, cutting back both time and financial investments needed for comprehensive studies involving new data.”
The team remarked on the intricate cooperative interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks through promoter-promoter interactions. These observations hint at the significant influence of such interactions not only on HKGs but also on genes specific to various cell types. Turning their attention to cancer cells, researchers discovered a subset of HK-CREs displaying reduced activity in diverse cancer subtypes due to aberrant methylation, particularly those linked to zinc finger genes clustered in sub-telomere regions of chromosome 19. Identifying genes such as ZNF135, ZNF154, ZNF667, and ZNF667-AS1 under the influence of these foundational core promoters, the research suggests their potential as housekeeping tumor suppressor genes.
“Genes detected in our study have exhibited decreased activity in multiple cancer cell lines, and survival analysis across various cancer projects have revealed significant increases in survival probability in diverse cancer types like pancreas adenocarcinoma and uveal melanoma,” states Dr. Loza.
In essence, the results of this research have uncovered a previously unknown class of HK-CREs critical for cellular stability, extending their influence beyond housekeeping gene regulation. “Our discovery on housekeeping tumor suppressor genes unveils a novel avenue in cancer therapy, harnessing the intrinsic elements within the DNA of every cell. Future approaches to cancer treatment, focusing on these housekeeping tumor suppressor genes, offer a unique solution that could potentially target a broad range of cancers, sidestepping the challenges associated with personalized medicine,” remarks Dr. Loza. He further adds, “Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes. We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.”
Technological advancements have enabled scientists to comprehensively explore genetic control elements, unraveling the complexities of gene activation mechanisms in our genetic code. New evidence challenges the simplistic view that cis-regulatory elements (CREs) are mere on/off switches for genes, emphasizing their ability to exhibit complex behaviors, such as the simultaneous enhancement of gene activity and initiation of gene transcription, e.g., simultaneous enhancer and promoter activities. These switches aren’t only important for the enhancement of specific genes but are crucial for the basic functions that keep our cells healthy. Now, a study conducted in Japan has revealed the existence of around 11,000 vital genetic switches active in every cell type — housekeeping cis-regulatory elements (HK-CREs) — that play a role in maintaining the stability and function of our cells, far beyond the regulation of housekeeping genes. This study was performed by scientists from the Laboratory of Functional Analysis in silico (Nakai-lab) at The Institute of Medical Science, The University of Tokyo, Japan: Professor Kenta Nakai, head of the laboratory, and Dr. Martin Loza, Assistant Professor, in collaboration with Dr. Alexis Vandenbon, Associate Professor, from the Institute of Life and Medical Sciences, Kyoto University, Japan. Their work was published in Nucleic Acids Research on December 12, 2023.
Discussing his motivation behind this study, Dr. Loza states, “Given the significant association between cancer and mutations in epigenetic components, every small insight we gain could be key in the ongoing battle against this disease, which has tragically claimed innumerable lives. Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.” The research team found that HK-CREs were not solely confined to regulating the well-studied housekeeping genes (HKGs), which only constituted less than 20% of the genes associated with these elements. Instead, these elements predominantly resided within core promoter regions of many more genes (around 8,000), indicating a broader regulatory role beyond typical housekeeping gene functions. By employing bioinformatics analyses and levering diverse public datasets, the team validated the robustness of HK-CREs across 50 randomly selected healthy cell types, confirming the location of HK-CREs within the genome. These elements were highly conserved, residing in unmethylated CpG-rich regions, a trait strongly associated with their housekeeping regulatory function.
Sharing his concerns about the analysis, Dr. Lozastates, “By leveraging bioinformatics analyses of multiomics data, we offer an approach to harnessing publicly available datasets for exploring diverse biological mechanisms. We anticipate that employing similar workflows can significantly streamline analyses, cutting back both time and financial investments needed for comprehensive studies involving new data.”
The team remarked on the intricate cooperative interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks through promoter-promoter interactions. These observations hint at the significant influence of such interactions not only on HKGs but also on genes specific to various cell types. Turning their attention to cancer cells, researchers discovered a subset of HK-CREs displaying reduced activity in diverse cancer subtypes due to aberrant methylation, particularly those linked to zinc finger genes clustered in sub-telomere regions of chromosome 19. Identifying genes such as ZNF135, ZNF154, ZNF667, and ZNF667-AS1 under the influence of these foundational core promoters, the research suggests their potential as housekeeping tumor suppressor genes.
“Genes detected in our study have exhibited decreased activity in multiple cancer cell lines, and survival analysis across various cancer projects have revealed significant increases in survival probability in diverse cancer types like pancreas adenocarcinoma and uveal melanoma,” states Dr. Loza.
In essence, the results of this research have uncovered a previously unknown class of HK-CREs critical for cellular stability, extending their influence beyond housekeeping gene regulation. “Our discovery on housekeeping tumor suppressor genes unveils a novel avenue in cancer therapy, harnessing the intrinsic elements within the DNA of every cell. Future approaches to cancer treatment, focusing on these housekeeping tumor suppressor genes, offer a unique solution that could potentially target a broad range of cancers, sidestepping the challenges associated with personalized medicine,” remarks Dr. Loza. He further adds, “Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes. We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.”