Publisher Health

Our genomes provide the instructions for proper growth and development. Millions of genomic switches, known as enhancers, control the location and timing of gene expression, which in turn ensures the correct proteins are made in the right cells at the right time throughout our lives. New research from University of California San Diego Assistant Professor Emma Farley’s lab shows how we can now predict which single base-pair changes to the DNA within our genomes will alter these instructions and disrupt development, causing extra digits and hearts.
We now have genome sequences for over half a million people and counting. These genomes hold the key to how each of us comes to be and the promise of attaining precision medicine tailored to an individual’s own genetic makeup. Yet we cannot take full advantage of these datasets since we don’t understand a critical aspect of the genome: enhancers, which act as switches to control when and where our genes are expressed as proteins. Most genetic variants or mutations that cause disease lie within these enhancers. A central challenge has been to determine which sequence changes within enhancers matter and which do not. Thus far, pinpointing such causal enhancer variants has been akin to searching for a needle in a haystack.
Publishing in the journal Nature, the Farley lab has addressed this challenge by achieving the ability to predict which changes to enhancers would cause changes in gene expression across thousands of enhancers and cell types. This ability to predict causal enhancer variants is rooted in a deep understanding of how enhancers function. The researchers showed that enhancers activate gene expression by binding proteins known as transcription factors very weakly. Adhering to this rule ensures enhancers activate gene expression, and thus protein production, at the right level, place and time. The Farley lab found that single-letter changes to our genome that strengthen the interaction of an enhancer with a transcription factor cause enhancers to switch on gene expression inappropriately and make proteins at the wrong level, time and/or place. Therefore, these single-letter changes to the enhancer DNA within our genome have dramatic effects on the genetic instructions, leading to extra fingers in mice and humans.
The Farley lab identified three human families in which such mutations cause extra fingers and was able to predict which mutations would lead to even more fingers and more severe limb defects. Their ability to predict which enhancer variants will alter genomic instructions is not limited to limbs and generalizes to thousands of enhancers across cell types and species. In a complementary study published in Developmental Cell, the Farley lab showed that within marine animals known as sea squirts, single-letter changes that make heart enhancers stronger led to the development of a second beating heart.
Pinpointing enhancer variants that alter the instructions for development encoded in a genome is key for seizing the full potential of genomic data for improving human health and obtaining the goals of precision medicine. Across thousands of enhancers, the Farley lab found that searching for DNA base-pair changes that make enhancers stronger enabled (up to) a seven-fold increase in their ability to find causal enhancer variants.
“Our study illustrates a key vulnerability in our genomes: single base-pair changes that make transcription factors bind to an enhancer even slightly stronger can cause developmental defects,” said Farley, a faculty member in the Departments of Medicine (School of Medicine) and Molecular Biology (School of Biological Sciences). “Taking advantage of this knowledge will allow us to better predict which enhancer variants underlie disease in order to harness the full potential of our genomes for better human health.”
Farley is a recipient of the New Innovator Award and National Science Foundation CAREER Award, which funded this work. For the Nature paper, the first authors of this work are two UC San Diego graduate students, Fabian Lim (Biological Sciences) and Joe Solvason (Bioinformatics and Systems Biology), and postdoctoral scholar Genevieve Ryan. They were supported by Farley lab members: Sophia Le, Granton Jindal, Paige Steffen and Simran Jandu.
The Developmental Cell paper was authored by postdoc Granton Jindal, graduate students Alexis Bantle (Biological Sciences) and Joe Solvason (Bioinformatics and Systems Biology), Jessica Grudzien, Agnieszka D’Antonio-Chronowska, Fabian Lim, Sophia Le, Benjamin Song, Michelle Ragsac, Adam Klie, Reid Larsen Kelly Frazer and Emma Farley.
The research was funded by National Institutes of Health (DP2HG010013, T32HL007444, T32GM127235, T32GM133351, T32GM008666 and U01HL107442), National Science Foundation (2239957, CMMI1728497), American Heart Association (18POST34030077), UC San Diego Chancellor’s Research Excellence Scholars Program and California Institute for Regenerative Medicine (CIRM GC1R-06673-B).

La Jolla Institute for Immunology (LJI) is working to guide the development of new tuberculosis vaccines and drug therapies.
Now a team of LJI scientists has uncovered important clues to how human T cells combat Mycobacterium tuberculosis, the bacterium that causes TB. Their findings were published recently in Nature Communications.
“This research gives us a better understanding of T cell responses to different stages in tuberculosis infection and helps us figure out is there are additional diagnostic targets, vaccine targets, or drug candidates to help people with the disease,” says LJI Research Assistant Professor Cecilia Lindestam Arlehamn, Ph.D., who led the new research in collaboration with LJI Professors Bjoern Peters, Ph.D., and Alessandro Sette, Dr.Biol.Sci.
The urgent need for TB research
According to the World Health Organization, more than 1.3 million people died of TB in 2022, making it the second-leading infectious cause-of-death after COVID-19. “TB is a huge problem in many countries,” says Lindestam Arlehamn.
Currently, a vaccine called bacille Calmette-Guerin (BCG) protects against some severe cases of TB. Unfortunately, BCG doesn’t consistently prevent cases of pulmonary TB, which can also be deadly. Although there are drug treatments for TB, more and more cases around the world have proven drug resistant.
To help stop TB, Lindestam Arlehamn and her colleagues are learning from T cells. T cells are critical for stopping infections from spreading in the body. Instead of targeting an entire pathogen, T cells look for specific markers, called peptides sequences, that belong to the pathogen. When a T cell recognizes a certain part of a pathogen’s peptide sequence, scientists call that area an “epitope.”
Uncovering T cell epitopes gives scientists vital information on how vaccines and drug treatments might take aim at the same epitopes to stop a pathogen.

T cells take aim at a range of TB epitopes
For the new study, the researchers worked with samples from patients who were mid-treatment for active TB. These samples came from study participants in Peru, Sri Lanka, and Moldova. By looking at T cells in patients from three different continents, the researchers hoped to capture a wide diversity of genetics — and environmental factors — that can affect immune system activity.
In their analysis, the LJI team uncovered 137 unique T cell epitopes. They found that 16 percent of these epitopes were targeted by T cells found in two or more patients. The immune system appeared to be working hard to zoom in on these epitopes.
Going forward, Lindestam Arlehamn’s laboratory will investigate which of these epitopes may be promising targets for future TB vaccines and drug therapies.
A step toward better diagnostics
The new study is also a step toward catching TB cases before they turn deadly.

Because Mycobacterium tuberculosis is an airborne bacteria, a person can be exposed without ever realizing it. Once exposed, many people go months or years without any symptoms. This inactive, or “latent,” TB can turn into active TB if a person’s immune system weakens, for example, during pregnancy or due to an infection such as HIV.
For the new study, the researchers also compared samples from active TB patients with samples from healthy individuals. The scientists uncovered key differences in T cell reactivity between the two groups. “For the first time, we could distinguish people with active TB versus those that have been exposed to TB — or unexposed individuals,” says Lindestam Arlehamn.
Lindestam Arlehamn says it may be possible to develop diagnostics that detect this tell-tale T cell reactivity that marks a person’s shift from latent to active TB. “Can we use this peptide pool to look for high-risk individuals and try and follow them over time?” she says.

A new report based on records from the Trump and Biden years found the average length of solitary detainment was longer than the duration the U.N. says can constitute torture.The United States government has placed detained immigrants in solitary confinement more than 14,000 times in the last five years, and the average duration is almost twice the 15-day threshold that the United Nations has said may constitute torture, according to a new analysis of federal records by researchers at Harvard and the nonprofit group Physicians for Human Rights.The report, based on government records from 2018 through 2023 and interviews with several dozen former detainees, noted cases of extreme physical, verbal and sexual abuse for immigrants held in solitary cells. The New York Times reviewed the original records cited in the report, spoke with the data analysts and interviewed former detainees to corroborate their stories.Overall, Immigration and Customs Enforcement is detaining more than 38,000 people — up from about 15,000 at the start of the Biden administration in January 2021, according to an independent tracking system maintained by Syracuse University. A growing proportion of detainees are being held in private prison facilities with little means of accountability, and preliminary data from 2023 suggests a “marked increase” in the use of solitary confinement, according to the report.A spokesman for ICE, Mike Alvarez, said in a statement that 15 entities oversee ICE detention facilities to “ensure detainees reside in safe, secure and humane environments, and under appropriate conditions of confinement.” He added that detained immigrants are able to file complaints about facilities or staff conduct via phone or through the Homeland Security inspector general.“Placement of detainees in segregation requires careful consideration of alternatives, and administrative segregation placements for a special vulnerability should be used only as a last resort,” he said, using the agency’s terminology for solitary confinement. “Segregation is never used as a method of retaliation.”ICE issued directives in 2013 and 2015 to limit the use of solitary confinement, saying it should be a “last resort.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published18 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Nick TriggleHealth correspondent@nicktriggleMany cancer patients will recognise the way the King was diagnosed – it is known as an incidental diagnosis, when the disease is spotted during care for another condition.The King, 75, went in for treatment for an enlarged prostate – and during that procedure, the signs of cancer were spotted, leading to the diagnosis made public on Monday.This route to diagnosis is surprisingly common. While there is a big focus on screening programmes and urgent referrals from GPs, one in five cancers is actually diagnosed when patients are being seen for something else, according to Macmillan Cancer Support analysis of NHS data.Waiting timeOver the past 12 months, 66,000 cancers have been diagnosed and treated through this route. But where the experience of the public differs from that of the King is how quickly all this happens – he was admitted to a private hospital, for treatment for the enlarged prostate, less than two weeks ago and has already started cancer treatment.The NHS target is for cancer treatment to start within 62 days of the disease being suspected. But over the past year, one out of every four patients diagnosed incidentally in England waited longer.And the waiting time has gradually lengthened during the past decade or so.It is a similar story for those diagnosed through other routes, such as via screening or a GP referral. Overall, more than one out of every three waits more than 62 days.There are many reasons why performance has deteriorated. An analysis by Cancer Research UK, last month, described a “long-term failure to plan and invest in the NHS workforce and key facilities and equipment”. Lack of diagnostic testing equipment is said to the biggest bottleneck – the NHS has four times fewer scanners than Germany, for example.And those having cancer treatment are well aware of this. A survey by Macmillan and YouGov, last year, found half of them were worried about pressures on the NHS affecting their chances of survival.King Charles’s cancer diagnosis Live: King spends night at home after starting cancer treatmentWhat does it mean for William, Harry and the other royals?Prince Harry to visit King Charles in coming daysWhat do we know about the King’s cancer diagnosis?But an incidental diagnosis such as the King’s also depends on another part of the NHS. Patients needing treatment for something that is not thought to be cancer-related are put on the general hospital waiting list.The backlog currently stands at 7.6 million, close to a record-high after a sharp increase since before the pandemic. People on the general hospital waiting list often face delays before they get to see a doctor or undergo tests that would lead to them being put on the cancer waiting list in the first place.Over the past year one in four people have waited longer than six weeks to even get tested and one in three spend more than 18 weeks in total.That is why Macmillan’s Kate Seymour says cancer patients diagnosed incidentally are facing a “double hit”. “They are having to wait for tests both before and after being moved onto the cancer pathway, as well as then waiting for diagnosis and treatment, adding to people’s stress and anxiety as their lives are turned upside down. “NHS staff are doing the very best they can, but chronic staff shortages in cancer care, long-standing delays and constant growing demand have led to a system struggling to cope. “People living with cancer deserve better and ultimately, we need to see people getting diagnosed and treated quicker.” More on this storyGive us credible offer and we’ll end strikes – BMAPublished3 JanuaryNHS consultant strike: How pay compares globallyPublished24 August 2023Junior doctor strikes return, after talks collapsePublished5 December 2023Nurses react with fury over doctor pay offerPublished28 November 2023Fresh pay offer could end NHS consultant strikesPublished27 November 2023Sunak to miss NHS target if doctors strike – AtkinsPublished3 December 2023Why talk of a UK doctor exodus is prematurePublished9 August 2023

Receiving multidose vaccinations in both arms, instead of just one, may increase the immune response, new research suggests.If you’ve presented the same arm for every dose of a particular vaccine, you may want to reconsider. Alternating arms may produce a more powerful immune response, a new study suggests.The researchers studied responses to the first two doses of Covid-19 vaccines. Those who alternated arms showed a small increase in immunity over those who got both doses in the same arm.For individuals who respond poorly to vaccines because of age or health conditions, even a small boost may turn out to be significant, the researchers said. At this point in the pandemic, with most people having had multiple vaccine doses or infections, alternating arms for Covid vaccines may not offer much benefit.Yet if confirmed by further study, the results could have implications for all multidose vaccines, including childhood immunizations.“I’m not making recommendations at this point, because we need to understand this a lot better,” said Dr. Marcel E. Curlin, an infectious disease physician at Oregon Health & Science University who led the work.But “all things being equal, we ought to consider switching up the arms.”The few studies comparing the two approaches have been small and have produced mixed results. And none of the studies shown a big difference in immunity.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Psychoactive mushrooms, illegal under federal law, are gaining popularity as therapy tools. Some experts worry that the market is growing faster than the research.Seizures of psychedelic mushrooms across the nation by law enforcement officials have increased significantly in recent years as attitudes regarding their use have grown more permissive, according to a government-funded study released Tuesday.Researchers found that law enforcement officials confiscated 844 kilos of mushrooms containing psilocybin in 2022, an increase of 273 percent from 2017. Psilocybin is the psychoactive component in the fungi commonly known as magic mushrooms.Officials at the National Institute on Drug Abuse, which commissioned the study, said that the increase in seizures of magic mushroom reflected rising use of the drugs, rather than an indication that counternarcotics officials were pursuing the substances more aggressively than before.The marketplace for magic mushrooms, which are illegal under federal law, has boomed in recent years as several clinical studies have shown that they may be effective as therapies to treat depression and other serious conditions. But many medical professionals say they worry that the hype surrounding psychedelics has moved faster than the science.Dr. Nora Volkow, the director of the N.I.D.A, said that preliminary clinical studies had shown that psychedelics might one day become an important tool for the treatment of psychiatric disorders, including addiction to other drugs. But she said she worried that many people were self-medicating with psychedelics.“Psychedelic drugs have been promoted as a potential cure for many health conditions without adequate research to support these claims,” Dr. Volkow said. “There are people who are very desperate for mental health care, and there are businesses that are very eager to make money by marketing substances as treatments or cures.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Last October, to commemorate Mental Health Awareness Week, a group of students at Sacopee Valley High School in Hiram, Maine, created the annual Hope Board. Shaped like an enormous tulip and displayed in the lobby, the board was covered with anonymous teenage aspirations. Some students hoped to pass driver’s education or have a successful playoff season. Others expressed more complicated desires. “To be more happy than angry,” wrote one student. Another wrote, “I hope people are kinder and more mature.”Camryn Baron, 17, created the board as a founder of Sacopee’s Yellow Tulip Team, a student group devoted to mental health. “It’s an outlet for some kids to be able to outwardly express and vocalize something that’s bothering them,” she said.Ms. Baron has struggled with an eating disorder, anxiety and depression; she is bisexual and has not always felt supported. “The things that a lot of us dismiss or struggle with here — to be able to share them with other people is validating,” she said.Sacopee’s Yellow Tulip Team is one of roughly 150 such clubs supported by the Yellow Tulip Project, a mental health education and advocacy nonprofit. Co-founded in 2016 by Julia Hansen, a high schooler in Maine who had lost her two best friends to suicide, the nonprofit works to destigmatize mental illness and help students prioritize their emotional well-being.At Sacopee Valley, the club plays upbeat music to welcome students each Monday and shares mental health information through morning announcements. Each fall, it plants a Hope Garden — 500 tulip bulbs this year — and will celebrate the flowers’ resilience in the spring with a youth wellness day of workshops and activities. At the group’s regular meetings, students might discuss stress reduction strategies, as well as the homophobia, socio-economic inequality and various stigma that many teenagers experience in their conservative-leaning, rural community.In recent years, nonprofits that support school-based mental health clubs have found their programs in demand. The increase is the result of two phenomena: the rising number of adolescents struggling with mental health and the dearth of resources to help them. As schools search for solutions, often it’s the students who are leading the effort.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Like many captive elephants, Nidia suffered from chronic foot problems. Fissures had formed in the 55-year-old Asian elephant’s foot pads, and her toenails had cracked and become ingrown. Painful abscesses lingered for months. Nidia had lost her appetite and she was losing weight.Dr. Quetzalli Hernández, the veterinarian in charge of Nidia’s care at a wildlife park in Mexico, was desperate. She decided to try cannabidiol, or CBD, the nonintoxicating therapeutic compound found in cannabis.For help, Dr. Hernández reached out to Dr. Mish Castillo, the chief veterinary officer at ICAN Vets, a company engaging in veterinary cannabis education and research in Mexico. To Dr. Castillo’s knowledge, no one had purposely given an elephant medical cannabis. But he and his colleagues hoped it would reduce Nidia’s pain and stimulate her appetite, as they had seen the drug do for cats, dogs and other species.They started low and eventually settled on a dose of 0.02 milligrams of CBD per pound of Nidia’s weight, which she took daily with a chunk of fruit. Calibrated by weight, the dose is one-tenth to one-fortieth of what Dr. Castillo gives to dogs or cats. Yet it worked.The first sign that the treatment was effective was when Nidia developed a serious case of the munchies. Within days of starting CBD, she went from finishing just one-third of her food to virtually all of it, and sometimes even went for seconds. Within five weeks, she had gained 555 pounds.After Nidia began eating, her demeanor changed. “She was always known as the grumpy one — she used to kick doors,” Dr. Castillo said. “Within the first week to 10 days of her treatment, she started coming out of her enclosure quicker and was in less of a bad mood.”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

While Buckingham Palace released little information on Charles’s diagnosis, some cancer experts not involved in his care have seen the illness detected during other routine medical procedures.A patient checks into the hospital for a routine procedure to treat an enlarged prostate. And, unexpectedly, a test done in the hospital — perhaps a blood test or an X-ray or an examination of the urethra and the bladder — finds a cancer.Apparently, something like that happened to King Charles III. When the British monarch was treated for an enlarged prostate in January, doctors found a cancer that the palace said is not prostate cancer. Charles started treatment Monday. The palace did not disclose what had led to the king’s diagnosis.While some prostate specialists like Dr. Peter Albertsen at the University of Connecticut called such situations “pretty rare,” other doctors said they were not unheard of.Dr. Otis Brawley, an oncologist at Johns Hopkins Medical Center in Baltimore, said a man had come in for routine prostate surveillance to monitor a low-risk cancer. One of Dr. Brawley’s residents ordered a chest X-ray “for no reason,” he said. But to the surprise of Dr. Brawley, the X-ray detected a lung cancer.Some cancers demand immediate treatment, while for others, treatment can wait, oncologists said. The palace did not describe the severity of Charles’s diagnosis, nor what treatment he was receiving.Some blood cancers are among those that need immediate treatment, Dr. Brawley said.“We even have a few leukemias and lymphomas where we want to start therapy less than 24 hours after suspicion,” he said. He said he doubted Charles had one of the most aggressive blood cancers, acute myeloid leukemia, nor Burkett’s lymphoma. But if he did, treatment would could not be put off.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

People with depression have higher body temperatures, suggesting there could be a mental health benefit to lowering the temperatures of those with the disorder, a new UC San Francisco-led study found.
The study, publishing today in Scientific Reports, doesn’t indicate whether depression raises body temperature or a higher temperature causes depression. It’s also unknown whether the higher body temperature observed in people with depression reflects decreased ability to self-cool, increased generation of heat from metabolic processes or a combination of both.
Researchers analyzed data from more than 20,000 international participants who wore a device that measures body temperature, and also self-reported their body temperatures and depression symptoms daily. The seven-month study began in early 2020 and included data from 106 countries.
The results showed that with each increasing level of depression symptom severity, participants had higher body temperatures. The body temperature data also showed a trend toward higher depression scores in people whose temperatures had less fluctuation throughout a 24-hour period, but this finding didn’t reach significance.
The findings shed light on how a novel depression treatment method might work, said Ashley Mason, PhD, the study’s lead author and associate professor of psychiatry at UCSF Weill Institute for Neurosciences. A small body of existing, causal studies has found that using hot tubs or saunas can reduce depression, possibly by triggering the body to self-cool, for example, through sweating.
“Ironically, heating people up actually can lead to rebound body temperature lowering that lasts longer than simply cooling people down directly, as through an ice bath,” said Mason, who is also a clinical psychologist at the UCSF Osher Center for Integrative Health. “What if we can track the body temperature of people with depression to time heat-based treatments well?”
“To our knowledge, this is the largest study to date to examine the association between body temperature — assessed using both self-report methods and wearable sensors — and depressive symptoms in a geographically broad sample,” added Mason. “Given the climbing rates of depression in the United States, we’re excited by the possibilities of a new avenue for treatment.”