New regimens in development, including once-weekly pills and semiannual shots, could help control the virus in hard-to-reach populations.A pill taken once a week. A shot administered at home once a month. Even a jab given at a clinic every six months.In the next five to 10 years, these options may be available to prevent or treat H.I.V. Instead of drugs that must be taken daily, scientists are closing in on longer-acting alternatives — perhaps even a future in which H.I.V. may require attention just twice a year, inconceivable in the darkest decades of the epidemic.“This period is the next wave of innovation, newer products meeting the needs of people, particularly in prevention, in ways that we didn’t ever have before,” said Mitchell Warren, executive director of the H.I.V. prevention organization AVAC.Long-acting therapies may obviate the need to remember to take a daily pill to prevent or treat H.I.V. And for some patients, the new drugs may ease the stigma of the disease, itself an obstacle to treatment.“To not have to remember that every morning is earth-changing for them,” said Dr. Rachel Bender Ignacio, an infectious diseases physician and researcher at the Fred Hutch Cancer Center in Seattle. “That stigma, that internalized stigma of taking that pill every morning, is what prevents them from taking it.”Dr. Rachel Bender Ignacio, principal investigator for University of Washington’s UW Positive, a clinical research site focusing on H.I.V.Grant Hindsley for The New York TimesWe 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.

Cedars-Sinai investigators have discovered how brain cells responsible for working memory — the type required to remember a phone number long enough to dial it — coordinate intentional focus and short-term storage of information.
The study detailing their discovery was published in the peer-reviewed journal Nature.
“We have identified for the first time a group of neurons, influenced by two types of brain waves, that coordinate cognitive control and the storage of sensory information in working memory,” said Jonathan Daume, PhD, a postdoctoral scholar in the Rutishauser Lab at Cedars-Sinai and first author of the study. “These neurons don’t contain or store information, but are crucial to the storage of short-term memories.”
Working memory, which requires the brain to store information for only seconds, is fragile and requires continued focus to be maintained, said Ueli Rutishauser, PhD, director of the Center for Neural Science and Medicine at Cedars-Sinai and senior author of the study. It can be affected by different diseases and conditions.
“In disorders such as Alzheimer’s disease or attention-deficit hyperactivity disorder, it is often not memory storage, but rather the ability to focus on and retain a memory once it is formed that is the problem,” said Rutishauser, who is a professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai. “We believe that understanding the control aspect of working memory will be fundamental for developing new treatments for these and other neurological conditions.”
To explore how working memory functions, investigators recorded the brain activity of 36 hospitalized patients who had electrodes surgically implanted in their brains as part of a procedure to diagnose epilepsy. The team recorded the activity of individual brain cells and brain waves while the patients performed a task that required use of working memory.
On a computer screen, patients were shown either a single photo or a series of three photos of various people, animals, objects or landscapes. Next, the screen went blank for just under three seconds, requiring patients to remember the photos they just saw. They were then shown another photo and asked to decide whether it was the one (or one of the three) they had seen before.

When patients performing the working memory task were able to respond quickly and accurately, investigators noted the firing of two groups of neurons: “category” neurons that fire in response to one of the categories shown in the photos, such as animals, and “phase-amplitude coupling,” or PAC, neurons.
PAC neurons, newly identified in this study, don’t hold any content, but use a process called phase-amplitude coupling to ensure the category neurons focus and store the content they have acquired. PAC neurons fire in time with the brain’s theta waves, which are associated with focus and control, as well as to gamma waves, which are linked to information processing. This allows them to coordinate their activity with category neurons, which also fire in time to the brain’s gamma waves, enhancing patients’ ability to recall information stored in working memory.
“Imagine when the patient sees a photo of a dog, their category neurons start firing ‘dog, dog, dog’ while the PAC neurons are firing ‘focus/remember,'” Rutishauser said. “Through phase-amplitude coupling, the two groups of neurons create a harmony superimposing their messages, resulting in ‘remember dog.’ It is a situation where the whole is greater than the sum of its parts, like hearing the musicians in an orchestra play together. The conductor, much like the PAC neurons, coordinates the various players to act in harmony.”
PAC neurons do this work in the hippocampus, a part of the brain that has long been known to be important for long-term memory. This study offers the first confirmation that the hippocampus also plays a role in controlling working memory, Rutishauser said.
This study was conducted as part of a multi-institutional consortium funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, or The BRAIN Initiative, and led by Cedars-Sinai. The data in this study is pooled across Cedars-Sinai, the University of Toronto, and the Johns Hopkins School of Medicine, resulting in a statistically powerful study that a single institution could not accumulate on its own given the difficulty of these experiments.
“One of the aims of the BRAIN Initiative is to uncover — through the use of innovative technologies — properties of the human brain that have so far been difficult, if not impossible, to study” said Dr. John Ngai, PhD, director of the NIH BRAIN Initiative. “Here, by leveraging unusual opportunities supported by the initiative to illuminate complex processes in humans, the Rutishauser Lab is shedding light on the way certain neurons support how memories are stored in the brain — a process that is far from understood in devastating brain disorders such as Alzheimer’s disease and other dementias.”

Humans, Homo sapiens, have unique features compared with other closely related hominin species and primates, including the shape of the base of the skull. The evolutionary changes underlying these features were significant in allowing the evolution of our increased brain size. Now, in a study recently published in the American Journal of Human Genetics, a team from Tokyo Medical and Dental University (TMDU), the University of Helsinki, and the University of Barcelona has analyzed a genomic variant responsible for this unique human skull base morphology.
Most of the genomic changes that occurred during human evolution did not occur directly to genes themselves, but in regions responsible for controlling and regulating the expression of genes. Variants in these same regions are often involved in genetic conditions, causing aberrant gene expression throughout development. Identifying and characterizing such genomic changes is therefore crucial for understanding human development and disease.
The development of the basicranial region, the base of the skull where it joins the bones of the neck, was key in the evolution of Homo sapiens, as we developed a highly flexed skull base that allowed our increased brain size. Therefore, variants that affect the development of this region are likely to have been highly significant in our evolution.
First, the team searched for variants in just a single letter of the DNA code, called single nucleotide polymorphisms (SNPs), that caused different regulation of genes in the basicranial region in Homo sapiens compared with other extinct hominins. One of these SNPs stood out, located in a gene called TBX1.
They then used cell lines to show that the SNP, called “rs41298798,” is located in a region that regulates the expression levels of the TBX1 gene, and that the “ancestral” form of the SNP, found in extinct hominins, is associated with lower TBX1 expression, while the form found in Homo sapiens gives us higher levels of TBX1.
“We then employed a mouse model with lower TBX1 expression,” explains lead author Noriko Funato, “which resulted in distinct alterations to the morphology at the base of the skull and premature hardening of a cartilage joint where the bones fuse together, restricting the growth ability of the skull.” The changes in the Tbx1-knockout mice were reminiscent of the known basicranial morphology of Neanderthals.
These morphological changes are also reflected in human genetic conditions associated with lower TBX1 gene dosage, such as DiGeorge syndrome and velocardiofacial syndrome, further indicating the significance of this genetic variant in the evolution of our unique skull base morphology.
The identification of this genomic variant sheds light on human evolution, as well as providing insight into common genetic conditions associated with lower expression of the TBX1 gene, paving the way for greater understanding and management of these conditions.

Almost 1 in 5 adults with congenital heart disease living in Israel had or developed an abnormal heart rhythm/arrhythmia during a five-year study, according to new research published today in the Journal of the American Heart Association, an open access, peer-reviewed journal of the American Heart Association.
The study of more than 11,000 adults with congenital heart disease between 2007 and 2011 found that those who developed forms of abnormal heart rhythms had an increased risk for hospitalization and twice the risk of early death compared to study participants who did not have an irregular heart rhythm.
“Our findings highlight the need for ongoing, lifelong, clinical follow-up for people with congenital heart disease,” said lead study author Nili Schamroth-Pravda, MBBCh, a cardiologist at the Rabin Medical Center in Petah Tikva, Israel. “With the improvement of medical and surgical techniques, the number of patients with congenital heart disease reaching adulthood is increasing, as well as the complications associated with these heart conditions.
“The health care system should be aware of the unfavorable effects of arrhythmias in this increasing population and the consequent increase in both primary care visits and hospitalizations,” Schamroth-Pravda said.
The analysis found: Almost 20% of adults with congenital heart disease had irregular heart rhythms at the study’s start or developed them over five years. Adults with congenital heart disease who developed a fast heart rate originating in the heart’s upper chambers — atrial tachyarrhythmia — faced a 65% increased risk of dying earlier compared with those who did not have an irregular heartbeat. Those who developed a fast heart rate caused by rapid contracting of the heart’s lower chambers — ventricular tachyarrhythmia — faced a twofold increase of dying earlier compared with those who did not have an irregular heartbeat. Patients who experienced abnormal heart rhythms (atrial arrythmia, ventricular arrythmia or atrioventricular block — a slowed heartbeat) within the previous six months had up to a 33% higher rate of hospitalization compared to those without an abnormal heart rhythm.Researchers note that surgical scar tissue in the heart, even years after repairing a congenital heart defect, may increase the risk for abnormal heart rhythms later in life. The challenge to clinicians is to achieve early detection and early management of arrhythmias that could pose life-threatening health risks. Learning more about the frequency of these different types of arrhythmias and how they progress among adults with congenital heart disease can help improve treatment for these patients and prevent complications and hospitalizations.
The study is among the first to analyze health care use in association with arrhythmias among adults with congenital heart disease.

“Our study suggests that the development of arrythmias is a critical point in the life of adult patients with congenital heart disease and this has a profound impact on the health care system providing care for these patients,” Schamroth-Pravda said.
“Our study is from large, real-world data and gives insights into a population that is under-studied,” she said. “Congenital heart disease can be varied with people having simple or complex heart lesions, however, they all carry some risk of an abnormal heart rhythm in later life and should be assessed individually and monitored on a regular basis.”
According to the 2024 Heart Disease and Stroke Statistics: A Report of U.S. and Global Data From the American Heart Association, an estimated 13.3 million people globally were living with congenital heart diseases in 2019. Occurrences increased by 28% between 1990 and 2019, driven largely by increases in the number of adolescents, younger adults and middle-aged adults living with congenital heart diseases.
Study background and details: The study included 11,653 adults with a diagnosis of congenital heart disease living in Israel between January 2007 and December 2011 and followed for 5 years. Citizens of Israel have universal health insurance, and this data was taken from the two largest national health services. The average age of participants at the start of the study period was 47 years; 52% were women; 70% were Jewish, about 7% were Arab and 23% were noted as “mixed.” “Mixed” referred to the group in which the locality of where the patients lived could not clarify the patient’s ethnicity since there are regions in Israel with mixed Jewish/Arab residents. The analysis of the data was conducted in 2023. Most study participants had a single heart defect, and all had at least one documented congenital heart lesion or a specific congenital heart malformation repair procedure. At least 18 distinct types of congenital heart defects — some are simple and some are complex — are recognized according to the American Heart Association. Thirty percent of adults in this study had an atrial septal defect; 26% had aortic valve disease; and 14% had a ventricular septal defect. A total of 8.7% of patients were diagnosed with tachyarrhythmia (abnormally fast heart rate), at the start of the study; 1.5% had a conduction disturbance, which is the slowing or abnormal conduction of electrical signals in the heart; and 0.5% had both conditions. Among the subgroup with tachyarrhythmia 60% had abnormally fast heart rates in the upper atrial regions of the heart and 5.7% had abnormally fast heart rates in the lower ventricular regions of the heart. Patients without arrhythmia at baseline were younger, with a median age of 45 years compared to patients with arrhythmia having a median age of 50 years.One of the limitations of the findings is that it is based solely on patients in Israel. How these findings might translate to adults with congenital heart disease in the United States or elsewhere is unclear.

Researchers have used artificial intelligence techniques to massively accelerate the search for Parkinson’s disease treatments.
The researchers, from the University of Cambridge, designed and used an AI-based strategy to identify compounds that block the clumping, or aggregation, of alpha-synuclein, the protein that characterises Parkinson’s.
The team used machine learning techniques to quickly screen a chemical library containing millions of entries, and identified five highly potent compounds for further investigation.
Parkinson’s affects more than six million people worldwide, with that number projected to triple by 2040. No disease-modifying treatments for the condition are currently available. The process of screening large chemical libraries for drug candidates — which needs to happen well before potential treatments can be tested on patients — is enormously time-consuming and expensive, and often unsuccessful.
Using machine learning, the researchers were able to speed up the initial screening process by ten-fold, and reduce the cost by a thousand-fold, which could mean that potential treatments for Parkinson’s reach patients much faster. The results are reported in the journal Nature Chemical Biology.
Parkinson’s is the fastest-growing neurological condition worldwide. In the UK, one in 37 people alive today will be diagnosed with Parkinson’s in their lifetime. In addition to motor symptoms, Parkinson’s can also affect the gastrointestinal system, nervous system, sleeping patterns, mood and cognition, and can contribute to a reduced quality of life and significant disability.
Proteins are responsible for important cell processes, but when people have Parkinson’s, these proteins go rogue and cause the death of nerve cells. When proteins misfold, they can form abnormal clusters called Lewy bodies, which build up within brain cells stopping them from functioning properly.

“One route to search for potential treatments for Parkinson’s requires the identification of small molecules that can inhibit the aggregation of alpha-synuclein, which is a protein closely associated with the disease,” said Professor Michele Vendruscolo from the Yusuf Hamied Department of Chemistry, who led the research. “But this is an extremely time-consuming process — just identifying a lead candidate for further testing can take months or even years.”
While there are currently clinical trials for Parkinson’s currently underway, no disease-modifying drug has been approved, reflecting the inability to directly target the molecular species that cause the disease.
This has been a major obstacle in Parkinson’s research, because of the lack of methods to identify the correct molecular targets and engage with them. This technological gap has severely hampered the development of effective treatments.
The Cambridge team developed a machine learning method in which chemical libraries containing millions of compounds are screened to identify small molecules that bind to the amyloid aggregates and block their proliferation.
A small number of top-ranking compounds were then tested experimentally to select the most potent inhibitors of aggregation. The information gained from these experimental assays was fed back into the machine learning model in an iterative manner, so that after few iterations, highly potent compounds were identified.
“Instead of screening experimentally, we screen computationally,” said Vendruscolo, who is co-Director of the Centre for Misfolding Diseases. “By using the knowledge we gained from the initial screening with our machine learning model, we were able to train the model to identify the specific regions on these small molecules responsible for binding, then we can re-screen and find more potent molecules.”
Using this method, the Cambridge team developed compounds to target pockets on the surfaces of the aggregates, which are responsible for the exponential proliferation of the aggregates themselves. These compounds are hundreds of times more potent, and far cheaper to develop, than previously reported ones.
“Machine learning is having a real impact on the drug discovery process — it’s speeding up the whole process of identifying the most promising candidates,” said Vendruscolo. “For us this means we can start work on multiple drug discovery programmes — instead of just one. So much is possible due to the massive reduction in both time and cost — it’s an exciting time.”
The research was conducted in the Chemistry of Health Laboratory in Cambridge, which was established with the support of the UK Research Partnership Investment Fund (UKRPIF) to promote the translation of academic research into clinical programmes.

Researchers at Weill Cornell Medicine have developed a powerful, new technique to generate “movies” of changing protein structures and speeds of up to 50 frames per second.
Senior author, Dr. Simon Scheuring, the Distinguished Professor of Anesthesiology Research at Weill Cornell Medicine and colleagues developed the new approach to gain a better understanding of how biological molecules change structurally over time. Although investigators in this field routinely image static proteins and other molecules finely enough to resolve the positions of individual atoms, the resulting structural pictures or models are snapshots. Recording the dynamics of molecular structures — making movies — has been a much harder challenge. The lead author of the study is Yining Jiang, a doctoral candidate in the Weill Cornell Graduate School of Biomedical Sciences.
In their study, published April 17 in Nature Structural & Molecular Biology, the researchers used a relatively new measurement technique called high-speed atomic-force microscopy (HS-AFM), which employs an extremely sensitive probe to scan across molecules’ surfaces, essentially feeling their structures. As a key innovation, the scientists found a method to isolate their target molecule, a single protein, thus avoiding effects from protein-to-protein interactions and enabling faster and more precise scanning.
The researchers applied their new single-molecule HS-AFM approach to a protein called GltPh, a “transporter” that sits in the cell membrane, directing neurotransmitter molecules into the cell. Such transporters are among the favorite targets of structural biologists due to their complex and puzzling dynamics, and their importance in health and disease.
The researchers obtained dynamic structural data on GltPh with an unprecedented combination of high spatial and time resolution — and stability, so that they could record tiny fluctuations in GltPh’s structure continuously for minutes. An unsolved phenomenon in such proteins was termed ‘wanderlust’ kinetics, meaning that molecules were reported to functionally change between high and low activity modes, for no obvious reason. The work revealed a previously unseen structural state of GltPh, in which the transporter is locked and functionally asleep, uncovering the basis of ‘wanderlust’ kinetics.
The researchers emphasized that their new approach, which they are continually trying to optimize, is generalizable for studying other proteins, including membrane-embedded proteins. Overall, they said, this work opens up new possibilities to track the precise structure of a protein moment-by-moment during its cycles of activity and rest.
This research was supported by the National Institute of Health (NIH), National Center for Complementary and Integrative Health, grant DP1AT010874, and the National Institute of Neurological Disorders and Stroke, R01NS110790.

New research, published in Nature Communications, finds that the macronutrient balance in the diet of male mice affects the level of anxiety-like behaviour of sons and the metabolic health of daughters.
The research provides a step towards understanding how the effect of diet can transmit from one generation to the next via a father’s sperm. It could ultimately inform dietary guidelines for fathers-to-be, with the goal of lowering the risk of metabolic disease and mood disorders in the next generation.
Parents like to believe they can shape the interests and behaviour of their children, with mixed success. But a new study from an international team of researchers confirms this is the case for mice, with father’s shaping their offspring’s health through their own diet.
Scientists have already discovered that a mouse father’s diet can have an impact not only on his own reproductive health but on that of his offspring. Over- or under-feeding male mice can affect their offspring’s metabolism and behaviour, as well as their risk of cancer. What is less understood is whether there are diverse types of health impacts on the health of offspring, depending on the type and composition of the diet of male mice before conception.
This was the starting point for the research by scientists in the international GECKO consortium, with lead investigators in Copenhagen, Sydney, and Chicago.
At the University of Sydney’s Charles Perkins Centre in Australia researchers fed male mice one of ten diets differing in the proportions of protein, fats, and carbohydrates, then allowed them to mate with females reared on standard diet. The behaviour and physiology of the resulting pups were then studied.
Dietary composition as important as number of calories
The scientists discovered that male mice fed low protein and high carbohydrate diets were more likely to have male offspring with higher levels of anxiety, as measured by time spent in the safety zones of their maze. They also found that male mice that were fed high fat diets were more likely to have daughters with higher levels of body fat and markers of metabolic disease.

“Our study shows that the type of diet eaten before conception can program specific characteristics of the next generation,” says co-senior author and leader of the GECKO consortium Professor Romain Barrès, from the University of Copenhagen and Université Côte d’Azur, Nice.
“It is extraordinary that by titrating mixtures of protein, fat and carbs in the father’s diet we could influence specific features of his sons and daughters health and behaviour. There is some important biology at play here,” said Professor Stephen Simpson, co-senior author and Academic Director of the Charles Perkins Centre at the University of Sydney.
The team also observed that males on a low protein diet also ate more food overall. However, thanks to the study design, they could determine that both the amount of calories, and the macronutrient composition of the males’ diets, influenced the health of their offspring.
“Our study shows that it’s not just eating too much or too little, but the composition of the diet that can have an impact on future children,” says Professor Romain Barrès.
The work was conducted in mice and has opened the way for the team to study the molecular mechanisms involved. The mouse work is part of a broader series of studies within the GECKO consortium, involving humans and other mammals at partner institutions.
“We think our study is a step towards establishing dietary guidelines for fathers to be, with the ultimate goal of lowering the risk of metabolic disease and mood disorders in the next generation,” says Professor Romain Barrès.

More than five million central lines are placed in patients who need prolonged drug delivery, such as those undergoing cancer treatments, in the United States every year, yet the common procedure can lead to a bevy of complications in almost a million of those cases. To help decrease the rate of infections, blood clots and other complications associated with placing a central line catheter, Penn State researchers developed an online curriculum coupled with a hands-on simulation training to provide trainee physicians with more practice.
Deployed in 2022 at the Penn State College of Medicine, the researchers recently assessed how the training impacted the prevalence of central line complications by comparing error rates from 2022-23, when the training had been fully implemented, to two prior years, 2016-17 and 2017-18, from before implementing the training. They found that all complication types — mechanical issues, infections and blood clots — were significantly lower after the training was launched.
They published their results in the Journal of Surgical Education. The researchers hold patents on the technology used in this work. In addition to working to improve the central line placement training, the team is also applying the framework to other common procedures with high complication rates, such as colonoscopies and laparoscopic surgeries.
“Our approach is focused on reducing preventable errors — this paper is the first significant clinical evidence that we are moving the needle on the gap in clinical education and clinical practice,” said Scarlett Miller, professor of industrial engineering and of mechanical engineering at Penn State and principal investigator on the project. “If we ensure physicians going through residency training are proficient in a skill, like placing central lines, we can minimize the risk on human life.”
Traditional training for placing a central line and other routine surgical procedures starts with a resident watching a more senior doctor complete the process. Then, the resident is expected to do the procedure themselves, and, finally, they teach someone else to do the procedure.
“The problem with that approach is that there are very few checks in the process, and the resident only improves by working with patients — who are at risk of complications,” Miller said. “The simulation approach allows someone to try the procedure hundreds, thousands of times without putting anyone at risk.”
The new approach — the result of interdisciplinary work between engineers and clinicians, Miller said — uses online- and simulation-based training to perform standardized ultrasound-guided internal jugular central venous catheterization (US-IJCVC), which is a central line placed into the internal jugular vein via the neck.

Residents first complete online training, which includes pre- and post-tests to evaluate knowledge gained. They then take that knowledge and apply in a skills lab, where they practice placing the central line on a novel dynamic haptic robotic trainer that can simulate various conditions and reactions. Residents can use ultrasound to image the line placement, like they would on a real person, on the robotic trainer, which offers automated feedback.
“We started with 25 surgical residents at the Penn State Health Milton S. Hershey Medical Center, then expanded to all of the residents at Hershey and partnered with Cedars-Sinai Medical Center in Los Angeles to bring the training to their residents,” Miller said. “In total, we have trained about 700 physicians to date, and we train about 200 a year with our current funding.”
It seems practice may get physicians closer to perfect, without the risk to human life, according to Miller. In this study, Miller and her team compared error rates from 2022, the first year the simulation training was fully deployed, to error rates from 2016 and 2017, when the training was not yet established. They did not use data from 2018-21, as the training was partially implemented but undergoing startup adjustments and challenges related to COVID that could not be controlled for a direct comparison. The researchers found that the range of reported error rates for mechanical complications — such as puncturing an artery or misplacing the catheter — increased from 10.4% in 2016 to 12.4% in 2017 but dropped to 7.3% in 2022. The same trend continued for error rates related to infections, with the 6.6% rate in 2016 increasing to 7.6% in 2017 and dropping to 4.1% in 2022. For blood clots, the error rates decreased from 12.3% in 2016 to 11.4% in 2017 to 8.1% in 2022.
“We’re very motivated by the results to improve the system and hopefully expand it to other hospitals,” Miller said. “We’re reducing the error rates in a significant way, but we want more. We want zero errors.”
Miller is also affiliated with the School of Engineering Design in the Penn State College of Engineering, the College of Information Sciences and Technology and the Department of Surgery in the Penn State College of Medicine. Paper co-authors include Jessica M. Gonzalez-Vargas, postdoctoral scholar in industrial engineering at Penn State; Elizabeth Sinz, associate medical director of the West Virginia University Critical Care and Trauma Institute; and Jason Moore, professor of mechanical engineering at Penn State.
The U.S. National Science Foundation and the National Institutes of Health’s National Heart, Lung, and Blood Institute supported this work.

The author of the best-selling book series said she had been undergoing treatment for glioblastoma, an aggressive brain tumor, after a diagnosis in 2022.Sophie Kinsella, the best-selling English author of the “Shopaholic” book series, revealed on social media on Wednesday that she had been undergoing treatment for an aggressive and often fatal form of brain cancer.Kinsella said that she had been diagnosed with glioblastoma in 2022, but waited to make the diagnosis public so her children could “ hear and process the news privately and adapt to our ‘new normal.’” She added that her condition was stable after a successful operation and ongoing chemotherapy and radiation at University College Hospital in London.Kinsella, whose real name is Madeleine Wickham, has written a string of hit novels, starting with “Confessions of a Shopaholic” in 2000, about a financial journalist in New York City with a serious shopping addiction. About a decade later, a movie starring Isla Fisher based on the original novel and a sequel was released.Since the smashing success of the first novel, nine sequels following the life of the protagonist Rebecca Bloomwood have been released, earning Kinsella, 54, a loyal following and a reigning position among authors of romantic comedy books.Kinsella said that readers’ response to her latest novel, “The Burnout,” had “buoyed” her during a difficult time undergoing treatment. The novel, about a couple of worn-out office workers who meet at a dilapidated British seaside resort, was published last year.Glioblastoma is an extremely aggressive brain tumor. There is no cure, and most patients do not survive beyond one and a half to two years. “It’s such a terrible, devastating disease,” said Dr. Wajd Al-Holou, a neurosurgeon at University of Michigan Health. The condition is relatively rare; the National Brain Tumor Society estimated that more than 14,490 Americans were expected to receive a glioblastoma diagnosis in 2023.Doctors typically try to remove as much of the tumor as possible in surgery, and patients also receive chemotherapy and radiation to try to slow the growth of the cancer. The tumor often grows back.Glioblastoma most frequently occurs among people between the ages of 50 and 70, Dr. Al-Holou said, and is more common in men than women, for reasons doctors do not fully understand. Doctors are also not certain what causes gliobastoma.“It’s completely random, it’s out of nowhere,” said Dr. Viviane Tabar, chair of the department of neurosurgery at Memorial Sloan Kettering Cancer Center.Symptoms can develop rapidly and vary depending on where in the brain the tumor is located. People can experience headaches that become more severe over a short period, blurred vision, weakness in an arm or leg, difficulty speaking, memory loss, nausea and vomiting and seizures. Sometimes, people’s personalities seem to change, Dr. Al-Holou said.Kinsella’s longtime publisher, The Dial Press, an imprint of Random House Books, did not immediately respond to a request for comment.

Researchers at the University of Toronto have discovered a DNA repair mechanism that advances understanding of how human cells stay healthy, and which could lead to new treatments for cancer and premature aging.
The study, published in the journal Nature Structural and Molecular Biology, also sheds light on the mechanism of action of some existing chemotherapy drugs.
“We think this research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells,” said Professor Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology at U of T’s Temerty Faculty of Medicine.
“It also makes many previously published discoveries in other organisms applicable in the context of human DNA repair, which should help science move even faster.”
DNA double-strand breaks arise when cells are exposed to radiation and chemicals, and through internal processes such as DNA replication. They are one of the most serious types of DNA damage because they can stall cell growth or put it in overdrive, promoting aging and cancer.
The new discovery, made in human cells and in collaboration with Professor Razqallah Hakem, a researcher at University Health Network and professor at Temerty Medicine, extends prior research on DNA damage in yeast by Mekhail and other scientists.
In 2015, Mekhail and collaborators showed how motor proteins deep inside the nucleus of yeast cells transport double-strand breaks to ‘DNA hospital-like’ protein complexes embedded in the nuclear envelope at the edge of the nucleus.

Other studies uncovered related mechanisms during DNA repair in flies and other organisms. However, scientists exploring similar mechanisms in human and other mammalian cells reported little to no DNA mobility for most breaks.
“We knew that nuclear envelope proteins were important for DNA repair across most of these organisms, so we wondered how to explain the limited mobility of damaged DNA in mammalian cells,” Mekhail says.
The answer is both surprising and elegant.
When DNA inside the nucleus of a human cell is damaged, a specific network of microtubule filaments forms in the cytoplasm around the nucleus and pushes on the nuclear envelope. This prompts the formation of tiny tubes, or tubules, which reach into the nucleus and catch most double-strand breaks.
“It’s like fingers pushing on a balloon,” says Mekhail. “When you squeeze a balloon, your fingers form tunnels in its structure, which forces some parts of the balloon’s exterior inside itself.”
Further research by the study authors detailed several aspects of this process. Enzymes called DNA damage response kinases and tubulin acetyltransferase are the master regulators of the process, and promote the formation of the tubules.

Enzymes deposit a chemical mark on a specific part of the microtubule filaments, which causes them to recruit tiny motor proteins and push on the nuclear envelope. Consequently, the repair-promoting protein complexes push the envelope deep into the nucleus, creating bridges to the DNA breaks.
“This ensures that the nucleus undergoes a form of reversible metamorphosis, allowing the envelope to temporarily infiltrate DNA throughout the nucleus, capturing and reconnecting broken DNA,” says Mekhail.
The findings have significant implications for some cancer treatments.
Normal cells use the nuclear envelope tubules to repair DNA, but cancer cells appear to need them more. To explore the mechanism’s potential impact, the team analyzed data representing over 8,500 patients with various cancers. The need was visible in several cancers, including triple-negative breast cancer, which is highly aggressive.
“There is a huge effort to identify new therapeutic avenues for cancer patients, and this discovery is a big step forward,” says Hakem, a senior scientist at UHN’s Princess Margaret Cancer Centre and a professor in U of T’s department of medical biophysics and department of laboratory medicine and pathobiology.
“Until now, scientists were unclear as to the relative impact of the nuclear envelope in the repair of damaged DNA in human cells. Our collaboration revealed that targeting factors that modulate the nuclear envelope for damaged DNA repair effectively restrains breast cancer development,” Hakem says.
In the aggressive triple negative breast cancer, there are elevated levels of the tubules, likely because they have more DNA damage than normal cells. When the researchers knocked out the genes needed to control the tubules, cancer cells were less able to form tumours.
One medication used to treat triple negative breast cancer is a class of drugs called PARP inhibitors. PARP is an enzyme that binds to and helps repair damaged DNA. PARP inhibitors block the enzyme from performing repair, preventing the ends of a DNA double-strand break in cancer cells from reconnecting to one another.
The cancer cells end up joining two broken ends that are not part of the same pair. As more mismatched pairs are created, the resulting DNA structures become impossible for cells to copy and divide.
“Our study shows that the drug’s ability to trigger these mismatches relies on the tubules. When fewer tubules are present, cancer cells are more resistant to PARP inhibitors,” says Hakem.
Partnerships among researchers in distinct fields was essential for the findings in cancer cells. The study underscores the importance of cross-disciplinary collaboration, Mekhail says.
“The brain power behind every project is crucial. Every team member counts. Also, every right collaborator added to the research project is akin to earning another doctorate in a new specialty; it’s powerful,” he says.
Mekhail notes the discovery is also relevant to premature aging conditions like progeria. The rare genetic condition causes rapid aging within the first two decades of life, commonly leading to early death.
Progeria is linked to a gene coding for lamin A. Mutations in this gene reduce the rigidity of the nuclear envelope. The team found that expression of mutant lamin A is sufficient to induce the tubules, which DNA damaging agents further boosted. The team thinks that even weak pressure on the nuclear envelope spurs the creation of tubules in premature aging cells.
The findings suggest that in progeria, DNA repair may be compromised by the presence of too many or poorly regulated tubules. The study results also have implications for many other clinical conditions, Mekhail says.
“It’s exciting to think about where these findings will lead us next,” says Mekhail. “We have excellent colleagues and incredible trainees here at Temerty Medicine and in our partner hospitals. We’re already working toward following this discovery and using our work to create novel therapeutics.”