Publisher Health

When it comes to the architecture of the human genome, it’s only a matter of time before harmful genes — genes that could compromise future generations — arise in a population. These mutations accumulate in the gene pool, primarily affected by a population’s size and practices like marrying within a small community, according to researchers.
But much of the information about the effects of a population’s mutation load is based on genetic theory, with limited direct evidence concerning the effects on evolutionary fitness, or fertility.
New research from University of California, Davis, provides rare direct evidence showing that increased homozygosity — meaning two identical alleles in a genome — leads to negative effects on fertility in a human population. The paper was published Oct. 17 in the Proceedings of the National Academy of Sciences journal.
“People have known since Darwin that if you take people who are first cousins and they have children together, the children are more likely to develop certain diseases or be less healthy,” said Brenna Henn, an associate professor of anthropology in the College of Letters and Science at UC Davis.
The research assesses the consequences of homozygosity among Namibia’s Himba community, an isolated, agro-pastoralist population in which marriage between people with the same ancestor occurs. The research was led by Natalie Swinford, who received her doctoral degree in 2022 in evolutionary anthropology and human population genetics, and Henn.
“They’re what we call an ‘endogamous population,’ meaning people are meeting their partners just from within that Himba group,” said Henn. “They also have a unique system of marriage and reproduction, where men and women can have multiple boyfriends or girlfriends during their marriage. That means there are a lot of half-siblings in the population. That’s a unique feature and it means that we can leverage that social structure to look at different genetic effects.”
Echoes in the genome
In the study, the team gathered genetic data from 681 individuals from the Himba population. Genetic analyses revealed that the Himba have genetic markers that show higher levels of inbreeding.

People who have experienced traumatic events in childhood such as abuse, neglect or household dysfunction may be more likely to experience headache disorders as adults, according to a meta-analysis published in the October 25, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology. This research does not prove that such experiences cause headaches; it only shows an association.
“Traumatic events in childhood can have serious health implications later in life,” said study author Catherine Kreatsoulas, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts. “Our meta-analysis confirms that childhood traumatic events are important risk factors for headache disorders in adulthood, including migraine, tension headaches, cluster headaches, and chronic or severe headaches. This is a risk factor that we cannot ignore.”
The meta-analysis involved 28 studies, including 154,739 participants across 19 countries.
Of the total participants, 48,625 people, or 31%, reported at least one traumatic childhood event, and 24,956 people, or 16%, were diagnosed with primary headaches. Among participants with at least one traumatic childhood event, 26% were diagnosed with a primary headache disorder, compared to 12% of participants that had no traumatic childhood events.
Researchers found that people who had experienced one or more traumatic childhood events were 48% more likely to have headache disorders than those who had not experienced such traumatic events.
They also found that as the number of traumatic childhood events increased, the odds of having headaches also increased. When compared to people who have not experienced childhood trauma, people who had experienced one type of traumatic event had a 24% increased risk of a headache disorder, while people who had experienced four or more types of traumatic events were more than twice as likely to have a headache disorder.
Researchers also looked at the association between types of traumatic childhood events. Events categorized as threat traumas included physical abuse, sexual abuse, emotional abuse, witnessing and/or threat of violence, or serious family conflicts. Events categorized as deprivation traumas included neglect, economic adversities, having an incarcerated household member, divorce or separation, parental death, and living in a household with mental illness, chronic disability or disease, or alcohol or substance abuse.
They found that threat traumas were linked to a 46% increase in headaches and deprivation traumas were linked to a 35% increase in headaches. Among the top types of threat traumas, experiencing physical and sexual abuse was linked to a 60% increased risk for headaches; among deprivation traumas, those who experienced neglect in childhood had an almost three-fold increased risk for headache disorders.
“This meta-analysis highlights that childhood traumatic events categorized as threat or deprivation traumas are important and independent risk factors for headache disorders in adulthood,” said Kreatsoulas. “Identifying the specific types of childhood experiences may help guide prevention and treatment strategies for one of the leading disabling disorders worldwide. A comprehensive public health plan and clinical intervention strategies are needed to address these underlying traumatic childhood events.”
“It is important to note that the true estimate of the association is likely higher due to the sensitive nature of reporting childhood traumatic events,” Kreatsoulas added.

Atrial fibrillation (AF) diagnosis was associated with a 45% increased risk of mild cognitive impairment (MCI) among a cohort of 4.3 million individuals in the UK, according to a new study published in JACC: Advances. These findings suggest that cardiovascular risk factors and multiple comorbidities could further the progression from MCI to dementia in this cohort.
MCI is an early stage of cognitive function decline. In some cases it can be reversed, but it can indicate development of early dementia-associated disease. There has not been sufficient research on the development of MCI in AF patients and the subsequent development of dementia, so the authors of this study sought to investigate the association between MCI and AF diagnosis in the UK.
“Our study showed that AF was associated with a 45% increase in the risk of MCI, and that cardiovascular risk factors and multi-comorbidity appear to associate with this outcome,” said Rui Providencia, MD, PhD, Full Professor at the Institute of Health informatics Research at University College London and the study’s senior author.
The researchers used the UK primary electronic health record (EHR) data of 4.3 million individuals to investigate the risk of MCI after AF diagnosis, identifying 233,833 individuals with incident AF and 233,747 without AF.
In addition to the 45% increased risk of MCI after AF diagnosis, the study found that older age, female sex, higher socioeconomic deprivation, clinical history of depression, stroke and multimorbidity were associated with a higher MCI risk. However, these factors did not modify the link between AF and MCI. For individuals over 74 years old, AF and MCI were frequently diagnosed when multi-comorbidity was detected, including diabetes, depression, hypercholesterolemia, and peripheral artery disease.
Patients with AF who were treated with digoxin did not experience an increased MCI risk. The risk of MCI was higher in patients with AF who did not receive oral anticoagulant treatment and amiodarone treatment. Similarly, patients with AF who received oral anticoagulant treatment and amiodarone treatment were not at risk of MCI.
During the study period, there were 1,117 individuals diagnosed with dementia on or after a diagnosis of MCI. AF was linked with a higher risk of dementia among those who had developed MCI. Sex, asthma, smoking, chronic kidney disease and multi-comorbidity were associated with an elevated subsequent dementia risk.
“Progression from MCI to dementia appears to be, at least partially, mediated by cardiovascular risk factors and the presence of multiple comorbidities,” Providencia said.
The researchers said these findings suggest that integrated AF care, such as combining anticoagulation and comorbidity-management, could help prevent cognitive deterioration and the progression to dementia. A confirmatory clinical trial is needed to explore this topic further.

People often experience headaches and body pain after a lack of sleep, but the mechanisms behind this phenomenon are unclear. A new study led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB) and published in Nature Communications reveals that a certain chemical messenger, or neurotransmitter, plays a major role.
Through experiments conducted in mice, the researchers found that the heightened pain sensitivity than can result from chronic sleep disruption (CSD) — or CSD-induced hyperalgesia — involved signaling from a part of a brain known as the thalamic reticular nucleus (TRN).
Analyses of metabolites showed that the level of N-arachidonoyl dopamine (NADA), a type of neurotransmitter called an endocannabinoid, decreased in the TRN as a result of sleep deprivation.
Activity of the cannabinoid receptor 1, which is involved in controlling pain perception, also decreased in the thalamic reticular nucleus after CSD.
Administering NADA to the TRN reduced CSD-induced hyperalgesia in mice.
This beneficial effect of administered NADA could be countered by blocking the cannabinoid receptor 1, suggesting that both the receptor and NADA play a role in pain sensitivity due to sleep deprivation.
“We provide a mechanism as to how sleep disruption leads to exaggerated pain, suggesting that harnessing the endocannabinoid system might break the vicious cycle between pain and sleep loss,” says co-senior author Shiqian Shen, MD, the clinical director of MGH’s Tele Pain Program.

University of Alberta researchers have developed a new statistical tool to evaluate the results of clinical trials, with the aim of allowing smaller trials to ask more complex research questions and get effective treatments to patients more quickly.
In their paper, the team reports on their new “Chauhan Weighted Trajectory Analysis,” which they developed to improve on the Kaplan-Meier estimator, the standard tool since 1959.
The Kaplan-Meier test limits researchers because it can only assess binary questions, such as whether patients survived or died on a treatment. It can’t include other factors such as adverse drug reactions or quality-of-life measures such as being able to walk or care for yourself. The new tool allows simultaneous evaluation and visualization of multiple outcomes in one graph.
“In general, diseases aren’t binary,” explains first author Karsh Chauhan, a fourth-year MD student at the U of A. “Now we can capture the severity of diseases — whether they make patients sick, whether they put them in hospital, whether they lead to death — and we can capture both the rise and the fall of how patients do on different treatments.”
John Mackey, a breast cancer medical oncologist and professor emeritus of oncology, added this tool allows researchers to do a smaller, less expensive, quicker trial with fewer patients, and get the overall benefit of a new treatment more rapidly out there in the world.
The two began working on the statistical tool three years ago when they were designing a clinical trial for a new device to prevent bedsores, which affect many patients with long-term illness. They wanted to look at how the severity of illness changed during treatment, but the Kaplan-Meier test wasn’t going to help.
“Dr. Mackey said to me, ‘If the tool doesn’t exist, then why don’t you build it yourself?’ That was very exciting,” says Chauhan, who also has a BSc in engineering physics, which he calls a degree in “problem-solving.”

Researchers report October 25 in the journal Neuron that cocaine addiction disrupts the dopamine neurons that govern how we perceive and learn from rewards. Though people with cocaine addiction have similar expectations of rewards compared to controls, their dopamine neurons send out much weaker signals when these rewards are actually received. This dysregulation could make it more difficult for people with cocaine addiction to learn from their experiences and change addictive behavior.
“Our results support the medical model of addiction as a disorder of the brain that deserves treatment,” says senior author Rita Goldstein, a neuroscientist and addiction expert at the Icahn School of Medicine at Mount Sinai. “Addiction is a disorder and not a choice or a moral weakness.”
“If you’re not tracking the reward signal appropriately, it makes it much harder to disengage from something that’s no longer rewarding,” says first author Anna Konova, a neuroscientist at Rutgers University.
It’s well documented from both animal and human studies that cocaine addiction impacts multiple aspects of dopamine signaling in the brain. However, it’s unclear whether certain parts of the dopamine signaling pathway are more important than others. Rather than general errors with dopamine signaling, addictive behavior is thought to be due to disruptions to the reward prediction error, a system that calibrates future expectations based on past experiences by comparing expected rewards to actual rewards as encoded by dopamine neurons in the midbrain. However, few studies have directly demonstrated the impact of cocaine use on reward prediction error in humans.
To examine the role of prediction error in cocaine addiction, the research team used fMRI scanning to examine neural activity in people with cocaine addiction compared to healthy controls while they were performing a simple decision-making task: choosing between a “safe” monetary reward and a “risky” reward that carried a chance of being either much higher or lower in value than the safe option. The researchers compared brain activity during the two phases of the prediction error calculation: first during the expectation phase (while participants were making their decision and anticipating the resulting reward), and then during the actual reward phase (when participants were presented with the outcome).
They found that people with cocaine addiction had reduced prediction error responses, consistent with animal studies. When they broke the prediction error response down into its component parts, they found that signals of reward expectation were similar for both groups, but the signal for received reward was weaker for people with cocaine addiction. This weakened reward signal was visible in the ventral striatum, the brain region where prediction error is processed, and there was also reduced activity in the orbitofrontal cortex, a brain region involved in integrating the prediction error signal to inform future behavior.
“We found evidence that people with chronic cocaine addiction have reduced prediction error responses, and this difference seems to be caused by differences in the subjective perception of received reward,” says Konova. “The reduced reward signal seems to propagate to other regions of the brain that would receive this information to then update your expectations for the next time you encounter this same situation.”
The team also showed that people with cocaine addiction were more likely to choose risky options compared with controls, and this risk tolerance was more apparent in people who had begun using cocaine at an earlier age, pointing to potential predisposing factors for developing addiction.
Understanding the mechanisms behind addictive behavior could inform treatment strategies for addiction, the researchers say. “Our findings suggest that interventions that boost the perception of received rewards might be a valuable component of addiction treatment,” says Goldstein. “Understanding the brain mechanisms behind addiction is also extremely valuable for the public and for the person experiencing addiction.”
Next, the team wants to understand how this dysregulation of reward signaling changes during different stages of addiction and recovery and whether reward perception is involved in other types of substance disorder, for example in addiction to opioids such as heroin. “We want to understand how this signal changes through the progression of recovery, or as a function of different stages of addiction to understand whether it’s really driven by chronic cocaine exposure or something that comes on earlier, maybe even before you start substance use,” says Goldstein.

T cells are soldiers on the front lines of the human immune system. They are responsible for many important roles, including attacking viral- or bacterial-infected cells and certain cancer cells, and immunological memory — remembering the specific pathogens or the cancer signatures that originally trigger T cells.
Until now, understanding how a T cell forms into a specific role, for example a cell-killing (cytotoxic) T cell or memory T cell, has eluded us. In a paper that will be published online by Cell Reports on October 25, ISB researchers made the breakthrough discovery that the genetically encoded T-cell receptor (TCR) sequence that humans develop in early childhood determines a T cell’s function.
“That receptor sequence is the major determinant — not signaling proteins such as cytokines or other blood components,” said Daniel Chen, first author of the paper. “It is that receptor sequence — the proteins on the T cell that bind to foreign antigens — that determines what this cell’s phenotype is, and thus determines what its function is going to be.”
In a human clinical study involving 68 patients, the team explored around 700 T cells that specifically interacted with antigens from either SARS-CoV-2, influenza, or cytomegalovirus.
The potential of this fundamental discovery is promising for developing custom immune responses to specific antigens.
“T-cell receptor-engineered T cell cancer immunotherapies are an emerging treatment for solid tumors. In such therapies, the T cells that comprise the drug are typically engineered to aggressively kill cancer cells. We know that a successful immune response requires a balance of T cell phenotypes, some of which kill tumor cells, but others which can form memory or do other functions,” said ISB President and Professor Dr. James R. Heath, corresponding author of the paper.
“We show that there is basically a card catalog available,” Heath added. “If you want to engineer a balanced immune response, you go to that card catalog, you find the particular TCR genes that, when engineered to build the cell therapy, can provide that balanced response.”
A different “card catalog” is required for different antigens. However, many antigens are immunogenic, meaning that for different patients afflicted with the same disease, their T cells will often target the same antigen.
“This is important,” said Chen, “because it means that what we learn for one patient is likely going to be applicable for another.”
This work was funded by the WA State Andy Hill CARE Foundation, by the National Cancer Institute, and by the Parker Institute for Cancer Immunotherapy.

Researchers at Stockholm University have unveiled the hidden intricacies of how sperm go from passive bystanders to dynamic swimmers. This transformation is a pivotal step in the journey to fertilization, and it hinges on the activation of a unique ion transporter.
Imagine sperm as tiny adventurers on a quest to reach the ultimate treasure, the egg. They don’t have a map, but they make use of something even more extraordinary: chemo-attractants. These are chemical signals released by the egg that act as siren call, directing and activating the sperm. When these signals bind to receptors on the sperm’s surface, it triggers a series of events, starting their movement towards the egg. And in this intricate scenario, one key player is a protein known as “SLC9C1.”
It’s exclusively found in sperm cells, and it is usually not active. However, when the chemo-attractants interact with the sperm’s surface, everything changes.
“SLC9C1 operates like a highly sophisticated exchange system. It swaps protons from inside the cell for sodium ions from the outside, temporarily creating a less acidic environment within the sperm. This change in the internal environment triggers increased sperm motility,” says David Drew, Professor in Biochemistry at Stockholm University.
The activation of SLC9C1 is driven by a change in voltage that occurs when chemo-attractants attach to the sperm. To accomplish this, SLC9C1 uses a unique feature called a voltage-sensing domain (VSD). Typically, VSD domains are associated with voltage-gated ion channels. But in the case of SLC9C1, it’s something truly exceptional in the realm of transporters.
Researchers, led by David Drew, have unveiled the secrets behind SLC9C1’s inner workings and provides the first example of voltage-sensing domain activation of a transporter and its connection via an unusually long voltage-sensing (S4) helix.
“The VSD domain responds to the change in voltage by pushing its rodlike S4 helix inwards. This clears the way for ion exchange by SLC9C1, ultimately initiating sperm motility,” says David Drew.
“Transporters work very differently than channels and, as such, the VSD is coupled to the sperm protein in a way that we have just never seen before, or even imagined. Its exciting to see how nature has done this and perhaps, in the future, we can learn from this to make synthetic proteins that can be turned-on by voltage or develop novel male contraceptives that work by blocking this protein,” David Drew notes.
The research was made possible through funding from the European Research Council (ERC) grant EXCHANGE.

Researchers have developed a new way of improving diagnosis of bipolar disorder that uses a simple blood test to identify biomarkers associated with the condition.
The researchers, from the University of Cambridge, used a combination of an online psychiatric assessment and a blood test to diagnose patients with bipolar disorder, many of whom had been misdiagnosed with major depressive disorder.
The researchers say the blood test on its own could diagnose up to 30% of patients with bipolar disorder, but that it is even more effective when combined with a digital mental health assessment.
Incorporating biomarker testing could help physicians differentiate between major depressive disorder and bipolar disorder, which have overlapping symptoms but require different pharmacological treatments.
Although the blood test is still a proof of concept, the researchers say it could be an effective complement to existing psychiatric diagnosis and could help researchers understand the biological origins of mental health conditions. The results are reported in the journal JAMA Psychiatry.
Bipolar disorder affects approximately one percent of the population — as many as 80 million people worldwide — but for nearly 40% of patients, it is misdiagnosed as major depressive disorder.
“People with bipolar disorder will experience periods of low mood and periods of very high mood or mania,” said first author Dr Jakub Tomasik, from Cambridge’s Department of Chemical Engineering and Biotechnology. “But patients will often only see a doctor when they’re experiencing low mood, which is why bipolar disorder frequently gets misdiagnosed as major depressive disorder.”
“When someone with bipolar disorder is experiencing a period of low mood, to a physician, it can look very similar to someone with major depressive disorder,” said Professor Sabine Bahn, who led the research. “However, the two conditions need to be treated differently: if someone with bipolar disorder is prescribed antidepressants without the addition of a mood stabiliser, it can trigger a manic episode.”

In a study of different types of distraction involving more than 1,000 participants, researchers statistically derived a novel measure — dubbed the “d factor” — that could represent a person’s general tendency towards distraction and may be linked with attention-deficit/hyperactivity disorder (ADHD). Han Zhang of the University of Michigan, Ann Arbor, and colleagues present these findings in the open-access journal PLOS ONE on October 25, 2023.
Prior research has explored various types of distraction, such as external stimulations, repetitive negative thinking, or daydreaming. Some research has suggested that vulnerability to different types of distraction could potentially be mathematically captured by an overarching “distractibility factor.” However, the evidence for a distractibility factor has been limited, and most studies have not considered a comprehensive collection of different types of distraction — including some associated with ADHD.
To better understand different types of distraction and their potential relationship with ADHD, Zhang and colleagues asked a total of 1,220 participants to complete an extensive series of questionnaires to evaluate their tendency to experience different kinds of distraction in their daily lives, such as difficulty concentrating with a TV on or losing oneself in daydreaming. The questionnaires also evaluated symptoms of ADHD and hyperfocus — a long-lasting state of intense concentration sometimes linked to ADHD.
Analysis of participants’ answers surfaced three key, distinct factors that could statistically explain patterns observed in the data: external distraction, unwanted intrusive thoughts, and mind-wandering. The researchers found that the statistical relationships between these three factors could be accounted for by a single, higher-level factor — which they named the d factor.
Further analysis showed strong statistical links between the d factor and a person’s ADHD symptoms. The d factor was also linked to hyperfocus, suggesting that hyperfocus might, in part, reflect attention difficulties.
These findings could help lead to better understanding of people’s distractibility and its relationship to ADHD. The authors note the need for additional research to further explore the nature of the d factor and its links to ADHD, as well as the need to employ additional data-gathering methods, such as behavioral tasks or tests.
The authors add: “A critical finding of our study is the identification of a higher-order factor that could be construed to represent a general distractibility trait. People who score high on the ‘general distractibility’ trait are more easily distracted in many situations.”