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For more than a century, scientists have worked to characterize, understand, and predict the consequences of mutations. For almost as long, scientists-always on the lookout for general principles-have categorized these mutations, hoping that putting them into labeled boxes might help reveal the molecular logic that governs mutational effects. Here, I will dive into one of these boxes, labeled "gain-of-function", a term that will ring familiar to undergraduates, (clinical) geneticists, and virologists alike. I will emerge from the box with a profound sense of bewilderment and the conclusion that its contents appear to have very little in common. What is a gain-of-function mutation? What do we know (or can reasonably assume) about a mutation once it has attracted this label? Do gain-of-function mutations share anything in common in terms of their molecular features or the consequences they cause? I will argue that the answers to these three questions are "I don't know," "not much," and "not really," and that the term gain-of-function tells us rather little. Worse, it often misleads our intuition regarding what a given mutation is or does. I will suggest that this is because the gain-of-function label has historically been applied, with liberal abandon, across different levels of biological complexity, from the behavior of individual proteins, to protein complexes, to cells, to whole-organism physiology. I will discuss the implications (all bad…) of this heterogeneous labeling history for recent efforts to train machine learning algorithms to discriminate different types of mutations. Above all, I hope to highlight that the myriad ways in which mutational effects can percolate through biological systems often defy easy categorization and that, while classifying things is often useful, it is best not to forget that molecular biology is a glorious mess.

Among the many excellent presentations and posters of this conference, I was tasked with making sense of two of the most esoteric. This is my meat and potatoes. I hasten to add that they are not esoteric because they are peripheral; au contraire, they are central. They are only esoteric because you have to be an intellectual searcher to delve into them. In the face of them, they are formidable; but, relax, and contemplate them, and they are most intellectually gratifying. McDowell shows us how, through the same sort of selection processes that both animals and their habits are subject to, the basic laws of behavior arise. This is foundational-where do our laws come from?-McDowell gives us a glimpse. Cox tells us what those laws do; or don't. He demonstrates these in the contexts that matter-very large data sets form the world of action-where our cloistered predictions may be evaluated, and improved. His Natural Language Programming Machines provide visions of what we say and do that can only be seen at this higher level. If we are to move our field to higher relevance, this is the way.

Although the focus on sleep disturbances in children who have experienced adversity has increased, little is known about sleep among children in foster care (CFC). This study aimed to review what research tells us about the relationship between foster care experience and sleep disturbances and to identify knowledge gaps. This study used Arksey and O'Malley's (2005) 5-part methodology for conducting scoping reviews and the Reporting Checklist for Scoping Reviews (PRISMA-ScR) guidelines. 14 studies met inclusion criteria. Data were synthesized using the 6-phased approach to thematic analysis outlined by Braun and Clarke (2006, 2021). The majority of included studies were conducted in the United States, used cross-sectional designs, and collected data from foster caregivers. Three themes emerged: sleep quality and disorders; relationships among sleep, trauma, and behavior-related outcomes; and intervention approaches (behavioral, pharmacological, and digital). The most commonly mentioned sleep problems were waking during the night, difficulty falling asleep, night terrors, bed wetting, and sleep efficiency and/or quality. Several studies suggested that trauma exposure played a central role in sleep disturbances in CFC and that unresolved trauma and environmental instability contributed to ongoing fear and insecurity at bedtime and difficulty maintaining sleep. Only 2 studies evaluated intervention effectiveness. This review suggests that sleep disturbances are a pervasive yet underrecognized issue among CFC. Overall, the literature underscores that sleep health in CFC is both a marker and a mechanism of broader emotional and physiological dysregulation.

This case report describes the rapid clinical response to etifoxine, an oral translocator protein 18 kDa (TSPO) ligand, in a patient with severe, treatment-resistant obsessive-compulsive disorder (OCD) with comorbid bipolar I disorder. Despite extensive prior pharmacological treatments and neurosurgical interventions, the patient experienced significant symptom amelioration within days of etifoxine initiation (the Yale-Brown Obsessive-Compulsive Scale (YBOCS) score decreased from 50 to 29). We discussed the potential mechanisms underlying this rapid response, including direct γ-aminobutyric acid (GABA) receptor modulation, increased endogenous neurosteroidogenesis, reduced neuroinflammation, and modulation of the gut-brain axis. This case highlights etifoxine as a novel therapeutic option for treatment-resistant OCD and underscores the need for further research into TSPO ligands in this context. A dramatic improvement in obsessive thoughts after taking a medicine usually used for anxiety This case report tells the story of a man with long-standing obsessive-compulsive disorder (OCD) who had not improved despite trying many medications and even undergoing brain surgery. He was given a medicine called etifoxine, which is usually used to treat anxiety. Surprisingly, within just two days, he experienced a major improvement in his obsessive thoughts and suicidal feelings. However, he developed a mild allergic skin reaction and swelling in his legs, so the medicine was stopped. After the side effects went away, his doctor slowly reintroduced etifoxine at a lower dose. His symptoms improved again, but not as dramatically as the first time. This is the first report of etifoxine being used for OCD. Researchers believe it might work by helping the brain make calming chemicals, reducing inflammation, and possibly affecting the gut-brain connection. This case gives hope that etifoxine could become a new treatment option for people whose OCD doesn’t respond to usual therapies. More research is needed to understand how it works and how to use it safely.

Farm animal welfare is assessed for compliance with legislation and labelling schemes, to evaluate the impacts of management change and for animal welfare research. Here, we ask: how can we assess how the animal experiences its life on farm? Animal welfare is what the animal experiences and spans from very negative to very positive emotional states. Welfare is influenced by nutrition, the environment, health and the behavioural interactions that animals have, integrated through the impacts that these have on the mental state of the animal. Whilst we can often readily measure and describe the conditions under which the animal is housed on farm (inputs), and the physical state of the animal within these conditions, these are not sufficient to tell us what the animal is experiencing. The Gold Standard for animal welfare, therefore, would be a measure that tells us something about the mental state of the animal. Currently, this is not considered a directly measurable entity, and it may remain a hypothetical rather than a realistic construct in welfare assessment. Thus, welfare assessment relies on a series of measurable outputs, or indicators, that serve as proxies for the welfare state. Emotional state and welfare are then inferred from these measures. Animal-based measures are considered the most relevant to understanding animal experience, although these require rigorous assessment of the validity and reliability of measurement. Many animal-based measures rely on the assessment of behaviour. These may be ongoing changes in response, such as approach or avoidance, facial expression, Qualitative Behaviour Assessment and circadian rhythms or complex patterns of behaviour, such as preferences, motivational priorities, or perceptions, which allow deeper insight into the likely mental state of the animal. Many measures are only suitable for research purposes at present and can be challenging to assess on farm, but some may be amenable to the use of sensors or automated methods in the future. These have technological and ethical challenges to overcome and require an understanding of what is being measured and how this relates to the animal's mental state but may offer opportunities for continual assessment of animal behaviour and welfare in the future. Currently, however, theoretical understanding of animal welfare, particularly positive welfare and cumulative 'Quality of Life', is not well-captured in existing on-farm welfare assessment. We conclude that there is a need for a more comprehensive and integrated approach to the development of methods that can truly address the animal's experience on farm.

Mammalian oocyte activation is driven by intracellular calcium (Ca2+) oscillations induced by sperm-specific phospholipase C zeta (PLCζ). Sperm PLCζ deficiency is linked to male infertility caused by oocyte activation deficiency. Using whole exome sequencing, we report finding a previously reported loss-of-activity pathogenic mutation of PLCZ1 from two unrelated males in a separate ethnicity, homozygous in both cases. We examined sperm PLCζ using immunoblotting and immunofluorescence to compare levels with fertile control sperm. We also utilised bioinformatics tools to characterise the effect of this variant. The variant caused a guanine (G)-to-adenine (A) change at position 1,154 (c.1154G>A), resulting in an arginine (R)-to-glutamine (Q) change at amino acid 385 (p.Arg385Gln; R385Q), disrupting the local protein fold in the Y domain of the active site in a highly deleterious and pathogenic manner. A previous study identified this mutation as heterozygous, while we identified this variant as homozygous in an ethnically distinct population from this previous study. Sperm PLCζ was significantly reduced compared to controls. The R385Q change indicated a reduction in PIP2 interaction with PLCζ following docking analyses. Pathogenic PLCζ mutation may be common in men with repeated fertilisation failure. Raw ejaculate analysis, rather than density gradient washed sperm, could provide a more accurate assessment of PLCζ levels, especially in men with low sperm count or ejaculate volume. Such pathogenic cases may underlie higher proportions of sperm exhibiting abnormal PLCζ localisation and could stand to aid a larger number of patients seeking fertility treatment. In this study, we examined two unrelated men who had been unable to have children despite multiple in vitro fertilisation attempts. We discovered that both men carried the same mutation in a gene called PLCZ1. This gene normally produces a protein in sperm that tells the egg to begin developing into an embryo, but because of the mutation in these men, the sperm could not deliver that message to the egg. Interestingly, this same mutation had previously only been reported in Chinese patients, and this was the first time it was found in men from a different ethnic background, suggesting that this mutation may be a globally occurring mutation. This finding could help doctors recognise similar fertility problems in other patients and could lead to more effective treatments in the future.

Public health crises such as the global epidemic of so-called 'lifestyle diseases' are often framed as the failure of individuals to make the right health-related choices or to take responsibility for managing their bodies in ways that promote the health of present and future selves. Through his early writings on healthism, Robert Crawford was one amongst a number of scholars who documented the emergence of neoliberal logics of self-care in response to these perceived failings. Although these debates are well covered in the critical literature, less attention has been paid to the ways in which the central tenets of healthism were and are received as ideology travels from place to place. This paper seeks to address this lacuna through a detailed analysis of the discourse surrounding the World Health Organization's 'Global Strategy on Diet, Physical Activity and Health'. Chosen for its framing of lifestyle diseases as a global public health problem whose causes are rooted in the spread of the 'western lifestyle', the paper argues that a focus on the strategy and the international response to it is revealing for what it tells us about what happens when ideas and theories travel.

Neonatal encephalopathy (NE) following perinatal hypoxia-ischemia (HI) can lead to a wide range of neurodevelopmental consequences, ranging from mild motor problems to severe cerebral palsy, epilepsy, cognitive impairments, and behavioral issues. There is growing recognition of the long-term effects of NE during childhood, but little is known about the outcomes in adulthood, particularly from the perspective of the individuals affected and their families. Existing research primarily relies on outcome measures from neurodevelopmental assessments, which often fail to capture the lived experiences of those affected, limiting our understanding of the meaning and impact of the consequences of NE on their everyday lives. This paper tells the stories of four adults with varying outcomes following NE due to HI, ranging from largely typical development to cerebral palsy to subtle but significant cognitive challenges. Their narratives demonstrate that the long-term consequences of NE are highly variable and influenced by a complex interaction of medical, social, and environmental factors. They shared experiences of challenges, e.g., memory issues, which significantly affect their lives but are not routinely assessed in neurodevelopmental follow-up. Moreover, their narratives underscore that difficulties may emerge or evolve over time, emphasizing the need for ongoing, individualized care. Importantly, the stories of these adults also show that despite the challenges that they have faced and continue to face, they live fulfilling lives that go beyond what results from developmental assessments may indicate. These insights from lived experience experts emphasize the need for a holistic, patient-centered approach in both research and long-term follow-up care.

Autonomic control of the heart is an important indicator of self-regulation and overall mental and physical health. The vagus nerve plays a central role in this regulation, and resting-state heart rate variability (HRV), reflecting fluctuations in inter-beat intervals (IBIs), is the primary noninvasive marker of vagal activity. As males and females differ in aspects of self-regulation, HRV may help elucidate underlying neurobiological differences. However, sex differences in commonly used HRV metrics, such as natural log transformed root mean square of successive RR interval differences (lnRMSSD) and high-frequency HRV (lnHF-HRV) derived from 5-minute recordings, appear smaller in young adults than in other age groups. These metrics capture vagally mediated activity as averaged linear measures and may therefore overlook rapid, spontaneous IBI fluctuations. In the present study, we tested whether a similarity graph theory algorithm could better capture sex differences in nonlinear, rapid IBI variability within 2-5-seconds time windows. Electrocardiogram (ECG) recordings of 269 young, healthy adults between 18 and 30 years old (M = 21.5, SD = 3.0) were pooled from three different studies. Males accounted for 52.4% of participants, indicating a comparable distribution between sexes. Similarity graph-theory metrics were computed to quantify nonlinear, rapid interbeat interval (IBI) variability using sliding windows of 2-5 s and ≥12 s. In addition, conventional linear and nonlinear heart rate variability metrics, including lnRMSSD and lnHF-HRV, were calculated. Logistic regression models were used to assess the predictive value of graph-theory and HRV metrics for sex, both separately and in combined models for comparison. All models were adjusted for age, body mass index, mean heart rate, and respiratory rate. Males showed higher graph-metric values, indicating lower IBI variability compared with females (odds ratio 2.78; 95% CI 1.32-5.86). Neither lnRMSSD nor lnHF-HRV distinguished sexes alone; however, lnRMSSD became predictive when combined with the graph metric (odds ratio 1.73; 95% CI 1.06-2.81), although this effect was attenuated after controlling for mean heart rate. These findings suggest that nonlinear methods sensitive to rapid spontaneous IBI changes can complement traditional short-term HRV metrics for assessing sex differences in autonomic heart regulation. The way our heart adjusts from beat to beat tells us a lot about how well we can adapt to stress, emotions, and everyday demands. This natural variation in heartbeats is called heart rate variability (HRV) and is usually measured using sensors that record the heart’s electrical activity. Men and women often differ in how they regulate emotions and behavior, and these differences can sometimes be seen in HRV. In many studies, women tend to show more flexible heart activity than men. However, in young adults, these differences are often hard to detect using standard methods. This may be because young hearts are especially adaptable and change quickly in response to the situation. To address this, we used a new method that looks at very short-term changes in heartbeat patterns using a mathematical approach called graph theory. This method was able to detect differences that traditional measures missed, showing that young women had more flexible heart activity than young men when these rapid fluctuations were taken into account.