Sex differences in shared genetic determinants between severe mental disorders and metabolic traits.

High rates of metabolic risk factors contribute to premature mortality in patients with severe mental disorders, but the molecular underpinnings of this association are largely unknown. We performed the first analysis on shared genetic factors between severe mental disorders and metabolic traits considering the effect of sex. We applied an integrated analytical pipeline on the largest sex-stratified genome-wide association datasets available for bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and for body mass index (BMI) and waist-to-hip ratio (WHR) (all including participants of European origin). We observed extensive genetic overlap between all severe mental disorders and variants associated with BMI in women or men and identified several genetic loci shared between BD, or SZ and BMI in women (24 and 91, respectively) or men (13 and 208, respectively), with mixed directions of effect. A large part of the identified genetic variants showed sex differences in terms of location, genes modulated in adipose tissue and/or brain regions, and druggable targets. By providing a complete picture of disorder specific and cross-disorder shared genetic determinants, our results highlight potential sex differences in the genetic liability to metabolic comorbidities in patients with severe mental disorders.

Epidemiology and Clinical Characteristics of Ocular Tuberculosis in the United States, 1993-2019.

Background: Data regarding ocular tuberculosis (OTB) in the United States have not been previously reported. We evaluated trends of OTB compared with other extrapulmonary TB (EPTB). Methods: We estimated the proportion of all EPTB cases (with or without concurrent pulmonary involvement) with OTB reported to the National Tuberculosis Surveillance System during 1993-2019. We compared demographics and clinical characteristics of people with OTB and other EPTB during 2010-2019. P values were calculated by chi-square test for categorical variables and Kruskal-Wallis for continuous variables. Results: During 1993-2019, 1766 OTB cases were reported, representing 1.6% of 109 834 all EPTB cases: 200 (0.5% of 37 167) during 1993-1999, 395 (1.0% of 41 715) during 2000-2009, and 1171 (3.8% of 30 952) during 2010-2019. In contrast to persons with other EPTB, persons with OTB were older (median, 48 vs 44 years; P < .01), more likely to be US-born (35% vs 28%; P < .01), more likely to have diabetes (17% vs 13%; P < .01), and less likely to have HIV (1% vs 8%; P < .01). OTB was less likely to be laboratory confirmed (5% vs 75%; P < .01), but patients were more likely to be tested by interferon gamma release assay (IGRA; 84% vs 56%; P < .01) and to be IGRA positive (96% vs 80%; P < .01). Conclusions: Reported OTB increased during 1993-2019 despite decreasing TB, including EPTB; the largest increase occurred during 2010-2019. OTB was rarely laboratory confirmed and was primarily diagnosed in conjunction with IGRA results. More research is needed to understand the epidemiology of OTB to inform clinical and diagnostic practices.

Diffuse optical spectroscopy of lactating and non-lactating human mammary physiology.

Breastfeeding provides widely recognized advantages for infant and maternal health. Unfortunately, many women experience trouble with breastfeeding. Nevertheless, few suitable imaging modalities are available to study human lactation and determine the possible causes of breastfeeding problems. In this study, we apply broadband, quantitative diffuse optical spectroscopy (DOS) for this purpose. We present a study of fourteen lactating and eight similarly aged, premenopausal, non-lactating women to investigate the feasibility of DOS to study the optical and physiological differences between 1) lactating and non-lactating breasts, 2) the areolar and non-areolar region within the breast, and 3) lactating breasts before and after milk extraction. Our study shows that i) the median total hemoglobin concentration [tHb] of the lactating breast is 51% higher than for the non-lactating breast. ii) the median [tHb] of the lactating breast is 37% higher in the areolar region compared to the non-areolar region. iii) lactating breasts exhibit a positive median difference of 8% in [tHb] after milk extraction. Our findings are consistent with the expected physiological changes that occur during the lactation period. Importantly, we show that DOS provides unique insight into breast tissue composition and physiology, serving as a foundation for future application of the technique in lactation research.

Brain-wide dynamics linking sensation to action during decision-making.

Perceptual decisions rely on learned associations between sensory evidence and appropriate actions, involving the filtering and integration of relevant inputs to prepare and execute timely responses1,2. Despite the distributed nature of task-relevant representations3-10, it remains unclear how transformations between sensory input, evidence integration, motor planning and execution are orchestrated across brain areas and dimensions of neural activity. Here we addressed this question by recording brain-wide neural activity in mice learning to report changes in ambiguous visual input. After learning, evidence integration emerged across most brain areas in sparse neural populations that drive movement-preparatory activity. Visual responses evolved from transient activations in sensory areas to sustained representations in frontal-motor cortex, thalamus, basal ganglia, midbrain and cerebellum, enabling parallel evidence accumulation. In areas that accumulate evidence, shared population activity patterns encode visual evidence and movement preparation, distinct from movement-execution dynamics. Activity in movement-preparatory subspace is driven by neurons integrating evidence, which collapses at movement onset, allowing the integration process to reset. Across premotor regions, evidence-integration timescales were independent of intrinsic regional dynamics, and thus depended on task experience. In summary, learning aligns evidence accumulation to action preparation in activity dynamics across dozens of brain regions. This leads to highly distributed and parallelized sensorimotor transformations during decision-making. Our work unifies concepts from decision-making and motor control fields into a brain-wide framework for understanding how sensory evidence controls actions.

Management of iron overload: lessons from transfusion-dependent hemoglobinopathies.

Prior to the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, non-invasive monitoring of organ specific iron loading in humans and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

Opioid Prescriptions for US Patients Undergoing Long-Term Dialysis or with Kidney Transplant from 2011 to 2020.

BACKGROUND: Pain is important for patients with kidney failure, but opioid medication prescriptions are associated with morbidity and mortality. The Centers for Disease Control and Prevention issued opioid prescription guidelines in 2016 and 2022, associated with dramatically decreased prescription rates in the United States. It is critical to know if nationwide opioid prescription rates for patients with kidney failure have decreased. METHODS: We analyzed the USRDS database from 2011 to 2020 to describe trends in the proportion of ESKD patients who received one or more, or long-term opioid prescriptions, examined factors associated with long-term opioid prescriptions, and evaluated associations of all-cause death with short-term or long-term opioid prescriptions. RESULTS: From 2011-2022, the percentage of patients with kidney failure (dialysis and kidney transplant) who received at least one or more, or who had received long-term opioid medication prescriptions decreased steadily, from 60% to 42%, and from 23% to 13%, respectively (both P for trend <0.001). The largest reductions in prescription rates were for hydrocodone and oxycodone. Similar trends existed for dialysis and kidney transplant patients. Women, the poor and those in rural settings were more likely to receive long-term opioid prescriptions. Prescription rates were highest in White patients and those 45 to 64 years old. Short-term and long-term opioid medication prescriptions were associated with higher mortality in both dialysis and kidney transplant patients. CONCLUSIONS: ESKD patients' opioid prescription rates decreased between 2011 and 2020. Higher mortality risk was associated with both short-term and long-term opioid prescriptions. Mortality risk was monotonically associated with morphine milligram equivalents in patients with kidney failure who received long-term opioid prescriptions.

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [18F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

IL-1ß Induces Human Endothelial Surface Expression of IL-15 by Relieving let-7c-3p Suppression of Protein Translation.

Expression of IL-15 on the surface of human graft endothelial cells (ECs) bound to the IL-15Rα subunit can increase the activation of CTLs, potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1ß synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-κB. In this article, we report that cultured human ECs express eight differently spliced IL-15 transcripts. Remarkably, IL-1ß does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1ß causes an NF-κB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p anti-miR can induce EC surface expression of IL-15/IL-15Rα in the absence of complement activation or of IL-1, enabling IL-15 transpresentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for transpresentation.

Wirelessly Powered Visible Light-Emitting Implant for Surgical Guidance during Lumpectomy.

Achieving negative surgical margins, defined as no tumor found on the edges of the resected tissue, during lumpectomy for breast cancer is critical for mitigating the risk of local recurrence. To identify nonpalpable tumors that cannot be felt, pre-operative placements of wire and wire-free localization devices are typically employed. Wire-free localization approaches have significant practical advantages over wired techniques. In this study, we introduce an innovative localization system comprising a light-emitting diode (LED)-based implantable device and handheld system. The device, which is needle injectable and wire free, utilizes multiple wirelessly powered LEDs to provide direct visual guidance for lumpectomy. Two distinct colors, red and blue, provide a clear indication of tissue depth: blue light is absorbed strongly in tissue, visible within a close range of <1 cm, while red light remains visible through several centimeters of tissue. The LEDs, integrated with an impedance-matching circuit and receiver coil, are encapsulated in biocompatible epoxy for injection with a 12 G needle. Our findings demonstrate that the implant exhibits clearly perceivable depth-dependent color changes and remains visible through >2 cm of ex vivo chicken breast and bovine muscle tissue using less than 4 W of transmitted power from a handheld antenna. These miniaturized needle-injectable localization devices show promise for improving surgical guidance of nonpalpable breast tumors.

Virtual Reality Tennis Training: Performance Gains Derived from User Characteristics.

There is growing interest in virtual reality (VR) training among competitive athletes and casual sports players alike as a tool to supplement real-life play within a highly controlled, intellectually stimulating environment. We examined data from a commercially available, recently released VR software for tennis for changes in and correlates of performance. Two most frequently used tasks were evaluated-Baseline Center and Quick Volley, which include Efficiency (both), Concentration (both), and Reaction Time (Quick Volley only) subtasks. In all, 1,124 (Baseline Center) and 745 (Quick Volley) users met inclusion criteria (completed more than four trials; active sometime between November 2022 and July 2023). We found that most users were male adults and were about evenly split between advanced/pro users and intermediate/beginner users. Two or three trajectories emerged across the subtasks. Performance gains were most pronounced on movement efficiency, especially early on. Adult users generally exhibited more improvement than junior users. Additionally, women and right-handed users improved more on Baseline Center subtasks, and advanced/pro users did better than intermediate/beginner users on Quick Volley subtasks. We discuss that, despite strong performance gains within VR environment, VR training may still reflect in better real-world performance, may increase confidence and accuracy of relevant movement, lower risk of injury, and present a welcome diversion from a potential monotony of performing sport-related tasks in purely real-world settings. Future research should explore the extent to which VR training transfers to real-world performance.

High Performance Organic Mixed Ionic-electronic Polymeric Conductor with Stability to Autoclave Sterilization.

We present a series of newly developed donor-acceptor (D-A) polymers designed specifically for organic electrochemical transistors (OECTs) synthesized by a straightforward route. All polymers exhibited accumulation mode behavior in OECT devices, and tuning of the donor comonomer resulted in a three-order-of-magnitude increase in transconductance. The best polymer gFBT-g2T, exhibited normalized peak transconductance (gm,norm) of 298±10.4 S cm-1 with a corresponding product of charge-carrier mobility and volumetric capacitance, µC*, of 847 F V-1 cm-1 s-1 and a µ of 5.76 cm2 V-1 s-1, amongst the highest reported to date. Furthermore, gFBT-g2T exhibited exceptional temperature stability, maintaining the outstanding electrochemical performance even after undergoing a standard (autoclave) high pressure steam sterilization procedure. Steam treatment was also found to promote film porosity, with the formation of circular 200 - 400 nm voids. These results demonstrate the potential of gFBT-g2T in p-type accumulation mode OECTs, and pave the way for the use in implantable bioelectronics for medical applications.

Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

Isostructural Series of a Cyclometalated Iron Complex in Three Oxidation States.

An isostructural series of FeII, FeIII, and FeIV complexes [Fe(ImP)2]0/+/2+ utilizing the ImP 1,1'-(1,3-phenylene)bis(3-methyl-1-imidazol-2-ylidene) ligand, combining N-heterocyclic carbenes and cyclometalating functions, is presented. The strong donor motif stabilizes the high-valent FeIV oxidation state yet keeps the FeII oxidation state accessible from the parent FeIII compound. Chemical oxidation of [Fe(ImP)2]+ yields stable [FeIV(ImP)2]2+. In contrast, [FeII(ImP)2]0, obtained by reduction, is highly sensitive toward oxygen. Exhaustive ground state characterization by single-crystal X-ray diffraction, 1H NMR, Mössbauer spectroscopy, temperature-dependent magnetic measurements, a combination of X-ray absorption near edge structure and valence-to-core, as well as core-to-core X-ray emission spectroscopy, complemented by detailed density functional theory (DFT) analysis, reveals that the three complexes [Fe(ImP)2]0/+/2+ can be unequivocally attributed to low-spin d6, d5, and d4 complexes. The excited state landscape of the FeII and FeIV complexes is characterized by short-lived 3MLCT and 3LMCT states, with lifetimes of 5.1 and 1.4 ps, respectively. In the FeII-compound, an energetically low-lying MC state leads to fast deactivation of the MLCT state. The distorted square-pyramidal state, where one carbene is dissociated, can not only relax into the ground state, but also into a singlet dissociated state. Its formation was investigated with time-dependent optical spectroscopy, while insights into its structure were gained by NMR spectroscopy.

Cognitive Dysfunction in the Addictions (CDiA): A Neuron to Neighbourhood Collaborative Research Program on Executive Dysfunction and Functional Outcomes in Outpatients Seeking Treatment for Addiction.

BACKGROUND: Substance use disorders (SUDs) are pressing global public health problems. Executive functions (EFs) are prominently featured in mechanistic models of addiction. However, there remain significant gaps in our understanding of EFs in SUDs, including the dimensional relationships of EFs to underlying neural circuits, molecular biomarkers, disorder heterogeneity, and functional ability. To improve health outcomes for people with SUDs, interdisciplinary clinical, preclinical and health services research is needed to inform policies and interventions aligned with biopsychosocial models of addiction. Here, we introduce Cognitive Dysfunction in the Addictions (CDiA), an integrative team-science and translational research program, which aims to fill these knowledge gaps and facilitate research discoveries to enhance treatments for people living with SUDs. METHODS: The CDiA Program comprises seven complementary interdisciplinary projects that aim to progress understanding of EF in SUDs and investigate new biological treatment approaches. The projects draw on a diverse sample of adults aged 18-60 (target N=400) seeking treatment for addiction, who are followed prospectively over one year to identify EF domains crucial to recovery. Projects 1-3 investigate SUD symptoms, brain circuits, and blood biomarkers and their associations with both EF domains (inhibition, working memory, and set-shifting) and functional outcomes (disability, quality of life). Projects 4 and 5 evaluate interventions for addiction and their impacts on EF: a clinical trial of repetitive transcranial magnetic stimulation and a preclinical study of potential new pharmacological treatments in rodents. Project 6 links EF to healthcare utilization and is supplemented with a qualitative investigation of EF-related barriers to treatment engagement for those with substance use concerns. Project 7 uses innovative whole-person modeling to integrate the multi-modal data generated across projects, applying clustering and deep learning methods to identify patient subtypes and drive future cross-disciplinary initiatives. DISCUSSION: The CDiA program has promise to bring scientific domains together to uncover the diverse ways in which EFs are linked to SUD severity and functional recovery. These findings, supported by emerging clinical, preclinical, health service, and whole-person modeling investigations, will facilitate future discoveries about cognitive dysfunction in addiction and could enhance the future clinical care of individuals seeking treatment for SUDs.

Control of nuclear localization of the nucleocapsid protein of SARS-CoV-2.

The nucleocapsid (N) protein of coronaviruses is a structural protein that binds viral RNA for assembly into the mature virion, a process that occurs in the cytoplasm. Several coronavirus N proteins also localize to the nucleus. Herein, we identify that two sequences (NLSs) are required for nuclear localization of the SARS-CoV-2 N protein. Deletion or mutation of these two sequences creates an N protein that does not localize to the nucleus in HEK293T cells. Overexpression of both wild-type and NLS-mutated N proteins dysregulate a largely overlapping set of mRNAs in HEK293T cells, suggesting that these N proteins do not have direct nuclear effects on transcription. Consistent with that hypothesis, both N proteins induce nuclear localization of NF-κB p65 and dysregulate a set of previously identified NF-κB-dependent genes. The effects of N on nuclear properties are proposed to alter host cell functions that contribute to viral pathogenesis or replication.

The devil is in the details: Experiment reveals how a forest-dwelling scavenger, and their excrement, may buffer ecosystem processes from climate change.

This article is an Invited Commentary on Stephenson et al. (2024). This commentary attempts to provide broader context of the research within the body of literature on species loss and ecosystem functioning and highlights its relevance to conservation and global change.

Sex chromosome turnover and biodiversity in fishes.

The impact of sex chromosomes and their turnover in speciation remains a subject of ongoing debate in the field of evolutionary biology. Fishes are the largest group of vertebrates, and they exhibit unparalleled sexual plasticity, as well as diverse sex-determining (SD) genes, sex chromosomes, and sex determination mechanisms. This diversity is hypothesized to be associated with the frequent turnover of sex chromosomes in fishes. Although it is evident that amh and amhr2 are repeatedly and independently recruited as SD genes, their relationship with the rapid turnover of sex chromosomes and the biodiversity of fishes remains unknown. We summarize the canonical models of sex chromosome turnover and highlight the vital roles of gene mutation and hybridization with empirical evidence. We revisit Haldane's rule and the large X-effect and propose the hypothesis that sex chromosomes accelerate speciation by multiplying genotypes via hybridization. By integrating recent findings on the turnover of SD genes, sex chromosomes, and sex determination systems in fish species, this review provides insights into the relationship between sex chromosome evolution and biodiversity in fishes.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.