Search

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research., Competing Interests: Competing interests CMB reports receiving royalties from Pearson Education, Inc. The authors have no conflicts of interest to declare., (© 2024. The Author(s).)

Access to defined glycans and glycoconjugates is pivotal for discovery, dissection, and harnessing of a range of biological functions orchestrated by cellular glycosylation processes and the glycome. We previously employed genetic glycoengineering by nuclease-based gene editing to develop sustainable production of designer glycoprotein therapeutics and cell-based glycan arrays that display glycans in their natural context at the cell surface. However, access to human glycans in formats and quantities that allow structural studies of molecular interactions and use of glycans in biomedical applications currently rely on chemical and chemoenzymatic syntheses associated with considerable labor, waste, and costs. Here, we develop a sustainable and scalable method for production of glycans in glycoengineered mammalian cells by employing secreted Glycocarriers with repeat glycosylation acceptor sequence motifs for different glycans. The Glycocarrier technology provides a flexible production platform for glycans in different formats, including oligosaccharides, glycopeptides, and multimeric glycomodules, and offers wide opportunities for use in bioassays and biomedical applications., (© 2024. The Author(s).)

Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex fluid is rich in extracellular vesicles (EVs). Here, we have applied a microfluidic technology, lipid-based protein immobilization (LPI) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) to characterize the proteome of human milk EVs. Mature milk from six mothers was subjected to EV isolation by ultracentrifugation followed by size exclusion chromatography. Three of the samples were carefully characterized; suggesting a subset enriched by small EVs. The EVs were digested by trypsin in an LPI flow cell and in-solution digestion, giving rise to two fractions of peptides originating from the surface proteome (LPI fraction) or the complete proteome (in-solution digestion). LC-MS/MS recovered peptides corresponding to 582 proteins in the LPI fraction and 938 proteins in the in-solution digested samples; 400 of these proteins were uniquely found in the in-solution digested samples and were hence denoted "cargo proteome". GeneOntology overrepresentation analysis gave rise to distinctly different functional predictions of the EV surfaceome and the cargo proteome. The surfaceome tends to be overrepresented in functions and components of relevance for the immune system, while the cargo proteome primarily seems to be associated with EV biogenesis., Competing Interests: Emelie Ahlberg, Maria C. Jenmalm and Lina Tingö report no conflict of interest. Anders Karlsson and Roger Karlsson are affiliated to a company, Nanoxis Consulting AB. The company did not have influence on the study design, data collection, data analysis or interpretation of data, the writing of the paper or the decision to submit for publication., (© 2024 The Author(s). Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Pedestrian action prediction is crucial for many applications such as autonomous driving. However, state-of-the-art methods lack the explainability needed for trustworthy predictions. In this paper, a novel framework called MulCPred is proposed that explains its predictions based on multi-modal concepts represented by training samples. Previous concept-based methods have limitations, including the following: (1) they cannot be directly applied to multi-modal cases; (2) they lack the locality needed to attend to details in the inputs; (3) they are susceptible to mode collapse. These limitations are tackled accordingly through the following approaches: (1) a linear aggregator to integrate the activation results of the concepts into predictions, which associates concepts of different modalities and provides ante hoc explanations of the relevance between the concepts and the predictions; (2) a channel-wise recalibration module that attends to local spatiotemporal regions, which enables the concepts with locality; (3) a feature regularization loss that encourages the concepts to learn diverse patterns. MulCPred is evaluated on multiple datasets and tasks. Both qualitative and quantitative results demonstrate that MulCPred is promising in improving the explainability of pedestrian action prediction without obvious performance degradation. Moreover, by removing unrecognizable concepts, MulCPred shows improved cross-dataset prediction performance, suggesting its potential for further generalization.

Importance: Schizophrenia and bipolar disorder are highly heritable psychiatric disorders with strong genetic and phenotypic overlap. Twin and molecular methods can be leveraged to predict the shared genetic liability to these disorders., Objective: To investigate whether twin concordance for psychosis depends on the level of polygenic risk score (PRS) for psychosis and zygosity and compare PRS from cases and controls from several large samples and estimate the twin heritability of psychosis., Design, Setting, and Participants: In this case-control study, psychosis PRS were generated from a genome-wide association study (GWAS) combining schizophrenia and bipolar disorder into a single psychosis phenotype and compared between cases and controls from the Schizophrenia and Bipolar Twin Study in Sweden (STAR) project. Further tests were conducted to ascertain if twin concordance for psychosis depended on the mean PRS for psychosis. Structural equation modeling was used to estimate heritability. This study constituted an analysis of existing clinical and population datasets with genotype and/or twin data. Included were twins from the STAR cohort and from the Swedish Twin Registry. Data were collected during the 2006 to 2013 period and analyzed from March 2023 to June 2024., Exposures: PRS for psychosis based on the most recent GWAS of combined schizophrenia/bipolar disorder., Main Outcomes and Measures: Psychosis case status was assessed by clinical interviews and/or Swedish National Register data., Results: The final cohort comprised 87 pairs of twins with 1 or both affected and 59 unaffected pairs from the STAR project (for a total of 292 twins) as well as 443 pairs with 1 or both affected and 20 913 unaffected pairs from the Swedish Twin Registry. Among the 292 twins (mean [SD] birth year, 1960 [10.8] years; 158 female [54.1%]; 134 male [45.9%]), 134 were monozygotic twins, and 158 were dyzygotic twins. PRS for psychosis was higher in cases than in controls and associated with twin concordance for psychosis (1-SD increase in PRS, odds ratio [OR], 2.12; 95% CI, 1.23-3.87 on case status in monozygotic twins and OR, 2.74; 95% CI, 1.56-5.30 in dizygotic twins). The association between PRS for psychosis and concordance was not modified by zygosity. The twin heritability was estimated at 0.73 (95% CI, 0.30-1.00), which overlapped with the estimate in the full Swedish Twin Registry (0.69; 95% CI, 0.43-0.85)., Conclusions and Relevance: In this case-control study, using the natural experiment of twins, results suggest that twins with greater inherited liability for psychosis were more likely to have an affected co-twin. Results from twin and molecular designs largely aligned. Even as illness vulnerability is not solely genetic, PRS carried predictive power for psychosis even in a modest sample size.

Staphylococcus aureus is a pathogen known to cause a wide range of infections. To find new targets for identification and to understand host-pathogen interactions, many studies have focused on surface proteins. We performed bacterial-cell surface-shaving, followed by tandem mass tag for quantitative mass spectrometry proteomics, to examine the surfaceome of S. aureus . Two steps were performed, the first step including surface protein-deficient mutants of S. aureus Newman strain lacking important virulence genes ( clfA and spa , important for adhesion and immune evasion and srtAsrtB , linking surface-associated virulence factors to the surface) and the second step including isolates of different clinical origin. All strains were compared to the Newman strain. In Step 1, altogether, 7880 peptides were identified, corresponding to 1290 proteins. In Step 2, 4949 peptides were identified, corresponding to 919 proteins and for each strain, approximately 20 proteins showed differential expression compared to the Newman strain. The identified surface proteins were related to host-cell-adherence and immune-system-evasion, biofilm formation, and survival under harsh conditions. The results indicate that surface-shaving of intact S. aureus bacterial strains in combination with quantitative proteomics is a useful tool to distinguish differences in protein abundance of the surfaceome, including the expression of virulence factors.

Dog ownership has been associated with several complex traits, and there is evidence of genetic influence. We performed a genome-wide association study of dog ownership through a meta-analysis of 31,566 Swedish twins in 5 discovery cohorts and an additional 65,986 European-ancestry individuals in 3 replication cohorts from Sweden, Norway, and the United Kingdom. Association tests with >7.4 million single-nucleotide polymorphisms were meta-analyzed using a fixed effect model after controlling for population structure and relatedness. We identified 2 suggestive loci using discovery cohorts, which did not reach genome-wide significance after meta-analysis with replication cohorts. Single-nucleotide polymorphism-based heritability of dog ownership using linkage disequilibrium score regression was estimated at 0.123 (CI 0.038-0.207) using the discovery cohorts and 0.018 (CI -0.002 to 0.039) when adding in replication cohorts. Negative genetic correlation with complex traits including type 2 diabetes, depression, neuroticism, and asthma was only found using discovery summary data. Furthermore, we did not identify any genes/gene-sets reaching even a suggestive level of significance. This genome-wide association study does not, by itself, provide clear evidence on common genetic variants that influence dog ownership among European-ancestry individuals., Competing Interests: Conflict of interest KHL, CT, and the members of 23andMe Research Team are listed as authors or were employed by and hold stock or stock options in 23andMe, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

The black fungus Exophiala causes a wide range of infections from superficial to subcutaneous, but also invasive fungal infections in immunocompromised patients as well as healthy individuals. In addition, Exophiala, is a common colonizer of the air ways of patients with cystic fibrosis. However, the source of infection and mode of transmission is still unclear. The aim of this study was to investigate the presence of Exophiala in samples collected from Swedish indoor environments. We found that the Exophiala species were commonly found in dishwashers and that Exophiala dermatitidis was the most common Exophiala species, being identified in 70% (26 out of the 37) of samples. Almost all E. dermatitidis isolates had the ability to grow at 42 °C (P = 0.0002) and were catalase positive. Voriconazole and posaconazole exhibited the lowest MICs, while caspofungin and anidulafungin lack the antifungal activities in vitro. Future studies are needed to illuminate the transmission mode of the fungi., (© 2024. The Author(s).)

Cognitive scientists believe that adaptable intelligent agents like humans perform spatial reasoning tasks by learned causal mental simulation. The problem of learning these simulations is called predictive world modeling. We present the first framework for a learning open-vocabulary predictive world model (OV-PWM) from sensor observations. The model is implemented through a hierarchical variational autoencoder (HVAE) capable of predicting diverse and accurate fully observed environments from accumulated partial observations. We show that the OV-PWM can model high-dimensional embedding maps of latent compositional embeddings representing sets of overlapping semantics inferable by sufficient similarity inference. The OV-PWM simplifies the prior two-stage closed-set PWM approach to the single-stage end-to-end learning method. CARLA simulator experiments show that the OV-PWM can learn compact latent representations and generate diverse and accurate worlds with fine details like road markings, achieving 69 mIoU over six query semantics on an urban evaluation sequence. We propose the OV-PWM as a versatile continual learning paradigm for providing spatio-semantic memory and learned internal simulation capabilities to future general-purpose mobile robots.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies., Competing Interests: Per Hoffmann receives Salary from the Life & Brain GmbH, Bonn, Germany. James L. Kennedy is a member of the Scientific Advisory Board for Myriad Neuroscience Inc. Ian B. Hickie was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-18). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. Andrew M. Mcintosh has received research support from Eli Lilly, Janssen, and The Sackler Trust. AMM has also received speaker fees from Illumina and Janssen. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He is paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Joel Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082; and is paid for editorial work for the journal “Complex Psychiatry.” Iiris Hovatta received speaker’s honoraria from Lundbeck. Ole A. Andreassen received speaker’s honorarium from Lundbeck and Sunovion, consultant for Cortechs.ai and Precision Health AS. Katharina Domschke has been a member of the Steering Committee Neurosciences, Janssen, Inc. until 2022 and is currently a member of the Board of the German National Society of Psychiatry (DGPPN) and the Neurotorium Editorial Board of the Lundbeck Foundation. Jordan W. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar Tempus Labs. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. Eduard Maron has received research support and has also received speaker fees from Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Indorsia, Neuraxpharm, Servier and Janssen Cilag. Henrik Larsson has served as a speaker for Evolan Pharma, Medici and Shire/Takeda and has received research grants from Shire/Takeda; all outside the submitted work. Gerome Breen is an advisory board member for Compass Pathways. Jürgen Deckert is a member of the board of the German Society of Biological Psychiatry and is on the scientific advisory boards of non-profit organizations and foundations. Volker Arolt worked as an advisor for Sanofi-Adventis Germany. Zach Fuller and Xin Wang are employees of 23andMe and hold stock or stock options in 23andMe. All other authors have no competing interests to declare.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment., (© 2024. The Author(s).)

Objective: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder., Methods: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219)., Results: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs., Conclusions: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes., Competing Interests: Dr. Ian Jones has received grant support from Akrivia Health and Takeda. Dr. Sullivan has served as a consultant for and is a shareholder in Neumora Therapeutics. Dr. Landén has received lecture honoraria from Lundbeck Pharmaceutical and has served as a consultant for AstraZeneca. The other authors report no financial relationships with commercial interests.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease., (© 2024. The Author(s).)

El Hierro is the smallest and westernmost island of the Canary Islands, whose population derives from an admixture of different ancestral components and that has been subjected to genetic isolation. We established the "El Hierro Genome Study" to characterize the health status and the genetic composition of ~10% of the current population of the island, accounting for a total of 1054 participants. Detailed demographic and clinical data and a blood sample for DNA extraction were obtained from each participant. Genomic genotyping was performed with the Global Screening Array (Illumina). The genetic composition of El Hierro was analyzed in a subset of 416 unrelated individuals by characterizing the mitochondrial DNA (mtDNA) and Y-chromosome haplogroups and performing principal component analyses (PCAs). In order to explore signatures of isolation, runs of homozygosity (ROHs) were also estimated. Among the participants, high blood pressure, hypercholesterolemia, and diabetes were the most prevalent conditions. The most common mtDNA haplogroups observed were of North African indigenous origin, while the Y-chromosome ones were mainly European. The PCA showed that the El Hierro population clusters near 1000 Genomes' European population but with a shift toward African populations. Moreover, the ROH analysis revealed some individuals with an important portion of their genomes with ROHs exceeding 400 Mb. Overall, these results confirmed that the "El Hierro Genome" cohort offers an opportunity to study the genetic basis of several diseases in an unexplored isolated population.

The NLRP3 inflammasome is an intracellular multiprotein complex described to be involved in both an effective host response to infectious agents and various diseases. Investigation into the NLRP3 inflammasome has been extensive in the past two decades, and often revolves around the analysis of a few specific readouts, including ASC-speck formation, caspase-1 cleavage or activation, and cleavage and release of IL-1β and/or IL-18. Quantification of these readouts is commonly undertaken as an endpoint analysis, where the presence of each positive outcome is assessed independently of the others. In this study, we apply time-resolved analysis of a human macrophage model (differentiated THP-1-ASC-GFP cells) to commonly accessible methods. This approach yields the additional quantifiable metrics time-resolved absolute change and acceleration, allowing comparisons between readouts. Using this methodological approach, we reveal (potential) discrepancies between inflammasome-related readouts that otherwise might go undiscovered. The study highlights the importance of time-resolved data in general and may be further extended as well as incorporated into other areas of research., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:co-author affiliated to Nanoxis Consulting AB - R.K. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Transformer-based models have gained popularity in the field of natural language processing (NLP) and are extensively utilized in computer vision tasks and multi-modal models such as GPT4. This paper presents a novel method to enhance the explainability of transformer-based image classification models. Our method aims to improve trust in classification results and empower users to gain a deeper understanding of the model for downstream tasks by providing visualizations of class-specific maps. We introduce two modules: the "Relationship Weighted Out" and the "Cut" modules. The "Relationship Weighted Out" module focuses on extracting class-specific information from intermediate layers, enabling us to highlight relevant features. Additionally, the "Cut" module performs fine-grained feature decomposition, taking into account factors such as position, texture, and color. By integrating these modules, we generate dense class-specific visual explainability maps. We validate our method with extensive qualitative and quantitative experiments on the ImageNet dataset. Furthermore, we conduct a large number of experiments on the LRN dataset, which is specifically designed for automatic driving danger alerts, to evaluate the explainability of our method in scenarios with complex backgrounds. The results demonstrate a significant improvement over previous methods. Moreover, we conduct ablation experiments to validate the effectiveness of each module. Through these experiments, we are able to confirm the respective contributions of each module, thus solidifying the overall effectiveness of our proposed approach.

Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively. Sema5A harbors seven thrombospondin type-1 repeats (TSR1-7) important for GAG binding, however the underlying molecular basis and functions in vivo remain enigmatic. Here we dissect the structural basis for Sema5A:GAG specificity and demonstrate the functional significance of this interaction in vivo. Using x-ray crystallography, we reveal a dimeric fold variation for TSR4 that accommodates GAG interactions. TSR4 co-crystal structures identify binding residues validated by site-directed mutagenesis. In vitro and cell-based assays uncover specific GAG epitopes necessary for TSR association. We demonstrate that HS-GAG binding is preferred over CS-GAG and mediates Sema5A oligomerization. In vivo, Sema5A:GAG interactions are necessary for Sema5A function and regulate Plexin-A2 dependent dentate progenitor cell migration. Our study rationalizes Sema5A associated developmental and neurological disorders and provides mechanistic insights into how multifaceted guidance functions of a single transmembrane cue are regulated by proteoglycans., (© 2024. The Author(s).)

Rapid advances over the last decade in DNA sequencing and statistical genetics enable us to investigate the genomic makeup of individuals throughout history. In a recent notable study, Begg et al. 1 used Ludwig van Beethoven's hair strands for genome sequencing and explored genetic predispositions for some of his documented medical issues. Given that it was arguably Beethoven's skills as a musician and composer that made him an iconic figure in Western culture, we here extend the approach and apply it to musicality. We use this as an example to illustrate the broader challenges of individual-level genetic predictions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B 12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health., (© 2023. The Author(s).)

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although many user-friendly workflows exist for identifications of peptides and proteins in mass-spectrometry-based proteomics, there is a need of easy to use, fast, and accurate workflows for identifications of microorganisms, antimicrobial resistant proteins, and biomass estimation. Identification of microorganisms is a computationally demanding task that requires querying thousands of MS/MS spectra in a database containing thousands to tens of thousands of microorganisms. Existing software can't handle such a task in a time efficient manner, taking hours to process a single MS/MS experiment. Another paramount factor to consider is the necessity of accurate statistical significance to properly control the proportion of false discoveries among the identified microorganisms, and antimicrobial-resistant proteins, and to provide robust biomass estimation. Recently, we have developed Microorganism Classification and Identification (MiCId) workflow that assigns accurate statistical significance to identified microorganisms, antimicrobial-resistant proteins, and biomass estimation. MiCId's workflow is also computationally efficient, taking about 6-17 minutes to process a tandem mass-spectrometry (MS/MS) experiment using computer resources that are available in most laptop and desktop computers, making it a portable workflow. To make data analysis accessible to a broader range of users, beyond users familiar with the Linux environment, we have developed a graphical user interface (GUI) for MiCId's workflow. The GUI brings to users all the functionality of MiCId's workflow in a friendly interface along with tools for data analysis, visualization, and to export results.