bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational phenotyping of aberrant belief updating in individuals with schizotypal traits and schizophrenia
Authors: Mikus Nace , Lamm Claus , Mathys Christoph 
Published: November 2023

AbstractPsychotic and psychotic-like experiences are thought to emerge from various patterns of disrupted belief updating. These include belief rigidity, overestimating the reliability of sensory information, and misjudging task volatility. Yet, these substrates have never been jointly addressed under one computational framework and it is not clear to what degree they reflect trait-like computational patterns. Here, we introduce a computational model that describes interindividual differences in how individuals update their beliefs about a volatile environment through noisy observations and use this model in a series of studies. In a test-retest study with healthy participants (N = 45, 4 sessions), we find that interclass correlations were moderate to high for session-level model parameters and excellent for averaged belief trajectories and learning rates estimated through hierarchical Bayesian inference. Across three studies (total N=590) we then demonstrate that two distinct computational patterns describe two different transdiagnostic categories. Higher uncertainty about the task volatility is related to schizotypal traits (N = 45, d = 0.687, P = 0.02, N = 437, d = 0.14, P = 0.032) and to positive symptoms in a sample of patients with schizophrenia (N = 108, d = 0.187, P = 0.039), when learning to gain rewards. In contrast, depressive-anxious traits were associated with more rigid beliefs about the underlying mean (N = 437, d = −0.125, P = 0.006) and outcome variance (N = 437, d = −0.111, P = 0.013), as were negative symptoms in patients with schizophrenia (d = - 0.223, P = 0.026, d = −0.298, P = 0.003), when learning to avoid losses. These findings suggest that individuals high on schizotypal traits across the psychosis continuum are less likely to learn or utilize higher-order statistical regularities of the environment and showcase the potential of clinically relevant computational phenotypes for differentiating symptom groups in a transdiagnostic manner.
RNA polymerase II transcription with partially assembled TFIID complexes
Authors: Hisler Vincent , Bardot Paul , Detilleux Dylane , Stierle Matthieu , Sanchez Emmanuel Garcia , Richard Claire , Arab Lynda Hadj , Ehrhard Cynthia , Morlet Bastien , Hadzhiev Yavor , Jung Matthieu , Le Gras Stéphanie , Négroni Luc , Müller Ferenc , Tora László , Vincent Stéphane D. 
Published: November 2023

SUMMARYThe recognition of core promoter sequences by the general transcription factor TFIID is the first step in the process of RNA polymerase II (Pol II) transcription initiation. Metazoan holo-TFIID is composed of the TATA binding protein (TBP) and of 13 TBP associated factors (TAFs). InducibleTaf7knock out (KO) results in the formation of a Taf7-less TFIID complex, whileTaf10KO leads to serious defects within the TFIID assembly pathway. Either TAF7 or TAF10 depletions correlate with the detected TAF occupancy changes at promoters, and with the distinct phenotype severities observed in mouse embryonic stem cells or mouse embryos. Surprisingly however, under eitherTaf7orTaf10deletion conditions, TBP is still associated to the chromatin, and no major changes are observed in nascent Pol II transcription. Thus, partially assembled TFIID complexes can sustain Pol II transcription initiation, but cannot replace holo-TFIID over several cell divisions and/or development.
Protein domain embeddings for fast and accurate similarity search
Authors: Iovino Benjamin Giovanni , Tang Haixu , Ye Yuzhen 
Published: November 2023

AbstractRecently developed protein language models have enabled a variety of applications with the protein contextual embeddings they produce. Per-protein representations (each protein is represented as a vector of fixed dimension) can be derived via averaging the embeddings of individual residues, or applying matrix transformation techniques such as the discrete cosine transformation to matrices of residue embeddings. Such protein-level embeddings have been applied to enable fast searches of similar proteins, however limitations have been found; for example, PROST is good at detecting global homologs but not local homologs, and knnProtT5 excels for proteins of single domains but not multi-domain proteins. Here we propose a novel approach that first segments proteins into domains (or subdomains) and then applies the discrete cosine transformation to the vectorized embeddings of residues in each domain to infer domain-level contextual vectors. Our approach, called DCTdomain, utilizes predicted contact maps from ESM-2 for domain segmentation, which is formulated as adomain segmentationproblem and can be solved using arecursive cutalgorithm (RecCut in short) in quadratic time to the protein length; for comparison, an existing approach for domain segmentation uses a cubic-time algorithm. We showed such domain-level contextual vectors (termed asDCT fingerprints) enable fast and accurate detection of similarity between proteins that share global similarities but with undefined extended regions between shared domains, and those that only share local similarities.
White matter lipidome alterations in the schizophrenia brain
Authors: Senko Dmitry , Osetrova Maria , Efimova Olga , Anikanov Nikolai , Tkachev Anna , Boyko Maria , Sharaev Maksim , Morozova Anna , Zorkina Yana , Kostyuk Georgiy , Stekolshchikova Elena , Khaitovich Philipp 
Published: November 2023

AbstractNumerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, affecting specific lipid classes. These alterations partly involved myelin-forming lipid classes, particularly sphingolipids, with the extent of alterations reflecting the myelin changes previously reported in structural brain imaging studies. The other part of the schizophrenia-associated alterations, which showed a significant decrease in the disorder, involved lipid classes abundant in mitochondria. A similar significant decrease was also observed in the mitochondria-enriched membrane fraction isolated from the white matter of individuals with schizophrenia. This suggests a substantial reduction in the number of mitochondria in subcortical white matter in schizophrenia, a hypothesis supported by quantitative mitochondria staining.
Random forest classifiers trained on simulated data enable accurate short read-based genotyping of structural variants in the alpha globin region at Chr16p13.3
Authors: Hansen Nancy F. , Wang Xunde , Tegegn Mickias B. , Liu Zhi , Gouveia Mateus H. , Hill Gracelyn , Lin Jennifer C. , Okulosubo Temiloluwa , Shriner Daniel , Thein Swee Lay , Mullikin James C. 
Published: November 2023

AbstractIn regions where reads don’t align well to a reference, it is generally difficult to characterize structural variation using short read sequencing. Here, we utilize machine learning classifiers and short sequence reads to genotype structural variants in the alpha globin locus on chromosome 16, a medically-relevant region that is challenging to genotype in individuals. Using models trained only with simulated data, we accurately genotype two hard-to-distinguish deletions in two separate human cohorts. Furthermore, population allele frequencies produced by our methods across a wide set of ancestries agree more closely with previously-determined frequencies than those obtained using currently available genotyping software.
Sleep loss impairs myelin function by altering cholesterol metabolism in oligodendroglia
Authors: Simayi Reyila , Ficiarà Eleonora , Faniyan Oluwatomisin , Cerdán Cerdá Antonio , Aboufares El Alaoui Amina , Fiorini Rosamaria , Cutignano Adele , Piscitelli Fabiana , Andújar Pablo , Santos Alexandra , Del Gallo Federico , de Vivo Luisa , De Santis Silvia , Bellesi Michele 
Published: November 2023

AbstractThe increasing prevalence of sleep deprivation in modern society demands comprehension of the biological consequences of sleep loss on brain functioning. Our study reveals significant effects of sleep deprivation on myelin integrity. As a result, we identify increased conduction delays in nerve signal propagation, hindered interhemispheric synchronization, and impaired motor performance associated with sleep loss. By profiling oligodendrocyte transcriptome and lipidome, we observe sleep loss-induced endoplasmic reticulum stress and lipid metabolism disruption, particularly affecting cholesterol homeostasis. This shift in cholesterol levels alters myelin physical properties. Boosting cholesterol transport to myelin sheaths prevents sleep loss effects on nerve signal propagation and behavior. Our findings highlight the critical role of oligodendrocyte cholesterol regulation in behavioral deficits associated with sleep loss and unveil a novel target for intervention.
Exploring Relationships BetweenIn VitroAqueous Solubility and Permeability andIn VivoFraction Absorbed
Authors: Fagerholm Urban 
Published: November 2023

ABSTRACTIntroductionSolubility/dissolution and permeability are essential determinants of gastrointestinal absorption of drugs.In vitroaqueous solubility (S) and apparent permeability (Papp) are commonly used as measurements and predictors ofin vivofraction absorbed (fa) and BCS-classing in humans. The objective of this study was to explore the relationships betweenin vitroaqueous S and Dose number (Do) andin vivofaandin vitroPappandin vivofaand the predictive power ofin vitroaqueous S, Doand Papp.MethodsIn vitroandin vivodata were taken from studies in the literature and correlated.In vitroS data were produced in various laboratories and with different methodologies.In vitroPappdata were produced using Caco-2 and MDCK cells in various laboratories and Caco-2 and RRCK cells in one laboratory each. Dowas estimated as oral dose / (S • 250 mL).Results452 S data and 1480 Pappdata were found and used. There was no correlation (R2=0.0) betweenin vitrolog S and Dovs in vivofa, not even at S<1 mg/L or not for compounds with <90 % and <30 %in vivofa. A R2of 0.43 was found between log Caco-2 Pappandin vivofa. The corresponding R2for Caco-2 from one laboratory was 0.65. The interlaboratory R2for the Caco-2 model was 0.48. R2-estimates for Caco-2vsMDCK and Caco-2vsRRCK Pappwere 0.23 and 0.21, respectively.Discussion and ConclusionAqueous S appears to have no predictive value ofin vivofain humans, not even at low S or after correction for dose. The shows that one should not base human biopharmaceutical predictions based on aqueous S. Log Caco-2 Pappexplains about half of the variance ofin vivofain humans. The poor correlations found between Caco-2 and the two other Papp-models (MDCK and RRCK) demonstrate considerable methodological differences. The unexplained variance does not appear to be explained by S and dose, but rather byin vitro-in vivodifference in permeability and poor/absent relationship betweenin vitroS andin vivodissolution potential.
Flight behaviour diverges more between seasonal forms than between species inPierisbutterflies
Authors: Kleckova Irena , Linke Daniel , Rezende Francisko De Moraes , Rauscher Luca , Le Roy Camille , Matos-Maraví Pável 
Published: November 2023

AbstractIn flying animals, wing morphology is typically assumed to influence flight behaviours. Whether seasonal polymorphism behaviour might be associated with divergent fore wing shapes.Pierisindividuals in the spring are small and have elongated fore wings, traits correlate with low fly speed and acceleration, and in butterfly morphology is linked to adaptive flight behaviour remains unresolved. Here we compare the flight behaviours and wing morphologies of the spring and summer forms of two closely related butterfly species,Pieris napiandP. rapae. We first quantify three-dimensional flight behaviour by reconstructing individual flight trajectories using stereoscopic high-speed videography in an experimental outdoor cage. We then measure wing size and shape, which are characteristics assumed to influence flight behaviours in butterflies. We show that seasonal, but not interspecific, differences in flight high flight curvature. Large summer individuals exhibit rounded fore wings, which correlate with high flight speed, acceleration, turning acceleration, and advance ratio. Our study provides quantitative evidence of different flight behaviours between seasonal forms ofPierisbutterflies, and these differences were better predicted by body size and forewing shape, rather than other factors (e.g., species identity, ambient temperature). This points toward a possible adaptive role of seasonal morphology determining flight behaviours, although this needs to be thoroughly investigated to distinguish the effects of microhabitat (e.g., behavioural thermoregulation, resource distribution between seasons, such as nectar and larval food plants), predator and parasitoid pressure, and possible sexual behavioural differences.
Sequence-based drug design using transformers
Authors: Zhang Shengyu , Huo Donghui , Horne Robert I. , Qi Yumeng , Ojeda Sebastian Pujalte , Yan Aixia , Vendruscolo Michele 
Published: November 2023

AbstractProtein-ligand interactions play central roles in biological processes and are of key importance in drug design. Deep learning-based approaches are emerging as cost-effective alternatives to high-throughput experimental methods for the screening of large libraries of ligands. Here, to predict the binding affinity between proteins and small molecules, we introduce Ligand-Transformer, a deep learning framework based on the AlphaFold2 transformer architecture. We applied Ligand-Transformer to screen inhibitors targeting the mutant EGFRLTCkinase, identifying compounds with low nanomolar potency. We then used this approach to predict the conformational population shifts induced by ABL kinase inhibitors. To show the applicability of Ligand-Transformer to disordered proteins, we explored the binding of small molecules to the Alzheimer’s Aβ peptide, identifying compounds that delayed its aggregation. Overall, Ligand-Transformer illustrates the potential of transformers in accurately predicting the interactions of small molecules with both ordered and disordered proteins, thus uncovering molecular mechanisms and facilitating the initial steps in drug discovery.
Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging
Authors: Dutta Naibedya , Gerke Joe A , Odron Sofia F , Morris Joseph D , Hruby Adam , Torres Toni Castro , Shemtov Sarah J , Clarke Jacqueline G , Chang Michelle C , Shaghasi Hooriya , Ray Marissa N. , Averbukh Maxim , Hoang Sally , Oorloff Maria , Alcala Athena , Vega Matthew , Mehta Hemal H , Thorwald Max A , Crews Phillip , Vermulst Marc , Garcia Gilberto , Johnson Tyler A , Higuchi-Sanabria Ryo 
Published: November 2023

ABSTRACTSmall molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine spongeC. mycofijiensisand its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizingC.elegansmodel demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMTand heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.
Molecular Regulation of Invasive Protrusion Formation at the Mammalian Fusogenic Synapse
Authors: Lu Yue , Walji Tezin , Ravaux Benjamin , Pandey Pratima , Li Bing , Lam Kevin H. , Zhang Ruihui , Goldhamer David J. , Li Rong , Schmidtke David W. , Pan Duojia , Chen Elizabeth H. 
Published: November 2023

AbstractInvasive membrane protrusions play a central role in a variety of cellular processes. Unlike filopodia, invasive protrusions are mechanically stiff and propelled by branched actin polymerization. However, how branched actin filaments are organized to create finger-like invasive protrusions remains a longstanding question in cell biology. Here, by examining the mammalian fusogenic synapse, where invasive protrusions are generated to promote cell membrane juxtaposition and fusion, we have uncovered the mechanism underlying invasive protrusion formation. We show that two Arp2/3 nucleation promoting factors (NPFs), WAVE and N-WASP, exhibit distinct and complementary localization patterns in the protrusions. While WAVE is at the leading edge, N-WASP is recruited by its interacting protein, WIP, to the shaft of the protrusion. During protrusion growth, new branched actin filaments are polymerized at the periphery of the shaft and crosslinked to preexisting actin bundles by the “pioneer” actin-bundling protein dynamin. The thickened actin bundles are further stabilized by WIP, which functions as a WH2 domain-mediated actin-bundling protein. Disrupting any of these components results in defective protrusions and myoblast fusion in cultured cells and/or in mouse embryos. Thus, our study has revealed the intricate spatiotemporal coordination between two NPFs and two actin-bundling proteins in creating invasive protrusions and has general implications in understanding protrusion formation in many cellular processes beyond cell-cell fusion.
Frontal cortex norepinephrine, serotonin, and dopamine dynamics in an innate fear-reward behavioral model
Authors: Yang Jen-Hau , Basu Aakash , Liu Rong-Jian , Staszko Stephanie M. , Yu Abigail L. , Rondeau Jocelyne , Glaeser-Khan Samira , Feng Jiesi , Li Yulong , Che Alicia , Kaye Alfred P. 
Published: November 2023

AbstractAnimals must survive by foraging for food in an uncertain and dangerous world. Experimental tasks such as Pavlovian learning have yielded insights into how neural circuits balance these conflicting motivational drives. Neuromodulators play a fundamental role in this process, enabling flexible switching between motivational drives. The question of how neuromodulators synergistically encode motivational state is thus fundamental to systems neuroscience, yet the interplay between these neuromodulators during naturalistic decision making are not fully understood. Here, we developed a naturalistic approach/avoidance task in mice involving a tradeoff between seeking reward versus safety in the presence of looming predation risk. We utilized multi-fiber photometry, computational behavior tracking, and slice electrophysiology to understand the. Mice that experienced looming stimuli showed increased c-fos expression in regions including frontal cortex, locus coeruleus, and ventral tegmental area, but decreased expression in dorsal raphe nucleus. Moreover, by using multi-fiber photometry combined with GPCR-based sensors, we found that cortical norepinephrine (NE) plays a more prominent role in encoding looming threats while dopamine (DA) represents reward and threat. In contrast, serotonin (5HT) dynamic negatively correlates to both emotional valences. To begin to understand neuromodulatory interactions, we usedex vivoslice physiology to understand 5HT impact on spontaneous firing of locus coeruleus NE neurons. In conclusion, monoamines such as NE, DA, 5HT can converge in their encoding of naturalistic motivated behaviors as well as dissociate from one another. By utilizing this approach, interactions between innate fear and incentive for food may be delineated in terms of basis in neurochemical signaling events during natural behavior, and may contribute to the understanding of neural mechanisms underlying emotional disorders including anxiety and post-traumatic stress disorder.
Genotypes and associations with symptoms in primary ciliary dyskinesia
Authors: Pedersen Eva SL , Goutaki Myrofora , Schreck Leonie D , Rindlisbacher Bernhard , Dixon Lucy ,   COVID-PCD patient advisory group, Lucas Jane S , Kuehni Claudia E 
Published: November 2023

AbstractBackgroundKnowledge about genotype-phenotype associations is crucial for understanding the clinical variability of primary ciliary dyskinesia (PCD). We studied how feasible it is to collect information about causative genes directly from people with PCD through questionnaires, and investigated associations between clinical characteristics, symptoms, and genotype.MethodsWe used data from the anonymous international participatory cohort COVID-PCD, set up in 2020 to follow people with PCD during the COVID-19 pandemic. A baseline questionnaire asked genetic test results, clinical characteristics, and current symptoms. We grouped reported causative genes into categories based on associated defects and studied differences between groups.ResultsAmong the 759 COVID-PCD study participants, 444 (58%) reported genetic testing, and of these, 289 (65%) reported that a gene was identified. We included 206 who knew and reported a causative gene. The most common genes wereDNAH5(n=71; 34%),DNAH11(n=27; 13%),CCDC40(n=21; 10%),DNAI1(n=18; 9%),CCDC39(n=13; 6%), and RSPH1 (n=8; 4%). The dynein structure (DS) group was the largest (n=127) followed by the nexin-dynein regulatory complex (ND-RC) group (n=38), dynein assembly (DA) group (n=21), and radial spoke and central complex (RS-CC, n=20) Current age and sex were similar across groups; but median age at diagnosis was markedly higher in the RS-CC group (11 years) compared to 4–7 years in the other groups (p=0.035). Laterality defects were reported by one person (5%) in RS-CC group, compared with 37%-60% in other groups (p=0.001). Overall, symptoms were frequently reported by participants in all 4 groups with little difference between groups.ConclusionOur results confirmed known differences in laterality defects and congenital heart disease between genotypes and showed frequent upper and lower respiratory symptoms in all groups regardless of reported gene.