bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying genetic variants that influence the abundance of cell states in single-cell data
Authors: Rumker Laurie , Sakaue Saori , Reshef Yakir , Kang Joyce B. , Yazar Seyhan , Alquicira-Hernandez Jose , Valencia Cristian , Lagattuta Kaitlyn A , Mah-Som Annelise , Nathan Aparna , Powell Joseph E. , Loh Po-Ru , Raychaudhuri Soumya 
Published: November 2023

Introductory ParagraphTo understand genetic mechanisms driving disease, it is essential but difficult to map how risk alleles affect the composition of cells present in the body. Single-cell profiling quantifies granular information about tissues, but variant-associated cell states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce GeNA (Genotype-Neighborhood Associations), a statistical tool to identify cell state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of scRNA-seq peripheral blood profiling from 969 individuals,1GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (p=1.96×10-11) associates with increased abundance of NK cells expressing TNF-α response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-TNF treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk.
Continuous evolution of user-defined genes at 1-million-times the genomic mutation rate
Authors: Rix Gordon , Williams Rory L. , Spinner Hansen , Hu Vincent J. , Marks Debora S. , Liu Chang C. 
Published: November 2023

AbstractWhen nature maintains or evolves a gene’s function over millions of years at scale, it produces a diversity of homologous sequences whose patterns of conservation and change contain rich structural, functional, and historical information about the gene. However, natural gene diversity likely excludes vast regions of functional sequence space and includes phylogenetic and evolutionary eccentricities, limiting what information we can extract. We introduce an accessible experimental approach for compressing long-term gene evolution to laboratory timescales, allowing for the direct observation of extensive adaptation and divergence followed by inference of structural, functional, and environmental constraints for any selectable gene. To enable this approach, we developed a new orthogonal DNA replication (OrthoRep) system that durably hypermutates chosen genes at a rate of >10−4substitutions per basein vivo. When OrthoRep was used to evolve a conditionally essential maladapted enzyme, we obtained thousands of unique multi-mutation sequences with many pairs >60 amino acids apart (>15% divergence), revealing known and new factors influencing enzyme adaptation. The fitness of evolved sequences was not predictable by advanced machine learning models trained on natural variation. We suggest that OrthoRep supports the prospective and systematic discovery of constraints shaping gene evolution, uncovering of new regions in fitness landscapes, and general applications in biomolecular engineering.
ESMBind and QBind: LoRA, QLoRA, and ESM-2 for Predicting Binding Sites and Post Translational Modification
Authors: Schreiber Amelie 
Published: November 2023

AbstractIn this study we discuss the viability of applying protein language models to the problem of predicting bindings sites of protein sequences from single sequences alone using Low Rank Adaptation (LoRA) and Quantized Low Rank Adaptation (QLoRA). No Multiple Sequence Alignment (MSA) or structural information for the proteins was used. Moreover, using LoRA and QLoRA shows improved performance over vanilla full finetuning, and significantly helps in mitigating overfitting. Also, due to the efficiency of LoRA and QLoRA, we are able to train the larger ESM-2 models on modest hardware, making the method very attractive and accessible. We also note that this technique serves as an important regularization technique and serves to improve generalization of models on unseen data.
Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades
Authors: Dadonaite Bernadeta , Brown Jack , McMahon Teagan E , Farrell Ariana G , Asarnow Daniel , Stewart Cameron , Logue Jenni , Murrell Ben , Chu Helen Y. , Veesler David , Bloom Jesse D 
Published: November 2023

AbstractSARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties that contribute to viral fitness such as ACE2 receptor binding and cell entry. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning to measure how >9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry, or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully impacted ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456, and 473—however, the antigenic impacts of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.
Neonatal Autonomic Regulation as a Predictor of Autism Spectrum Disorder in Very Preterm Infants
Authors: Bradshaw Jessica , O’Reilly Christian , Everhart Kayla C. , Dixon Elizabeth , Vinyard Amy , Tavakoli Abbas , Iskersky Victor , Dail Robin B. 
Published: November 2023

ABSTRACTInfants born preterm are at a significantly higher likelihood of having autism spectrum disorder (ASD). Preterm birth and ASD are both associated with neurological differences, notably autonomic nervous system (ANS) dysfunction, pointing to preterm ANS dysfunction as a potential pathway to ASD, particularly in VPT infants. In this study, a subset of very preterm (VPT) infants enrolled in a large, multisite clinical trial were enrolled in this study at birth (N=20). Continuous measures of minute-by-minute thermal gradients, defined by the difference between central and peripheral temperatures, and hour-by-hour abnormal heart rate characteristics (HRCs) were collected from birth-28 days (>40,000 samples/infant). Following NICU discharge, standardized measures of cognition, language, and motor skills were collected at adjusted ages 6, 9, and 12 months. At 12 months, assessments of social communication and early ASD symptoms were administered. Results suggest significant ASD concerns for half of the sample by 12 months of age. Neonatal abnormal HRCs were strongly associated with 12-month ASD symptoms (r=0.81, p<.01), as was birth gestational age (GA), birth weight (BW), and abnormal negative thermal gradients. ANS measures collected in the first month of neonatal life, more than a year prior to the ASD evaluation, were surprisingly strong predictors of ASD. This study highlights complementary ANS measures that describe how ANS dysfunction, likely resulting from an imbalance between the parasympathetic and sympathetic systems, may impact very early regulatory processes for neonates who later develop ASD. This finding offers a promising avenue for researching ANS-related etiological mechanisms and biomarkers of ASD.
Fibrosis and liver inflammation are key regulators of α1-acid glycoprotein fucosylation
Authors: Oltmanns Carlos , Bremer Birgit , Kusche Laura , Stål Per , Zenlander Robin , Tauwaldt Jan , Rydén Ingvar , Påhlsson Peter , Cornberg Markus , Wedemeyer Heiner 
Published: November 2023

AbstractBackground and AimsThere is an urgent need for new high-quality markers in the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2-bound α1-acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated S2-bound AGP for a predictive advantage in the early detection of HCC.MethodsIn a retrospective case-control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral agents (n=93), we measured S2-bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at treatment start, end of treatment and follow-up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). 31 patients chronically infected with HCV developed HCC after sustained virological response while 62 did not. In addition, samples of HBV, MASLD and HCC from different etiologies patients were measured.ResultsS2-bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2-bound AGP in early detection of HCC during treatment and follow-up. Interestingly, S2-bound AGP levels correlated with aspartate aminotransferase (ρ=0.56, p=9.5×10-15) and liver elastography (ρ=0.67, p=2.2×10-16). Of note, S2-bound AGP decreased in patients chronically infected with HCV after treatment-induced clearance of HCV.ConclusionFibrosis and liver inflammation are key regulators in the fucosylation of AGP. The potential role of S2-bound AGP as a novel tumor marker requires further investigation.Graphical abstract
Association of Genetic Variant in MC4R (rs17782313) Gene with Obesity and Other Health Behaviors among Selected Bangladeshi Population: A Population-based Case-control Study
Authors: Jhily Nusrat Jahan , Shill Lincon Chandra , Supti Dilara Akter , Munim Md Adnan , Rashid Rumana , Yeasmin Roksana , Alam Mohammad Rahanur 
Published: November 2023

AbstractBackground and AimsThis study aim to investigate the influence of a gene polymorphism (rs17782313) on obesity-related traits and biochemical parameters in the Bangladeshi population and the association between this polymorphism and lifestyle-related risk factors.MethodsThe study was carried out with 320 samples of which 160 were obese and 160 were healthy people. BMI, MUAC, waist and hip circumference, systolic and diastolic blood pressure, lipid profile, and other socio-demographic and anthropometric profile were accounted for to assess the metabolic properties which are associated with obesity. The tetra-primer Amplified Refractory Mutation System Polymerase chain reaction (ARMS-PCR) was used to genotype rs17782313 in the MC4R gene by using the isolated DNA from collected peripheral blood from the selected sample.ResultThe prevalence of hypertension, heart disease, and diabetes were significantly higher among the case group (p<.05) as compared with healthy people. BMI, waist circumference, and hip circumference were significantly higher among people carrying minor allele C (p<.05). We also found a significant difference in dominant (CC vs. CT+TT), co-dominant (CC vs. CT and TT), and recessive (TT vs. CC+CT) model between case and control group (p<.05), which may indicate that rs17782313 in MC4R significantly predict obesity.ConclusionIn conclusion, this study shows the significant association of rs17782313 in MC4R with obesity and obesity-related other health problems. The study has to be conducted further in a broad population to establish a strong association.
High-throughput screening assay for PARP-HPF1 interaction inhibitors to affect DNA damage repair
Authors: Dhakar Saurabh S. , Galera-Prat Albert , Lehtiö Lari 
Published: November 2023

AbstractADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone PARylation Factor (HPF1) forms a joint active site with PARP1/2. The interaction of HPF1 with PARP1/2 alters the automodification site from Aspartate, Glutamate to Serine, which has been shown to be a key ADP-ribosylation event in the context of DNA damage. Therefore disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug development to block the PARP1/2 activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against PARP-HPF1 interaction. We optimized the conditions for FRET signal and verified the interaction by competing the FRET pair in multiple ways. The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered two compounds, Dimethylacrylshikonin and Alkannin, with µM inhibition potency against PARP1/2-HPF1 interaction. The assay will facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potentially new effective anticancer agents.
Diurnal rhythm causes metabolic crises in the cyanobacterial mutants of c-di-AMP signalling cascade
Authors: Haffner Michael , Mantovani Oliver , Spät Philipp , Maček Boris , Hagemann Martin , Forchhammer Karl , Selim Khaled A. 
Published: November 2023

AbstractIn nature, the photoautotrophic lifestyle of cyanobacteria has to cope with the successive diurnal changes in light supply. Light supply throughout the day enables photosynthesis and glycogen biosynthesis, while night phases require the switch to a heterotrophic-like lifestyle relying on glycogen catabolism. We previously highlighted a unique function of the carbon control protein, SbtB, and its effector molecule c-di-AMP, for the nighttime survival of cyanobacteria through the regulation of glycogen anabolism. However, the extent to which c-di-AMP and SbtB impact the cellular metabolism for day-night survivability remained elusive. To gain better understanding of cellular processes regulated by SbtB or c-di-AMP, we compared the metabolomic and proteomic landscapes of ΔsbtBand the c-di-AMP-free (ΔdacA) mutants of the model strainSynechocystissp. PCC 6803. While our results indicate that the cellular role of SbtB is restricted to carbon/glycogen metabolism, the diurnal lethality of ΔdacAseems to be a sum of dysregulation of multiple metabolic processes. These processes include photosynthesis and redox regulation, which lead to elevated levels of intracellular ROS and glutathione. Further, we show an impact of c-di-AMP on central carbon as well as on nitrogen metabolism. Effects on nitrogen metabolism are linked to reduced levels of the global nitrogen transcription regulator NtcA and highlighted by an imbalance of the glutamine to glutamate ratio as well as reduced metabolite levels of the arginine pathway. We further identified the HCO3-uptake systems, BicA and BCT1 as novel SbtB targets, in agreement with its broader role in regulating carbon homeostasis.
Primary multistep phosphorelay activation comprises both cytokinin and abiotic stress responses in Brassicaceae
Authors: Mala Katrina Leslie Nicolas , Skalak Jan , Zemlyanskaya Elena , Dolgikh Vladislav , Jedlickova Veronika , Robert-Boisivon Helene S. , Havlicková Lenka , Panzarova Klara , Trtilek Martin , Bancroft Ian , Hejatko Jan 
Published: November 2023

AbstractMultistep phosphorelay (MSP) signaling integrates hormonal and environmental signals to control plant development and adaptive responses. The type-ARESPONSE REGULATORs(RRAs), the downstream members of the MSP cascade and cytokinin primary response genes, are supposed to mediate primarily the negative feedback regulation of (cytokinin-induced) MSP signaling. However, the transcriptional data suggest the involvement ofRRAsin stress-related responses as well. By employing evolutionary conservation with the well-characterizedArabidopsis thaliana RRAs, we identified 5 and 38 novel putativeRRAsinBrassica oleraceaandBrassica napus, respectively. Our phylogenetic analysis suggests the existence of gene-specific selective pressure, maintaining the homologs ofARR3, ARR6,andARR16as singletons during the evolution ofBrassica oleraceaandBrassica rapa. We categorizedRRAsbased on the kinetics of their cytokinin-mediated upregulation and observed both similarities and specificities in this type of response across Brassicaceae. Using bioinformatic analysis and experimental data demonstrating the cytokinin responsiveness ofArabidopsis-derivedTCSv2reporter, we unveil the mechanistic conservation of cytokinin-mediated upregulation ofRRAsinBrassica rapaandBrassica napus. Notably, we identify partial cytokinin dependency of cold stress-inducedRRAtranscription, thus corroborating the role of cytokinin signaling in the crop adaptive responses.HighlightsWe identifiedBrassicahomologs ofArabidopsistype-A response regulators (RRAs), demonstrate existence of selective pressure preventing severalRRAsmultiplication during Brassicaceae evolution and describe cytokinin dependency of cold-inducedRRAsupregulation.
Trans-eQTL hotspots shape complex traits by modulating cellular states
Authors: Renganaath Kaushik , Albert Frank W. 
Published: November 2023

AbstractRegulatory genetic variation shapes gene expression, providing an important mechanism connecting DNA variation and complex traits. The causal relationships between gene expression and complex traits remain poorly understood. Here, we integrated transcriptomes and 46 genetically complex growth traits in a large cross between two strains of the yeastSaccharomyces cerevisiae. We discovered thousands of genetic correlations between gene expression and growth, suggesting potential functional connections. Local regulatory variation was a minor source of these genetic correlations. Instead, genetic correlations tended to arise from multiple independenttrans-acting regulatory loci.Trans-acting hotspots that affect the expression of numerous genes accounted for particularly large fractions of genetic growth variation and of genetic correlations between gene expression and growth. Genes with genetic correlations were enriched for similar biological processes across traits, but with heterogeneous direction of effect. Our results reveal howtrans-acting regulatory hotspots shape complex traits by altering cellular states.
Comparing hormone dynamics in cereal crops via transient expression of hormone sensors
Authors: Dao Thai Q. , Drapek Colleen , Jones Alexander , Leiboff Samuel 
Published: November 2023

ABSTRACTPlant hormones are small molecules which elicit profound physiological responses. Although plant hormone biosynthesis and response genes have been critical for agricultural improvement, it has been difficult to experimentally compare hormone biology across species because of complex phenotypic outputs. We used transient expression of genetic hormone sensors and transcriptomics to quantify tissue-specific gibberellic acid (GA) and auxin responses across tissues and genotypes in cereal crops. We found that the FRET-based GPS2 biosensor detects exogenous GA treatments in maize, barley, sorghum, and wheat, in both vegetative and floral tissues. Measuring GPS2 output across GA dosages revealed tissue- and genotype-specific differences in GA sensor response. We observed marked differences in maize vs barley leaves and floral tissues and an unexpected drop in GPS2 output in the maized1GA biosynthesis mutant after GA treatment, likely reflecting differences in bioactive GA content, GA transport, and mechanisms of GA response. We then used RNAseq to measure transcriptional responses to GA treatment in leaves from maize wildtype,d1, and barley as well as floral tissues from maize and barley for a cross-tissue, cross-genotype, and cross-species GA-response comparison. After orthology prediction and analysis of within- and cross-species GO-term enrichment, we identified core sets of GA-responsive genes in each species as well as maize- barley orthogroups. Our analysis suggests that downregulation ofGA-INSENSITIVE DWARF1(GID1) and upregulation of α-Expansin1(EXPA1) orthologs comprises a universal GA-response mechanism that is independent of GA biosynthesis, and identifies F-Box proteins, hexokinase, and AMPK/SNF1 protein kinase orthologs as unexpected cross-tissue, cross-genotype, and cross-species GA-responsive genes. We then compared the transient expression of the DR5, DR5v2, and DII-mDII auxin reporters in barley and maize and find that although DR5 did not respond to exogenous auxin in barley, DR5v2 responded to auxin treatment with a similar magnitude as in maize. Both species display auxin-mediated DII degradation that requires the 26S proteasome.
Nucleus Reuniens: Modulating Negative Overgeneralization in Periadolescents with Anxiety
Authors: Rivera Núñez M. Vanessa , McMakin Dana , Mattfeld Aaron T. 
Published: November 2023

ABSTRACTBackgroundAnxiety affects 4.4-million children in the United States with an onset between childhood and adolescence, a period marked by neural changes that impact emotions and memory. Negative overgeneralization – or responding similarly to innocuous events that share features with past aversive experiences – is common in anxiety but remains mechanistically underspecified. The nucleus reuniens (RE) has been considered a crucial candidate in the modulation of memory specificity. Our study investigated its activation and functional connectivity with the medial prefrontal cortex (mPFC) and hippocampus (HPC) as neurobiological mechanisms of negative overgeneralization in anxious youth.MethodsAs part of a secondary data analysis, we examined data from 34 participants between 9-14 years (mean age ± SD, 11.4 ± 2.0 years, 16 females) with varying degrees of anxiety severity. During the Study session participants rated images as negative, neutral, and positive. After 12-hours, participants returned for a Test session, where they performed a memory recognition test with repeated (targets) and similar (lures) images. Labeling negative relative to neutral lures as “old” (false alarms) was our operational definition of negative overgeneralization.ResultsNegative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the CA1 (at Test only). Elevated anxiety severity was associated with reductions in the RE-mPFC functional coupling for neutral relative to negative stimuli. Exploratory analyses revealed similar patterns in activation and functional connectivity with positive stimuli.ConclusionsOur findings demonstrate the importance of the RE in the overgeneralization of memories in anxious youth.