bluuebunny/crossref_metadata_2025_split huggingface dataset:
Destabilization of neuromuscular junctions and deregulation of activity-dependent signalling pathways in Myotonic Dystrophy type I
Authors: Falcetta Denis , Quirim Sandrine , Cocchiararo Ilaria , Cornut Mélanie , Théodore Marine , Stiefvater Adeline , Lin Shuo , Tintignac Lionel , Ivanek Robert , Kinter Jochen , Rüegg Markus A. , Sinnreich Michael , Castets Perrine 
Published: March 2023

ABSTRACTMyotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. We compared changes in NMJs and activity-dependent signalling pathways inHSALRandMbnl1ΔE3/ΔE3mice, two established mouse models for DM1. DM1 muscle showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models displayed increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, expression of synaptic genes was up-regulated in DM1 muscle, which may be linked to the abnormally high activity of histone deacetylase 4 (HDAC4), a known target of CaMKII. Consistently, expression of myosin heavy chains was deregulated as well, leading to a major switch to type IIA fibres inMbnl1ΔE3/ΔE3muscle, and to a lesser extent inHSALRmuscle. Interestingly, although HDAC4 was efficiently induced upon nerve injury, synaptic gene up-regulation was abrogated in DM1 muscle, together with a reduced increase in AChR turnover. This suggested that HDAC4-independent mechanisms lead to the defective response to denervation in DM1 muscle. Our study shows that activity-dependent signalling pathways are disturbed in DM1 muscle, which may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.
Gene-level alignment of single cell trajectories
Authors: Sumanaweera Dinithi , Suo Chenqu , Cujba Ana-Maria , Muraro Daniele , Dann Emma , Polanski Krzysztof , Steemers Alexander S. , Lee Woochan , Oliver Amanda J. , Park Jong-Eun , Meyer Kerstin B. , Dumitrascu Bianca , Teichmann Sarah A. 
Published: March 2023

AbstractSingle-cell data analysis can infer dynamic changes in cell populations, for example across time, space or in response to perturbation. To compare these dynamics between two conditions, trajectory alignment via dynamic programming (DP) optimization is frequently used, but is limited by assumptions such as a definite existence of a match. Here we describeGenes2Genes, a Bayesian information-theoretic DP framework for aligning single-cell trajectories.Genes2Genesovercomes current limitations and is able to capture sequential matches and mismatches between a reference and a query at single gene resolution, highlighting distinct clusters of genes with varying patterns of expression dynamics. Across both real world and simulated datasets,Genes2Genesaccurately captured different alignment patterns, demonstrated its utility in disease cell state trajectory analysis, and revealed that T cells differentiatedin vitromatched to an immaturein vivostate while lacking expression of genes associated with TNFɑ signaling. This use case demonstrates that precise trajectory alignment can pinpoint divergence from thein vivosystem, thus guiding the optimization ofin vitroculture conditions.
Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network
Authors: Ahern Darcy T. , Bansal Prakhar , Faustino Isaac V. , Glatt-Deeley Heather R. , Massey Rachael , Kondaveeti Yuvabharath , Banda Erin C. , Pinter Stefan F. 
Published: March 2023

SUMMARYModeling the developmental etiology of viable human aneuploidy can be challenging in rodents due to syntenic boundaries, or primate-specific biology. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in 39,X-mice. To learn how human monosomy-X may impact early embryonic development, we turned to human 45,X and isogenic euploid induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because neural crest (NC) derived cell types are hypothesized to underpin craniofacial and cardiovascular changes in TS, we performed a highly-powered differential expression study on hiPSC-derived anterior neural crest cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7+SOX10+markers, and disrupted expression of other NCC-specific genes, relative to their isogenic euploid controls. In particular, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts that feature 5’ terminal oligopyrimidine (TOP) motifs, including those of ribosomal protein and nuclear-encoded mitochondrial genes. Such metabolic pathways are also over-represented in weighted co-expression gene modules that are preserved in monogenic neurocristopathy. Importantly, these gene modules are also significantly enriched in 28% of all TS-associated terms of the human phenotype ontology. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as a powerful model of early NC development in TS and inform new hypotheses towards its etiology.
Early alterations of thalamo- and hippocampo-cortical functional connectivity are biomarkers of epileptogenesis after traumatic brain injury
Authors: Weiler Marina , Lutkenhoff Evan S. , de Campos Brunno M. , Casseb Raphael F. , Vespa Paul M. , Monti Martin M. ,   the EpiBioS4Rx Study Group
Published: March 2023

ABSTRACTThe Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) study is a prospective multicenter clinical observational study to identify early biomarkers of epileptogenesis after moderate-to-severe traumatic brain injury (TBI). In this preliminary analysis of 37 patients, using a seed-based approach applied to acute (i.e., ≤ 14 days) functional magnetic resonance (MRI) imaging data, we directly test the hypothesis that the epileptogenic process following brain trauma is associated with functional changes within hippocampal and thalamo-cortical networks. Additionally, we hypothesize that the network connectivity involving thalamic and hippocampal circuits underlying early and late-onset epileptogenesis would differ. The three groups did not differ by sex distribution (χ2(2)= 1.8,p= .407), age (H(2)= 4.227,p= .121), admission Glasgow Coma Scale (H(2)= 3.850,p= .146) or postinjury day of the MRI session (H(2)= .695,p= .706). The primary finding is that patients with early seizures, a sign of early epileptogenesis, exhibited pattern 1, namely, an increased positive connectivity in thalamic and hippocampal networks, as compared to patients who had no epileptogenesis, or late epileptogenesis (p< .05, FWE-corrected at the cluster level). In contrast, this finding was absent in those patients who exhibited late seizures, with the latter group displayed pattern 2, namely, a lower positive and higher negative connectivity in the hippocampal network, as compared to patients who had no signs of epileptogenesis (p< .05, FWE-corrected at the cluster level). Patients with either pattern 1 or pattern 2 connectivity profiles in thalamic and hippocampal networks were significantly predictive of late (i.e., between 7 days and 2 years) epileptogenesis following brain trauma. A Receiver Operating Characteristic (ROC) Curve analysis model that included thalamic and hippocampal functional connectivity values presented an Area Under the Curve (AUC) 87.7, specificity 86.7, and sensitivity 84.6. Our results indicate that dysfunction in hippocampal and thalamo-cortical networks are potential biomarkers for early and late epileptogenesis following a TBI.
Genetic and neural bases of the neuroticism general factor
Authors: Kim Yuri , Saunders Gretchen R. B. , Giannelis Alexandros , Willoughby Emily A. , DeYoung Colin G. , Lee James J. 
Published: March 2023

AbstractWe applied structural equation modeling to conduct a genome-wide association study (GWAS) of the general factor measured by a neuroticism questionnaire administered to∼380,000 participants in the UK Biobank. We categorized significant genetic variants as acting either through the neuroticism general factor, through other factors measured by the questionnaire, or through paths independent of any factor. Regardless of this categorization, however, significant variants tended to show concordant associations with all items. Bioinformatic analysis showed that the variants associated with the neuroticism general factor disproportionately lie near or within genes expressed in the brain. Enriched gene sets pointed to an underlying biological basis associated with brain development, synaptic function, and behaviors in mice indicative of fear and anxiety. Psychologists have long asked whether psychometric common factors are merely a convenient summary of correlated variables or reflect coherent causal entities with a partial biological basis, and our results provide some support for the latter interpretation. Further research is needed to determine the extent to which causes resembling common factors operate alongside other mechanisms to generate the correlational structure of personality.
Cyclone: an accessible pipeline to analyze, evaluate and optimize multiparametric cytometry data
Authors: Patel Ravi K. , Jaszczak Rebecca G. , Kwok Im , Carey Nicholas D. , Courau Tristan , Bunis Daniel , Samad Bushra , Avanesyan Lia , Chew Nayvin W. , Stenske Sarah , Jespersen Jillian M. , Publicover Jean , Edwards Austin , Naser Mohammad , Rao Arjun A. , Lupin-Jimenez Leonard , Krummel Matthew F. , Cooper Stewart , Baron Jody , Combes Alexis J. , Fragiadakis Gabriela K. 
Published: March 2023

AbstractIn the past decade, high-dimensional single cell technologies have revolutionized basic and translational immunology research and are now a key element of the toolbox used by scientists to study the immune system. However, analysis of the data generated by these approaches often requires clustering algorithms and dimensionality reduction representation which are computationally intense and difficult to evaluate and optimize. Here we present Cyclone, an analysis pipeline integrating dimensionality reduction, clustering, evaluation and optimization of clustering resolution, and downstream visualization tools facilitating the analysis of a wide range of cytometry data. We benchmarked and validated Cyclone on mass cytometry (CyTOF), full spectrum fluorescence-based cytometry, and multiplexed immunofluorescence (IF) in a variety of biological contexts, including infectious diseases and cancer. In each instance, Cyclone not only recapitulates gold standard immune cell identification, but also enables the unsupervised identification of lymphocytes and mononuclear phagocytes subsets that are associated with distinct biological features. Altogether, the Cyclone pipeline is a versatile and accessible pipeline for performing, optimizing, and evaluating clustering on variety of cytometry datasets which will further power immunology research and provide a scaffold for biological discovery.
Memory systems integration in sleep complements rapid systems consolidation in wakefulness
Authors: Brodt Svenja , Schönauer Monika , Seewald Anna , Beck Jonas , Erb Michael , Scheffler Klaus , Gais Steffen 
Published: March 2023

AbstractSleep benefits memory performance by fostering systems consolidation, a process that embeds memories into neocortical networks and renders them independent of the hippocampus. Recent evidence shows that memory rehearsal during wakefulness likewise initiates systems consolidation and rapidly engenders neocortical engrams. Here, we investigate the effect of sleep-dependent consolidation for memories that have undergone rapid systems consolidation during wakefulness. After sleep compared to wakefulness, we find better memory retention and higher functional brain activity during memory retrieval in the medial parietal cortex, which hosts memory representations after rehearsal, and in the striatum and thalamus. Increased striatal and thalamic contributions were correlated with higher retrieval performance. Furthermore, all three regions decreased their functional connectivity to the hippocampus specifically after sleep. These findings show that besides continuing of systems consolidation initiated during wakefulness, sleep also acts to integrate different memory systems. Thus, rehearsal-induced and sleep-dependent consolidation seem to be complementary in nature.
TMS disruption of the lateral prefrontal cortex increases neural activity in the default mode network when naming facial expressions
Authors: Pitcher David , Sliwinska Magdalena W. , Kaiser Daniel 
Published: March 2023

AbstractRecognizing facial expressions is dependent on multiple brain networks specialized for different cognitive functions. In the current study participants (N=20) were scanned using functional magnetic resonance imaging (fMRI) while they performed a covert facial expression naming task. Immediately prior to scanning thetaburst transcranial magnetic stimulation (TMS) was delivered over the right lateral prefrontal cortex (PFC), or the vertex control site. A group whole-brain analysis revealed that TMS induced opposite effects in the neural responses across different brain networks. Stimulation of the right PFC (compared to stimulation of the vertex) decreased neural activity in the left lateral PFC but increased neural activity in three nodes of the default mode network (DMN): the right superior frontal gyrus (SFG), right angular gyrus and the bilateral middle cingulate gyrus. A region of interest (ROI) analysis showed that TMS delivered over the right PFC reduced neural activity across all functionally localised face areas (including in the PFC) compared to TMS delivered over the vertex. These results causally demonstrate that visually recognizing facial expressions is dependent on the dynamic interaction of the face processing network and the DMN. Our study also demonstrates the utility of combined TMS / fMRI studies for revealing the dynamic interactions between different functional brain networks.
Water Hyacinth microbiome: metagenomic cues from environment and functionality in urban aquatic bodies
Authors: Yadav Rakeshkumar , Rajput Vinay , Dharne Mahesh 
Published: March 2023

AbstractWater hyacinth (WH) is a widespread floating invasive aquatic plant having a prolific reproductive and dispersion rate. With the aid of its root-associated microbes, WH significantly modulates the ecosystem’s functioning. Despite their irrevocable importance, the WH microbiome remains unexplored in detail. Here, we present a shotgun analysis of WH rhizobiome (from urban rivers and a lake) and their surrounding water to unveil the diversity drivers and functional relationship. PCoA analysis revealed that microbial diversity of the WH is significantly shaped by the type of the aquatic bodies (River Vs Lake) (ANOSIM-R of 0.94 to 0.98 and R2of 0.36 to 0.54). Temporal variations (River WH_2020 vs WH_2022) (R of 0.8 to 1 and R2of 0.17 to 0.41) were observed in river WH, which could be mainly attributed to the transient taxa as there was higher sharing of core bacteria (48%). Also, the WH microbiome significantly differed (R= 0.46 to 1.0 and R2of 0.18 to 0.52) from its surrounding water. WH inhabited more unique core members (42 to 45%), suggesting vertical transfer and selectivity in the microbiome. Functional metagenomics depicted the WH microbiome to harbour 140 pollutant-degrading enzymes involved in the degradation of various xenobiotic pollutants such as hydrocarbons, plastics, and dye. Moreover, an observed higher prevalence of metal and biocide resistance genes highlighted the persistence of resistant microbes assisting WH in environmental remediation application.HighlightsWater hyacinth (WH) from urban water bodies inhabited by diverse microbial populationFirst study to report variability in WH microbiome amid aquatic bodies and their environmentLake WH showed more unique core (43%), and River WH shared core bacteria (48%) across time140 Pollutant degrading enzymes and 341 metal resistance genes indicates remediation potential
Requirement of GrgA forChlamydiainfectious progeny production
Authors: Lu Bin , Wang Yuxuan , Wurihan Wurihan , Yeung Sydney , Fondell Joseph D. , Wu Xiang , Fan Huizhou 
Published: March 2023

ABSTRACTHallmarks of the developmental cycle of the obligate intracellular pathogenic bacteriumChlamydiaare the primary differentiation of the infectious elementary body (EB) cell type into the proliferative reticulate body (RB) and the secondary differentiation of RBs back into EBs. The detailed mechanisms regulating these transitions are unclear. In this study, we developed a novel strategy termed DOPE (dependence on plasmid-mediated expression) that allows for the knockdown of essential genes inChlamydia. Importantly, we demonstrate that GrgA, aChlamydia-specific transcription factor, is essential for the secondary differentiation of RBs into EBs. Our development of a conditional GrgA-deficient chlamydiae should prove valuable for future studies examining chlamydial growth, development, and pathogenicity. Furthermore, because EB formation is absolutely required for chlamydial dissemination within infected individuals, and for chlamydial transmission to new hosts, our maturation-defective chlamydiae system may serve as an attractive attenuated vaccine methodology for the prevention of chlamydial diseases.
Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer
Authors: Gelbach Patrick E. , Finley Stacey D. 
Published: March 2023

1SummaryColorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment, which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the tumor microenvironment. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.
Cryo-EM structures of human arachidonate 12S-Lipoxygenase (12-LOX) bound to endogenous and exogenous inhibitors
Authors: Mobbs Jesse I. , Black Katrina A. , Tran Michelle , Venugopal Hariprasad , Holman Theodore R. , Holinstat Michael , Thal David M. , Glukhova Alisa 
Published: March 2023

AbstractHuman 12-lipoxygenase (12-LOX) is an enzyme involved in platelet activation and is a promising target for antiplatelet therapies. Despite the clinical importance of 12-LOX, the exact mechanisms of how it affects platelet activation are unclear, and the lack of structural information has limited drug discovery efforts. In this study, we used single-particle cryoelectron microscopy to determine the high-resolution structures (1.7 Å - 2.8 Å) of human 12-LOX for the first time. Our results showed that 12-LOX can exist in multiple oligomeric states, from monomer to hexamer, which may impact its catalytic activity and membrane association. We also identified different conformations within a 12-LOX dimer, likely representing different time points in its catalytic cycle. Furthermore, we were able to identify small molecules bound to the 12-LOX structures. The active site of the 12-LOX tetramer is occupied by an endogenous 12-LOX inhibitor, a long-chain acyl-Coenzyme A. Additionally, we found that the 12-LOX hexamer can simultaneously bind to arachidonic acid and ML355, a selective 12-LOX inhibitor that has passed a phase I clinical trial for treating heparin-induced thrombocytopenia and has received fast-track designation by the FDA. Overall, our findings provide novel insights into the assembly of 12-LOX oligomers, its catalytic mechanism, and small molecule binding, paving the way for further drug development targeting the 12-LOX enzyme.Key PointsThe first full-length structures of human arachidonate 12S-Lipoxygenase (12-LOX)Reveals mechanisms of oligomeric and conformational statesUncovers natural inhibitor of 12S-Lipoxygenase (12-lox)Reveals a binding site of inhibitor ML355
Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate ofAeromonas hydrophila
Authors: Chacón Luz , Kuropka Benno , González-Tortuero Enrique , Schreiber Frank , Rojas-Jiménez Keilor , Rodríguez-Rojas Alexandro 
Published: March 2023

AbstractExcessive discharge of quaternary ammonium disinfectants such as benzalkonium chloride (BAC) into aquatic systems can trigger several physiological responses in environmental microorganisms. In this study, we isolated a low susceptible strain ofAeromonas hydrophila, namely INISA09, to from a wastewater treatment plant in Costa Rica. We characterized its phenotypic response upon exposure to three different concentrations of BAC and determined the primary mechanisms related to its resistance using genomic and proteomic tools. The genome of the strain is 4.6-Mb with 4,273 genes, and we found a propound genome rearrangement and thousands of missense mutations when compared to the reference strainA. hydrophilaATCC 7966. We identified 15,762 missense mutations mainly associated with transport, antimicrobial resistance, and outer membrane proteins. In addition, quantitative proteomic analysis revealed the significant upregulation of several efflux pumps and the downregulation of porins when the strain was exposed to three BAC concentrations. Other genes related to membrane fatty acid metabolism and redox metabolic reactions also showed an altered expression. Our findings suggest that the response ofA. hydrophilaINISA09 to BAC primarily occurs at the membrane level, which is BAC’s primary target. This study sheds light on the mechanisms of antimicrobial susceptibility in tropical aquatic environments against a widely-used disinfectant, using an environmental strain that could serve as a new study model.