bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine Learning-based Modeling of Olfactory Receptors in their Inactive State: Human OR51E2 as a Case Study
Authors: Alfonso-Prieto Mercedes , Capelli Riccardo 
Published: February 2023

AbstractAtomistic-level investigation of olfactory receptors (ORs) is a challenging task due to the experimental/computational difficulties in the structural determination/prediction for members of this family of G-protein coupled receptors. Here we have developed a protocol that performs a series of molecular dynamics simulations from a set of structures predictedde novoby recent machine learning algorithms and apply it to a well-studied receptor, the human OR51E2. Our study demonstrates the need for simulations to refine and validate such models. Furthermore, we demonstrate the need for the sodium ion at a binding site near D2.50and E3.39to stabilize the inactive state of the receptor. Considering the conservation of these two acidic residues across human ORs, we surmise this requirement also applies to the other ∼400 members of this family.
Dispersal of PRC1 condensates disrupts polycomb chromatin domains and loops
Authors: Williamson Iain , Boyle Shelagh , Grimes Graeme , Friman Elias , Bickmore Wendy A. 
Published: February 2023

AbstractPolycomb-repressive complex 1 (PRC1) has a strong influence on 3D genome organization, mediating local chromatin compaction as well as localized and chromosome-wide clustering of target loci. Several subunits of PRC1 have been shown to have the capacity to form biomolecular condensates through liquid-liquid phase separationin vitroand when tagged and over-expressed in cells. Here, we use 1,6-hexandiol, which disrupts liquid-like condensates, to examine the role of endogenous PRC1 biomolecular condensates on local and chromosome-wide clustering of PRC1-bound loci. Using imaging and chromatin immunoprecipitation combined with deep sequencing analyses, we show that PRC1-mediated chromatin compaction and clustering of targeted genomic loci – at megabase and tens of megabase length scales – can be reversibly disrupted by the addition and subsequent removal of 1,6-hexandiol to mouse embryonic stem cells. Decompaction and dispersal of polycomb domains and clusters cannot be solely attributable to the reduction of PRC1 binding following 1,6-hexandiol treatment as the addition of 2,5-hexandiol has similar effects on binding despite this alcohol not perturbing PRC1-mediated 3D clustering, at least at the sub-megabase and megabase scales. These results suggest that weak hydrophobic interactions between PRC1 molecules, characteristic of liquid-liquid phase separation, have a role in polycomb-mediated genome organization.
Label-free histological analysis of retrieved thrombi in acute ischemic stroke using optical diffraction tomography and deep learning
Authors: Chung Yoonjae , Kim Geon , Moon Ah-Rim , Ryu Donghun , Hugonnet Herve , Lee Mahn Jae , Shin Dongseong , Lee Seung-Jae , Lee Eek-Sung , Park Yongkeun 
Published: February 2023

ABSTRACTFor patients with acute ischemic stroke, histological quantification of thrombus composition provides evidence for determining appropriate treatment. However, the traditional manual segmentation of stained thrombi is laborious and inconsistent. In this study, we propose a label-free method that combines optical diffraction tomography (ODT) and deep learning (DL) to automate the histological quantification process. The DL model classifies ODT image patches with 95% accuracy, and the collective prediction generates a whole-slide map of red blood cells and fibrin. The resulting whole-slide composition displays an average error of 1.1% and does not experience staining variability, facilitating faster analysis with reduced labor. The present approach will enable rapid and quantitative evaluation of blood clot composition, expediting the preclinical research and diagnosis of cardiovascular diseases.
A new look at the architecture and dynamics of theHydranerve net
Authors: Keramidioti Athina , Schneid Sandra , Busse Christina , von Laue Christoph Cramer , Bertulat Bianca , Salvenmoser Willi , Heß Martin , Alexandrova Olga , Glauber Kristine M. , Steele Robert E. , Hobmayer Bert , Holstein Thomas , David Charles N. 
Published: February 2023

AbstractTheHydranervous system is the paradigm of a “simple nerve net”. Nerve cells inHydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of theHydranerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells inHydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM and serial block face SEM show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.
Bayesian inference of toothed whale lifespans
Authors: Ellis Samuel , Croft Darren P , Nielsen Mia Lybkær Kronborg , Franks Daniel W , Weiss Michael N 
Published: February 2023

AbstractAccurate measures of lifespan and age-specific mortality are important both for understanding life history evolution and informing conservation and population management strategies. The most accurate data to estimate lifespan are from longitudinal studies, but for many species – especially those such as toothed whales that are wide-ranging and inhabit difficult-to-access environments - these longitudinal data are not available. However, other forms of age-structured data – such as from mass-strandings - are available for many toothed species, and using these data to infer patterns of age-specific mortality and lifespan remains an important outstanding challenge. Here we develop and test a Bayesian mortality model to derive parameters of a mortality function from age-structured data while accounting for potential error introduced by mistakes in age estimation, sampling biases and population growth. We then searched the literature to assemble a database of 269 published age-structured toothed whale datasets. We applied our mortality model to derive lifespan estimates for 32 species of female and 33 species of male toothed whale. We also use our model to characterise sex differences in lifespan in toothed whales. Our mortality model allows us to curate the most complete and accurate collection of toothed whale lifespans to date.
Seasonal and genetic effects on lipid profiles of juvenile Atlantic salmon
Authors: House Andrew H. , Debes Paul V. , Holopainen Minna , Käkelä Reijo , Donner Iikki , Frapin Morgane , Pashay Ehsan , Kurko Johanna , Ruhanen Hanna , Primmer Craig R. 
Published: February 2023

AbstractSeasonality can influence many physiological traits requiring optimal energetic capacity for life-history stage transitions. In Atlantic salmon, high-energy status is essential for the initiation of maturation. Atlantic salmon lipid reserves are predominantly found in the viscera and myosepta in the muscle while the liver is essential for maintaining lipid metabolism. A genomic study found a region including a transcription co-factor-coding gene,vgll3, linked to Atlantic salmon maturation timing, which acts as an inhibitor of adipogenesis in mice, and mediates maturation via condition factor in Atlantic salmon. Here we investigate the influence of season andvgll3genotypes associating with early (EE) and late (LL) maturation on lipid profiles in the muscle and liver in juvenile Atlantic salmon. We reared Atlantic salmon for two years until the occurrence of sexually mature males and sampled muscle and liver at two time points: spring and autumn of the second year. We found no seasonal or genotype effect in lipid profiles in muscle of immature males and females. However, in the liver we did detect a triacylglycerol (TG) enrichment and a genotype specific direction of change in membrane lipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), from spring to autumn. Specifically, from spring to autumn membrane lipid concentrations increased in vgll3*EE individuals and decreased in vgll3*LL individuals. This could be explained with two possible scenarios 1) a seasonally more stable capacity of endoplasmic reticulum (ER) functions invgll3*EE individuals compared tovgll3*LL individuals or 2)vgll3*LL individuals storing larger lipid droplets from spring to autumn in the liver compared tovgll3*EE individuals at the expense of ER capacity. This genotype specific seasonal direction of change in membrane lipid concentrations provides more indirect evidence that a mechanism linkingvgll3with lipid metabolism and storage exists.HighlightsSeasonal lipid species profile separation in muscle and liver in juvenile Atlantic salmonGenotype specific direction of change of membrane lipids from spring to autumnIndirect evidence that a mechanism linkingvgll3with lipid metabolism and storage exists
A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition
Authors: Petersen Marvin , Hoffstaedter Felix , Nägele Felix L. , Mayer Carola , Schell Maximilian , Rimmele D. Leander , Zyriax Birgit-Christiane , Zeller Tanja , Kühn Simone , Gallinat Jürgen , Fiehler Jens , Twerenbold Raphael , Omidvarnia Amir , Patil Kaustubh R. , Eickhoff Simon B. , Thomalla Götz , Cheng Bastian 
Published: February 2023

AbstractThe link between metabolic syndrome (MetS) and neurodegenerative as well cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, cortical morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.
A Systematic Review and Large-Scale tES and TMS Electric Field Modeling Study Reveals How Outcome Measure Selection Alters Results in a Person- and Montage-Specific Manner
Authors: Van Hoornweder Sybren , Nuyts Marten , Frieske Joana , Verstraelen Stefanie , Meesen Raf L.J. , Caulfield Kevin A. 
Published: February 2023

AbstractBackgroundElectric field (E-field) modeling is a potent tool to examine the cortical effects of transcranial magnetic and electrical stimulation (TMS and tES, respectively) and to address the high variability in efficacy observed in the literature. However, outcome measures used to report E-field magnitude vary considerably and have not yet been compared in detail.ObjectivesThe goal of this two-part study, encompassing a systematic review and modeling experiment, was to provide an overview of the different outcome measures used to report the magnitude of tES and TMS E-fields, and to conduct a direct comparison of these measures across different stimulation montages.MethodsThree electronic databases were searched for tES and/or TMS studies reporting E-field magnitude. We extracted and discussed outcome measures in studies meeting the inclusion criteria. Additionally, outcome measures were compared via models of four common tES and two TMS modalities in 100 healthy younger adults.ResultsIn the systematic review, we included 118 studies using 151 outcome measures related to E-field magnitude. Structural and spherical regions of interest (ROI) analyses and percentile-based whole-brain analyses were used most often. In the modeling analyses, we found that there was an average of only 6% overlap between ROI and percentile-based whole-brain analyses in the investigated volumes within the same person. The overlap between ROI and whole-brain percentiles was montage- and person-specific, with more focal montages such as 4×1 and APPS-tES, and figure-of-eight TMS showing up to 73%, 60%, and 52% overlap between ROI and percentile approaches respectively. However, even in these cases, 27% or more of the analyzed volume still differed between outcome measures in every analyses.ConclusionsThe choice of outcome measures meaningfully alters the interpretation of tES and TMS E-field models. Well-considered outcome measure selection is imperative for accurate interpretation of results, valid between-study comparisons, and depends on stimulation focality and study goals. We formulated four recommendations to increase the quality and rigor of E-field modeling outcome measures. With these data and recommendations, we hope to guide future studies towards informed outcome measure selection, and improve the comparability of studies.
In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression
Authors: Guet-McCreight Alexandre , Chameh Homeira Moradi , Mazza Frank , Prevot Thomas D. , Valiante Taufik A. , Sibille Etienne , Hay Etay 
Published: February 2023

AbstractReduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABAAreceptor (α5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of α5-PAM on the human brainin vivoare unknown, and currently cannot be assessed experimentally. We modeled the effects of α5-PAM on tonic inhibition as measured in human neurons, and testedin silicoα5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that α5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an α5-PAM dose response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate α5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.
Concerning the eXclusion in human genomics: The choice of sex chromosome representation in the human genome drastically affects number of identified variants
Authors: Pinto Brendan J. , O’Connor Brian , Schatz Michael C. , Zarate Samantha , Wilson Melissa A. 
Published: February 2023

AbstractOver the past 30 years, a community of scientists have pieced together every base pair of the human reference genome from telomere-to-telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under ‘normal’ circumstances, omitting any chromosome(s) from analysis of the human genome would be reason for concern—the exception being the sex chromosomes. Sex chromosomes in eutherians share an evolutionary origin as an ancestral pair of autosomes. In humans, they share three regions of high sequence identity (~98-100%), which—along with the unique transmission patterns of the sex chromosomes—introduce technical artifacts into genomic analyses. However, the human X chromosome bears numerous important genes—including more “immune response” genes than any other chromosome—which makes its exclusion irresponsible when sex differences across human diseases are widespread. To better characterize the effect that including/excluding the X chromosome may have on variants called, we conducted a pilot study on the Terra cloud platform to replicate a subset of standard genomic practices using both the CHM13 reference genome and sex chromosome complement-aware (SCC-aware) reference genome. We compared quality of variant calling, expression quantification, and allele-specific expression using these two reference genome versions across 50 human samples from the Genotype-Tissue-Expression consortium annotated as females. We found that after correction, the whole X chromosome (100%) can generate reliable variant calls—allowing for the inclusion of the whole genome in human genomics analyses as a departure from the status quo of omitting the sex chromosomes from empirical and clinical genomics studies.
Arf6 Regulates Endocytosis and Angiogenesis by Promoting Filamentous Actin Assembly
Authors: Francis Caitlin R. , Bell Makenzie L. , Skripnichuk Marina M. , Kushner Erich J. 
Published: February 2023

ABSTRACTClathrin-mediated endocytosis (CME) is a process vital to angiogenesis as well as general vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of CME have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for CME. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide a analysis of Arf6’s function in angiogenic endothelium, focusing on its role in lumenogenesis as well as its relation to actin and CME. We found that Arf6 localized to both filamentous actin and sites of CME in 2-dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, and this may be the primary driver underlying gross dysmorphogenesis during angiogenic sprouting in its absence. Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and CME.
Establishing the Validity of Compressed Sensing Diffusion Spectrum Imaging
Authors: Radhakrishnan Hamsanandini , Zhao Chenying , Sydnor Valerie J. , Baller Erica B. , Cook Philip A. , Fair Damien , Giesbrecht Barry , Larsen Bart , Murtha Kristin , Roalf David R. , Rush-Goebel Sage , Shinohara Russell , Shou Haochang , Tisdall M. Dylan , Vettel Jean , Grafton Scott , Cieslak Matthew , Satterthwaite Theodore 
Published: February 2023

AbstractDiffusion Spectrum Imaging (DSI) using dense Cartesian sampling ofq-space has been shown to provide important advantages for modeling complex white matter architecture. However, its adoption has been limited by the lengthy acquisition time required. Sparser sampling ofq-space combined with compressed sensing (CS) reconstruction techniques has been proposed as a way to reduce the scan time of DSI acquisitions. However prior studies have mainly evaluated CS-DSI in post-mortem or non-human data. At present, the capacity for CS-DSI to provide accurate and reliable measures of white matter anatomy and microstructure in the living human brain remains unclear. We evaluated the accuracy and inter-scan reliability of 6 different CS-DSI schemes that provided up to 80% reductions in scan time compared to a full DSI scheme. We capitalized on a dataset of twenty-six participants who were scanned over eight independent sessions using a full DSI scheme. From this full DSI scheme, we subsampled images to create a range of CS-DSI images. This allowed us to compare the accuracy and inter-scan reliability of derived measures of white matter structure (bundle segmentation, voxel-wise scalar maps) produced by the CS-DSI and the full DSI schemes. We found that CS-DSI estimates of both bundle segmentations and voxel-wise scalars were nearly as accurate and reliable as those generated by the full DSI scheme. Moreover, we found that the accuracy and reliability of CS-DSI was higher in white matter bundles that were more reliably segmented by the full DSI scheme. As a final step, we replicated the accuracy of CS-DSI in a prospectively acquired dataset (n=20, scanned once). Together, these results illustrate the utility of CS-DSI for reliably delineatingin vivowhite matter architecture in a fraction of the scan time, underscoring its promise for both clinical and research applications.
cGLRs are a diverse family of pattern recognition receptors in animal innate immunity
Authors: Li Yao , Slavik Kailey M. , Morehouse Benjamin R. , de Oliveira Mann Carina C. , Mears Kepler , Liu Jingjing , Kashin Dmitry , Schwede Frank , Kranzusch Philip J. 
Published: February 2023

SummarycGAS (cyclic GMP-AMP synthase) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates the protein STING and downstream immunity. Here we discover cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in animal innate immunity. Building on recent analysis inDrosophila, we use a bioinformatic approach to identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screen of 140 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of alternative nucleotide signals including isomers of cGAMP and cUMP-AMP. Using structural biology, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Together our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators
Authors: Roopnarine Osha , Yuen Samantha L. , Thompson Andrew R. , Roelike Lauren N. , Rebbeck Robyn T. , Bidwell Philip A. , Aldrich Courtney C. , Cornea Razvan L. , Thomas David D. 
Published: February 2023

AbstractWe have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA’s function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.