bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influenza A virus within-host evolution and positive selection in a densely sampled household cohort over three seasons
Authors: Bendall Emily E. , Zhu Yuwei , Fitzsimmons William J. , Rolfes Melissa , Mellis Alexandra , Halasa Natasha , Martin Emily T. , Grijalva Carlos G. , Talbot H. Keipp , Lauring Adam S. 
Published: August 2024

AbstractWhile influenza A virus (IAV) antigenic drift has been documented globally, in experimental animal infections, and in immunocompromised hosts, positive selection has generally not been detected in acute infections. This is likely due to challenges in distinguishing selected rare mutations from sequencing error, a reliance on cross-sectional sampling, and/or the lack of formal tests of selection for individual sites. Here, we sequenced IAV populations from 346 serial, daily nasal swabs from 143 individuals collected over three influenza seasons in a household cohort. Viruses were sequenced in duplicate, and intrahost single nucleotide variants (iSNV) were identified at a 0.5% frequency threshold. Within-host populations were subject to purifying selection with >75% mutations present at <2% frequency. Children (0-5 years) had marginally higher within-host evolutionary rates than adolescents (6-18 years) and adults (>18 years, 4.4x10-6vs. 9.42x10-7and 3.45x10-6, p <0.001). Forty-five iSNV had evidence of parallel evolution, but were not overrepresented in HA and NA. Several increased from minority to consensus level, with strong linkage among iSNV across segments. A Wright Fisher Approximate Bayesian Computational model identified positive selection at 23/256 loci (9%) in A(H3N2) specimens and 19/176 loci (11%) in A(H1N1)pdm09 specimens, and these were infrequently found in circulation. Overall, we found that within-host IAV populations were subject to purifying selection and genetic drift, with only subtle differences across seasons, subtypes, and age strata. Positive selection was rare and inconsistently detected.
CureSCi Metadata Catalog—finding and harmonizing studies for secondary analysis of hydroxyurea use for sickle cell disease
Authors: Wu Xin , Stratford Jeran , Kesler Karen , Ives Cataia , Hendershot Tabitha , Kroner Barbara , Qin Ying , Pan Huaqin 
Published: August 2024

AbstractObjectivesSickle cell disease (SCD) is a rare group of inherited red blood cell disorders that affect hemoglobin, resulting in serious multi-system complications. The limited number of patients available to participate in research studies can inhibit investigating sophisticated relationships. Secondary analysis is a research method that involves using existing data to answer new research questions. Data harmonization enables secondary analysis by combining data across studies, especially helpful for rare disease research where individual studies may be small. The National Heart, Lung, and Blood Institute Cure Sickle Cell Initiative (CureSCi) Metadata Catalog is a web-based tool to identify SCD study datasets for conducting data harmonization and secondary analysis. We present a proof-of-concept secondary analysis to explore factors associated with discontinuation of hydroxyurea, a safe and effective first line SCD therapy, to illustrate the utility of the CureSCi Metadata Catalog to expedite and enable more robust SCD research.MethodsWe performed secondary analysis of SCD studies using a multi-step workflow: develop research questions, identify study datasets, identify variables of interest, harmonize variables, and establish an analysis method. A harmonized dataset consisting of eight predictor variables across five studies was created. Secondary analysis involved a generalized linear model was employed to identify factors that significantly impact hydroxyurea discontinuation.ResultsThe CureSCi Metadata Catalog provided a platform to efficiently find relevant studies and design a harmonization strategy to prepare data for secondary analysis. Multivariate analysis of the harmonized identified that patients who are older, are female, had a history of blood transfusion therapy, had episodes of acute chest syndrome, and had the SC sickle cell genotype are more likely to stop hydroxyurea treatment.ConclusionThis secondary analysis provides a template for how the CureSCi Metadata Catalog expedites dataset discovery of sickle cell studies for identifying relationships between variables or validating existing findings.
Whole-brain mapping in adult zebrafish and identification of a novel tank test functional connectome
Authors: Rajput Neha , Parikh Kush , Squires Ada , Fields Kailyn K. , Wong Matheu , Kanani Dea , Kenney Justin W. 
Published: August 2024

AbstractIdentifying general principles of brain function requires the study of structure-function relationships in a variety of species. Zebrafish have recently gained prominence as a model organism in neuroscience, yielding important insights into vertebrate brain function. Although methods have been developed for mapping neural activity in larval animals, we lack similar techniques for adult zebrafish that have the advantage of a fully developed neuroanatomy and larger behavioral repertoire. Here, we describe a pipeline built around open-source tools for whole-brain activity mapping in freely swimming adult zebrafish. Our pipeline combines recent advances in histology, microscopy, and machine learning to capturecfosactivity across the entirety of the adult brain. Images captured using light-sheet microscopy are registered to the recently created adult zebrafish brain atlas (AZBA) for automated segmentation using advanced normalization tools (ANTs). We used our pipeline to measure brain activity after zebrafish were subject to the novel tank test. We found thatcfoslevels peaked 15 minutes following behavior and that several regions containing serotoninergic, dopaminergic, noradrenergic, and cholinergic neurons were active during exploration. Finally, we generated a novel tank test functional connectome. Functional network analysis revealed that several regions of the medial ventral telencephalon form a cohesive sub-network during exploration. We also found that the anterior portion of the parvocellular preoptic nucleus (PPa) serves as a key connection between the ventral telencephalon and many other parts of the brain. Taken together, our work enables whole-brain activity mapping in adult zebrafish for the first time while providing insight into neural basis for the novel tank test.
A simple inland culture system provides insights into ascidian post-embryonic developmental physiology
Authors: Mathiesen Birthe Thuesen , Ohta Mayu , De Magalhaes Boris Pinto , Castelletti Chiara , Perria Vincenzo , Christiaen Lionel , Ohta Naoyuki 
Published: August 2024

AbstractMaintenance and breeding of experimental organisms are fundamental to life sciences, but both initial and running costs, and hands-on zootechnical demands can be challenging for many laboratories. Here, we aimed to further develop a simple protocol for reliable inland culture of tunicate model species of theCionagenus. We cultured bothCiona robustaandCiona intestinalisin controlled experimental conditions, with a focus on dietary variables, and quantified growth and maturation parameters. From statistical analysis of these standardized datasets, we gained insights into the post-embryonic developmental physiology ofCiona, and inferred an improved diet and culturing conditions for sexual maturation. We showed that body length is a critical determinant of both somatic and sexual maturation, which suggests the existence of systemic control mechanisms of resource allocation toward somatic growth or maturation, and supports applying size selection as a predictor of reproductive fitness in our inland culture, to keep the healthiest animals at low density in the system. In the end, we successfully established a new protocol, including size selection, to promote both sperm and eggs production. Our protocol using small tanks will empower researchers to initiate inlandCionacultures with low costs and reduced space constraints.
A Deep Learning Framework for Predicting Prognostically Relevant Consensus Molecular Subtypes in HPV-Positive Cervical Squamous Cell Carcinoma from Routine Histology Images
Authors: Wang Ruoyu , Gunesli Gozde N. , Skingen Vilde Eide , Valen Kari-Anne Frikstad , Lyng Heidi , Young Lawrence S. , Rajpoot Nasir 
Published: August 2024

ABSTRACTDespite efforts in human papillomavirus (HPV) prevention and screening, cervical cancer remains the fourth most prevalent cancer among women globally. In this study, we propose an end-to-end deep learning framework to investigate histological correlates of the two consensus molecu-lar subtype (CMS) of HPV-positive cervical squamous cell carcinoma (CSCC) patients. Analysing three international CSCC cohorts (n=545 patients), we demonstrate that the genomically determined CMS can be predicted from routine haematoxylin and eosin (H&E)-stained histology slides, with our Digital-CMS scores achieving significant patient stratifications in terms of disease-specific survival (TCGA p=0.0022, Oslo p=0.0495) and disease-free survival (TCGA p=0.0495, Oslo p=0.0282). In addition, our extensive analyses reveal distinct tumour microenvironment (TME) differences between the two CMS subtypes of the CSCC cohorts. Notably, CMS-C1 CSCC subgroup has markedly increased lymphocyte presence, whereas CMS-C2 subgroup has high nuclear pleomor-phism, an elevated neutrophil-to-lymphocyte ratio, and increased neutrophil density. Analysis of representative histological regions reveals higher degree of malignancy in CMS-C2 patients, as-sociated with poor prognosis. This study introduces a potentially clinically advantageous Digital-CMS score derived from digitised WSIs of routine H&E-stained tissue sections, offers new insights into TME differences impacting patient prognosis and potential therapeutic targets, and identifies histological patterns serving as potential surrogate markers of the two CMS subtypes for clinical application.
Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques
Authors: Wu Xiaobo , Meier Linnea , Liu Tom X , Toldo Stefano , Poelzing Steven , Gourdie Robert G. 
Published: August 2024

AbstractPrecise quantification of myocardial infarction is crucial for evaluating the therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and the isolation and quantification of diffuse fibrosis in the heart. Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson’s trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue for the four staining techniques. Notably, the infarct region on a H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise in the infarct quantification. Additionally, our program can isolate and quantify the diffuse fibrotic elements from an MTS-stained cardiac section, which suggested the algorithm’s potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. In conclusion, we demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as the diffuse and patchy fibrosis in MTS-stained cardiac tissues.
Correlating amino acid profiles with improved expression capability of superior CHO based expression platforms
Authors: Sharma Vijeta , Guleria Richa , Mukherjee K. J. 
Published: August 2024

AbstractA novel modified CHO cell line was constructed by expressing a three gene combination of Bclx(L), Aven and BECN1 which are critical targets of the apoptosis and autophagy pathways. This synergistic combination significantly improved cell viability as well as Rituximab (RTX) expression by 7.5 fold. A comparative amino acid analysis of the modified and control cultures both with and without RTX expression showed interesting changes in amino acid uptake rates. We first compared the utilization of amino acids in the control cells without RTX expression to the control cells with RTX expression where it declined significantly in the later half of the culture with the maximum decrease observed with tyrosine, which instead of uptake got secreted into the medium. The uptake of aspartic and glutamic acid also fell drastically during this period demonstrating the deleterious effect of RTX expression on cellular health. When the modified cells were used for RTX expression, there was conversely a slight increase in amino acid consumption in the later part of the culture with the maximum increase observed with alanine and tyrosine. The differential amino acid consumption rates provided us with an indirect measure of improved cellular health and ability of the modified cells to counter the cellular stress associated with RTX expression. Amino acid analysis could thus become a useful predictive tool to identify the critical features of better host expression platforms.
Perisaccadic perceptual mislocalization strength depends on the visual appearance of saccade targets
Authors: Baumann Matthias P. , Denninger Anna F. , Hafed Ziad M. 
Published: August 2024

AbstractWe normally perceive a stable visual environment despite repetitive eye movements. To achieve such stability, visual processing integrates information across saccades, and laboratory hallmarks of such integration are robustly observed by presenting brief perimovement visual probes. In one classic phenomenon, perceived probe locations are grossly erroneous. This phenomenon is believed to depend, at least in part, on corollary discharge associated with saccade-related neuronal movement commands. However, we recently found that superior colliculus motor bursts, a known source of corollary discharge, can be different for different image appearances of the saccade target. Therefore, here we investigated whether perisaccadic perceptual mislocalization also depends on saccade-target appearance. We asked human participants to generate saccades to either low (0.5 cycles/deg) or high (5 cycles/deg) spatial frequency gratings. We always placed a high contrast target spot at grating center, to ensure matched saccades across image types. We presented brief perisaccadic probes, which were high in contrast to avoid saccadic suppression, and the subjects pointed (via mouse cursor) at their perceived locations. We observed stronger perisaccadic mislocalization for low spatial frequency saccade targets, and for upper visual field probe locations. This was despite matched saccade metrics and kinematics across conditions, and it was also despite matched probe visibility for the different saccade target images (low versus high spatial frequency gratings). To the extent that perisaccadic perceptual mislocalization depends on corollary discharge, our results suggest that such discharge might relay more than just spatial saccade vectors to the visual system; saccade-target visual features can also be transmitted.SignificanceBrief visual probes are grossly mislocalized when presented in the temporal vicinity of saccades. While the mechanisms of such mislocalization are still under investigation, one component of them could derive from corollary discharge signals associated with saccade movement commands. Here, we were motivated by the observation that superior colliculus movement bursts, one source of corollary discharge, vary with saccade-target image appearance. If so, then perisaccadic mislocalization should also do so, which we confirmed.
Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces
Authors: Yamamoto Erin A. , Koike Seiji , Wong Caitlyn , Dennis Laura E. , Luther Madison N. , Scatena Avery , Khambadkone Seva , Iliff Jeffrey J. , Lim Miranda M. , Levendovszky Swati R. , Elliott Jonathan E. , Barisano Giuseppe , Müller-Oehring Eva M. , Morales Angelica M. , Baker Fiona C. , Nagel Bonnie J. , Piantino Juan 
Published: August 2024

ABSTRACTBackground and PurposeAn association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI).Materials and MethodsThis analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3).ResultsOn average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a person’s BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a person’s average BMI was associated with a 0.021 mm3/cm3increase in MV-PVS volume (p<0.001).ConclusionThis longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a person’s mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.
Dysregulated Cholesterol Metabolism with Anomalous PI3K/Akt/mTOR pathway Predicts Poor Carboplatin Response in High Grade Serous Ovarian Cancer
Authors: Mahapatra Elizabeth , Saha Arka , Nag Niraj , Gope Animesh , Thakur Debanjan , Vernekar Manisha , Chakrabarti Jayanta , Basu Mukta , Pal Amit , Sengupta Sanghamitra , Mukherjee Sutapa 
Published: August 2024

ABSTRACTRapidly escalating High-Grade Serous Ovarian Cancer (HGSOC) incidences, relapse, and mortalities result from failed carboplatin therapy. In this regard, reprogrammed cholesterol metabolism arising from deregulated PI3K/Akt/mTOR signaling aggravates HGSOCs to evade carboplatin. Therefore, we designed a pilot study to ascertain their clinical relevance in determining the carboplatin response of HGSOC tumors.Non-NACT HGSOC (n=31) subjects were classified into optimum, borderline, and high cohorts based on blood cholesterol levels which positively correlated with their relative tissue cholesterol content. TCGA database showed that mutations in specific PI3K/Akt/mTOR candidates including cholesterol metabolism regulators (SREBP1, SREBP2, SRB-1, STAR, HMGCR) and prosurvival effectors (Akt, mTOR, p70S6K, P38MAPK, HIF-1α, COX2, VEGF) are characteristic to HGSOCs. We discerned dysregulations (expressions/activity) in SREBP2, SRB-1, STAR, and HMGCR along with Akt/pAktThr308, mTOR/pmTORSer2448, p70S6K, P38MAPK, HIF-1α, COX2, and VEGF proteins within high cohort. Herein, poorly differentiated tumors with escalated HMGCR activity overproduced cholesterol thereby rigidifying their cell membranes to restrain Pt-DNA adduct retention. With a carboplatin IC50of 5.23µM, high cohort tumors generated lesser drug-induced ROS and espoused unaltered mitochondrial-membrane depolarization and DNA damage profiles. These parameters were moderately altered in the borderline-HGSOC cohort possessing relatively less rigid membranes and a lower carboplatin IC50of 2.78µM. Accordingly, borderline and high cohorts were respectively denoted as intermediate responder and non-responder of carboplatin. On the contrary, the cholesterol-deficient optimum cohort (IC50-1.59µM) with fluid membranes was a carboplatin responder group.Our study established the candidature of abnormal cholesterol and PI3K/Akt/mTOR (protein-level) statuses as predictive markers to screen HGSOCs for carboplatin responses before therapy.
Manipulating rice canonical Gα and extra-large G protein subunits for improved agronomic traits
Authors: Cantos Christian F. , Assmann Sarah M. 
Published: August 2024

AbstractRice productivity is fundamentally linked to its architecture, governed by signaling networks including those based on heterotrimeric G proteins. In this study, we investigated the individual gene impacts and genetic interactions of the canonical Gα gene (RGA1), and the non-canonical extra-large Gα genes (OsXLG1, OsXLG3a, OsXLG3b, OsXLG4) in controlling plant architecture. We generatedOsXLGmutants using CRISPR/Cpf1 gene editing in Nipponbare (WT) andd1, a Nipponbare null mutant ofRGA1. We then phenotyped 25 different genotypes in the greenhouse for 19 different agronomic traits. In wild type (WT), mutations inRGA1,OsXLG3a,OsXLG3b, orOsXLG4, as well as any combination of Gα genes, resulted in a shorter stature, a desirable trait. Mutations inOsXLG1andOsXLG4increased the number of spikelets and grains per panicle, showcasing advantageous traits that led to higher yield. Mutations inOsXLG3a,OsXLG3b, any combination ofOsXLGs, or anyOsXLGcombined with thed1mutation, reduced seed production and yield. Flag leaf width was the only trait influenced solely by RGA1.RGA1transcript abundance in theosxlgmutants was positively correlated with height, culm length, panicle exsertion, and harvest index, implicating OsXLG regulation ofRGA1expression as an underlying mechanism. Overall, increasedRGA1expression is correlated with more favorable reproductive traits but less favorable vegetative traits. Our study reveals the complex interaction of RGA1 and OsXLGs within the signaling networks that shape rice architecture, from vegetative to post-harvest stages. Our results suggest modulation ofRGA1, OsXLG1, OsXLG3a,orOsXLG4expression as strategies to enhance yield.
Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma
Authors: Yates Josephine , Mathey-Andrews Camille , Park Jihye , Garza Amanda , Gagné Andréanne , Hoffman Samantha , Bi Kevin , Titchen Breanna , Hennessey Connor , Remland Joshua , Shannon Erin , Camp Sabrina , Balamurali Siddhi , Cavale Shweta Kiran , Li Zhixin , Raghawan Akhouri Kishore , Kraft Agnieszka , Boland Genevieve , Aguirre Andrew J. , Sethi Nilay S. , Boeva Valentina , Van Allen Eliezer 
Published: August 2024

AbstractEsophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.