bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and evaluation of a wearable peripheral vascular compensation sensor in a swine model of hemorrhage
Authors: Bonetta-Misteli Francesca , Collins Toi , Pavek Todd , Carlgren Madison , Frolova Antonina , Shmuylovich Leonid , O’Brien Christine M. 
Published: February 2023

AbstractPostpartum hemorrhage (PPH) is both the leading and most preventable cause of maternal mortality. PPH is currently diagnosed through visual estimation of blood loss or vital sign analysis of shock index (ratio of heart rate to systolic blood pressure). Visual assessment underestimates blood loss, particularly in the setting of internal bleeding, and compensatory mechanisms stabilize hemodynamics until hemorrhage is massive, beyond the point of pharmaceutical intervention. Quantitative monitoring of hemorrhage-induced compensatory processes, such as the constriction of peripheral vessels to shunt blood to the central organs, may provide an early alert for PPH. To this end, we developed a low-cost, wearable optical device that continuously monitors peripheral perfusion via laser speckle flow index (LSFI) to detect hemorrhage-induced peripheral vasoconstriction. The device was first tested using flow phantoms across a range of physiologically relevant flow rates and demonstrated a linear response. Subsequent testing occurred in swine hemorrhage studies (n=6) by placing the device on the posterior side of the swine’s front hock and withdrawing blood from the femoral vein at a constant rate. Resuscitation with intravenous crystalloids followed the induced hemorrhage. The mean LSFI vs. percent estimated blood volume loss had an average correlation coefficient of −0.95 during the hemorrhage phase and 0.79 during resuscitation, both of which were superior to the performance of the shock index. With continued development, this noninvasive, low-cost, and reusable device has global potential to provide an early alert of PPH when low-cost and accessible management strategies are most effective, helping to reduce maternal morbidity and mortality from this largely preventable problem.
Adult thymus-derived cMaf+RORγt+γδ T cells lack Scart2 chromatin accessibility and do not reach periphery
Authors: Yang Tao , Barros-Martins Joana , Janssen Anika , Wang Ziqing , León-Lara Ximena , Weiss Siegfried , Prinz Immo , Förster Reinhold , Ravens Sarina 
Published: February 2023

AbstractT cell receptor (TCR) Vγ4+expressing γδT cells can be divided into IFN-γ and IL-17-producing effector T cell subsets. A bias towards γδ17 effector fate decisions is observed during early ontogeny. In contrast, the existence of Vγ4+γδ17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immatureCd24+Gzma+Vγ4 cells was found that exhibit molecular programs of γδ17 cells. These adult thymus-derived immatureCd24a+cMaf+Vγ4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore,de novogenerated γδ17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal γδT cell precursors. Together, this study provides valuable insights into developmental traits of Vγ4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of γδ17-like cells within the adult thymus.HighlightsTranscriptional and epigenetic profiling identifies developmental plasticity ofGzma+Cd24a+Vγ4 cells in adult thymus.Thymic c-Maf+and RORγt+Vγ4 T cells can be generated during adulthood, but do not reach the periphery under steady-state conditions.Innate CD44highCD45RBnegγδ17 cells are completely absent upon induction of T cell development during adulthood.Scart2 expression might be a key molecule to track developmental traits of fetal-derived γδ17 cell precursors.
Epithelial multicellular clustering enabled by polarized macrophages on soft matrices
Authors: Zmuda Hannah , Pathak Amit 
Published: February 2023

AbstractFormation of epithelial structures of variegated geometries and sizes is essential for organogenesis, tumor growth, and wound repair. Although epithelial cells are predisposed with potential for multicellular clustering, it remains unclear whether immune cells and mechanical cues from their microenvironment influence this process. To explore this possibility, we co-cultured human mammary epithelial cells with pre-polarized macrophages on soft or stiff hydrogels. In the presence of M1 (proinflammatory) macrophages on soft matrices, epithelial cells migrated faster and subsequently formed larger multicellular clusters, compared to co-cultures with M0 (unpolarized) or M2 (anti-inflammatory) macrophages. By contrast, stiff extracellular matrix (ECM) disabled active clustering of epithelial cells due to their enhanced migration and cell-ECM adhesion, regardless of macrophage polarization. We found that the co-presence of soft matrices and M1 macrophages reduced focal adhesions, but enhanced fibronectin deposition and non-muscle myosin-IIA expression, which altogether optimize conditions for epithelial clustering. Upon Rho-associated kinase (ROCK) inhibition, epithelial clustering was abrogated, indicating a requirement for optimized cellular forces. In these co-cultures, Tumor Necrosis Factor (TNF)-α secretion was the highest with M1 macrophages and Transforming growth factor (TGF)-β secretion was exclusively detectable in case of M2 macrophages on soft gels, which indicated potential role of macrophage secreted factors in the observed epithelial clustering. Indeed, exogenous addition of TGB-β promoted epithelial clustering with M1 co-culture on soft gels. According to our findings, optimization of both mechanical and immune factors can tune epithelial clustering responses, which could have implications in tumor growth, fibrosis, and would healing.SummaryAuthors show proinflammatory macrophages on soft matrices enable epithelial cells to form multicellular clusters. This phenomenon is disabled on stiff matrices due to increased stability of focal adhesions. Inflammatory cytokine secretion is macrophage-dependent, and external addition of cytokines accentuates epithelial clustering on soft matrices.Impact StatementFormation of multicellular epithelial structures is critical to tissue homeostasis. However, it has not been shown how the immune system and mechanical environment affect these structures. The present work illustrates how macrophage type affects epithelial clustering in soft and stiff matrix environments.
PANGEA: A New Gene Set Enrichment Tool forDrosophilaand Common Research Organisms
Authors: Hu Yanhui , Comjean Aram , Attrill Helen , Antonazzo Giulia , Thurmond Jim , Li Fangge , Chao Tiffany , Mohr Stephanie E. , Brown Nicholas H. , Perrimon Norbert 
Published: February 2023

ABSTRACTGene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented in a gene list resulting from, for example, an ‘omics’ study. Gene Ontology (GO) annotation is the most frequently used classification mechanism for gene set definition. Here we present a new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis;https://www.flyrnai.org/tools/pangea/), developed to allow a more flexible and configurable approach to data analysis using a variety of classification sets. PANGEA allows GO analysis to be performed on different sets of GO annotations, for example excluding high-throughput studies. Beyond GO, gene sets for pathway annotation and protein complex data from various resources as well as expression and disease annotation from the Alliance of Genome Resources (Alliance). In addition, visualisations of results are enhanced by providing an option to view network of gene set to gene relationships. The tool also allows comparison of multiple input gene lists and accompanying visualisation tools for quick and easy comparison. This new tool will facilitate GSEA forDrosophilaand other major model organisms based on high-quality annotated information available for these species.
The impact of chemical fixation on the microanatomy of mouse brain tissue
Authors: Idziak Agata , Inavalli V.V.G. Krishna , Bancelin Stephane , Arizono Misa , Nägerl U. Valentin 
Published: February 2023

AbstractChemical fixation using paraformaldehyde (PFA) is a standard step for preserving cells and tissues for subsequent microscopic analyses such as immunofluorescence or electron microscopy. However, chemical fixation may introduce physical alterations in the spatial arrangement of cellular proteins, organelles and membranes. With the increasing use of super-resolution microscopy to visualize cellular structures with nanometric precision, assessing potential artifacts - and knowing how to avoid them - takes on special urgency.We addressed this issue by taking advantage of live-cell super-resolution microscopy that makes it possible to directly observe the acute effects of PFA on organotypic brain slices, allowing us to compare tissue integrity in a ‘before-and-after’ experiment. We applied super-resolution shadow imaging to assess the structure of the extracellular space (ECS) and regular super-resolution microscopy of fluorescently labeled neurons and astrocytes to quantify key neuroanatomical parameters.While the ECS volume fraction and micro-anatomical organization of astrocytes remained largely unaffected by the PFA treatment, we detected subtle changes in dendritic spine morphology and observed substantial damage to cell membranes. Our experiments show that PFA application via immersion does not cause a noticeable shrinkage of the ECS in brain slices, unlike the situation in transcardially perfused animals where the ECS typically becomes nearly depleted.In addition to the super-resolved characterization of fixation artefacts in identified cellular and tissue compartments, our study outlines an experimental strategy to evaluate the quality and pitfalls of various fixation protocols for the molecular and morphological preservation of cells and tissues.
Experimental alteration of the microRNA profile of the mouse embryo: heritable phenotypes in the adult
Authors: Sukranli Zeynep Yilmaz , Bayram Kezban Korkmaz , Taheri Serpil , Cuzin Francois , Ozkul Yusuf , Rassoulzadegan Minoo 
Published: February 2023

AbstractWe previously identified a unique genetic feature of Autism Spectrum Disorder (ASD) in human patients and established mouse models, namely the low to very low level of six microRNAs, miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p. We attempted to interfere experimentally with the expression in the mouse of two of them, miR19a-3p and miR499a-5p by microinjecting into the one-cell embryo either the complementary sequence or an excess of the microRNA. Both approaches resulted in low levels in the somatic tissues and sperm of the targeted microRNAs (nascent) and their pri and pre precursors. The altered miRNA profiles were inherited by progenies of crosses with untreated partners together with behavior alterations partly characteristic of ASD patients and animal models. An excess of miRNA in the eggs leads to a specific downregulation, we propose variations of single-stranded miRNA, as effectors of its own transcription in eukaryotes.
Repeated passive visual experience modulates spontaneous and non-familiar stimuli-evoked neural activity
Authors: Niraula Suraj , Hauser William L. , Rouse Adam G. , Subramanian Jaichandar 
Published: February 2023

AbstractFamiliarity creates subjective memory of repeated innocuous experiences, reduces neural and behavioral responsiveness to those experiences, and enhances novelty detection. The neural correlates of the internal model of familiarity and the cellular mechanisms of enhanced novelty detection following multi-day repeated passive experience remain elusive. Using the mouse visual cortex as a model system, we test how the repeated passive experience of a 45° orientation-grating stimulus for multiple days alters spontaneous and non-familiar stimuli evoked neural activity in neurons tuned to familiar or non-familiar stimuli. We found that familiarity elicits stimulus competition such that stimulus selectivity reduces in neurons tuned to the familiar 45° stimulus; it increases in those tuned to the 90° stimulus but does not affect neurons tuned to the orthogonal 135° stimulus. Furthermore, neurons tuned to orientations 45° apart from the familiar stimulus dominate local functional connectivity. Interestingly, responsiveness to natural images, which consists of familiar and non-familiar orientations, increases subtly in neurons that exhibit stimulus competition. We also show the similarity between familiar grating stimulus-evoked and spontaneous activity increases, indicative of an internal model of altered experience.
Investigating racial disparities in carcinomas through TCGA transcriptomic and proteomic database
Authors: Lei Brian , Jiang Xinyin , Saxena Anjana 
Published: February 2023

Simple Summary: Racial disparities in cancer incidence and outcome rates are prevalent in the US, with a variety of contributing factors such as socioeconomic status, differences in lifestyle and environmental exposures, and gene polymorphisms. The goal of this research was to broadly analyze public data to identify critical differences in molecular signatures and pathways between races. Additionally, to ensure the clinical translatability of our work, we analyzed the impact of these differences on patient survival. Our findings will help inform the use of novel biomarkers in clinical settings and the future development of precision therapies.Abstract:Epidemiological studies highlight a disparity in cancer incidence and outcome rates between racial groups in the United States. In our study, we investigated molecular differences among racial groups in 10 carcinoma types. We used publicly available data from The Cancer Genome Atlas to identify patterns of differential gene expression in tumors obtained from 4,112 White, Black/African American, and Asian patients. We identified race-dependent expression of numerous genes whose mRNA transcript levels were significantly correlated with patient survival. A small subset of these genes was differentially expressed in multiple carcinomas, including genes involved in cell cycle progression such asCCNB1,CCNE1,CCNE2, andFOXM1. In contrast, genes such as transcriptional factorETS1and apoptotic geneBAK1were differ-entially expressed and clinically significant only in specific cancer types. Our analyses also revealed race-dependent regulation of relevant pathways. Importantly, homology directed repair and ERBB4-mediated nuclear signaling were both upregulated in Black patients compared to Whites in four carcinoma types. This large-scale pan-cancer study refines our understanding of the cancer health disparity and can help inform the use of novel biomarkers in clinical settings as well as the future development of precision therapies.
Neuromechanical strategies for obstacle negotiation during overground locomotion following an incomplete spinal cord injury in adult cats
Authors: Lecomte Charly G. , Mari Stephen , Audet Johannie , Yassine Sirine , Merlet Angèle N. , Morency Caroline , Harnie Jonathan , Beaulieu Claudie , Gendron Louis , Frigon Alain 
Published: February 2023

AbstractFollowing incomplete spinal cord injury in animals, including humans, substantial locomotor recovery can occur. However, functional aspects of locomotion, such as negotiating an obstacle remains challenging. We collected kinematic and electromyography data in ten adult cats before and at weeks 1-2 and 7-8 after a lateral mid-thoracic hemisection while they negotiated obstacles of three different heights. Intact cats always cleared obstacles without contact. At weeks 1-2 after hemisection, the ipsilesional hindlimb contacted obstacles in ~50% of trials, triggering a stumbling corrective reaction or lack of response. When complete clearance occurred, we observed exaggerated ipsilesional hindlimb flexion when it crossed the obstacle with the contralesional limbs leading. At weeks 7-8 after hemisection, complete clearance increased in favor of absent responses while the proportion of stumbling corrective reactions remained relatively the same. We found redistribution of weight support after hemisection, with reduced diagonal supports and increased homolateral supports, particularly on the contralesional side. The main neural strategy for complete clearance in intact cats consisted of increased activation of muscles that flex the knee. After hemisection, knee flexor activation remained but it was insufficient or more variable as the limb approached the obstacle. Intact cats also increased their speed when stepping over an obstacle, an increase that disappeared after hemisection. The increase in complete clearance over time after hemisection paralleled the recovery of muscle activation patterns or new strategies. Our results suggest partial recovery of anticipatory control through neuroplastic changes in the locomotor control system.
Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder
Authors: Sanchez-Rodriguez Lazaro M. , Bezgin Gleb , Carbonell Felix , Therriault Joseph , Fernandez-Arias Jaime , Servaes Stijn , Rahmouni Nesrine , Tissot Cecile , Stevenson Jenna , Karikari Thomas K. , Ashton Nicholas J. , Benedet Andréa L. , Zetterberg Henrik , Blennow Kaj , Triana-Baltzer Gallen , Kolb Hartmuth C. , Rosa-Neto Pedro , Iturria-Medina Yasser 
Published: February 2023

AbstractNeuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-β (Aβ) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.
Laboratory evolution identifies elongated flavodoxins that support electron transfer to sulfite reductases
Authors: Truong Albert , Myerscough Dru , Campbell Ian , Atkinson Josh , Silberg Jonathan J. 
Published: February 2023

ABSTRACTFlavodoxins (Flds) mediate the flux of electrons between oxidoreductases in diverse metabolic pathways. While dozens of Fld-partner oxidoreductases have been discovered, these only represent a subset of the oxidoreductases that couple with ferredoxin (Fd) protein electron carriers. To investigate whether Flds can support electron transfer to a sulfite reductase (SIR) that evolved to couple with a Fd, we evaluated the ability of Flds to transfer electrons from a Fd-NADP reductase (FNR) to a Fd-dependent SIR using growth complementation of a microbe with a sulfur metabolism defect. We show that Flds from cyanobacteria complement the growth of this microbe when coexpressed with an FNR and an SIR that evolved to couple with a plant Fd. To better understand the interaction of Fld with these partner oxidoreductases, we evaluated the effect of peptide insertion on Fld-mediated electron transfer. We observe a high insertion sensitivity within regions predicted to be proximal to the cofactor and partner binding sites and a high insertion tolerance within the loop that is used to differentiate short- and long-chain flavodoxins. These results represent the first evidence that Flds can support electron transfer to assimilatory SIRs, and they suggest that the pattern of peptide-insertion tolerance is influenced by interactions with oxidoreductase partners in electron transfer pathways.
Oct4 redox sensitivity potentiates reprogramming and differentiation
Authors: Shen Zuolian , Wu Yifan , Manna Asit , Yi Chongil , Cairns Bradley R. , Evason Kimberley J. , Chandrasekharan Mahesh B. , Tantin Dean 
Published: February 2023

AbstractThe transcription factor Oct4/Pou5f1 is a component of the regulatory circuitry governing pluripotency and is widely used to induce pluripotency from somatic cells. Here we use domain swapping and mutagenesis to study Oct4’s reprogramming ability, identifying a redox-sensitive DNA binding domain cysteine residue (Cys48) as a key determinant of reprogramming and differentiation. Oct4 Cys48 sensitizes the protein to oxidative inhibition of DNA binding activity and promotes oxidation-mediated protein ubiquitylation.Pou5f1C48Spoint mutation has little effect on undifferentiated embryonic stem cells (ESCs), but upon retinoic acid (RA) treatment causes retention of Oct4 expression, deregulated gene expression and aberrant differentiation.Pou5f1C48SESCs also form less differentiated teratomas and contribute poorly to adult somatic tissues. Finally, we describePou5f1C48S(Janky) mice, which in the homozygous condition are severely developmentally restricted after E4.5. Rare animals bypassing this restriction appear normal at birth but are sterile. Collectively, these findings uncover a novel Oct4 redox mechanism involved in both entry into and exit from pluripotency.
Socio-cultural practices may have affected sexual dimorphism in stature in Early Neolithic Europe
Authors: Cox Samantha L , Nicklisch Nicole , Francken Michael , Wahl Joachim , Meller Harald , Haak Wolfgang , Alt Kurt W , Rosenstock Eva , Mathieson Iain 
Published: February 2023

AbstractThe rules and structure of human culture impact health and disease as much as genetics or the natural environment. To study the origin and evolution of these patterns, we take a multidisciplinary approach combining ancient DNA, skeletal metrics, paleopathology, and stable isotopes. Our analysis focuses on cultural, environmental, and genetic contributions to variation in stature in four populations of Early Neolithic Europe. In Central Europe, low female stature is likely due to male preference in resource allocation under conditions of stress. In contrast, shorter male stature in Mediterranean populations may reflect a lack of preference. Our analysis suggests that biological consequences of sex-specific inequities can be linked to culture as early as 7000 years before present. Understanding these patterns is key to interpreting the evolution of genetic and socio-cultural determinants of health, and our results show that culture, more than environment or genetics, drove height disparities in Early Neolithic Europe.