bluuebunny/crossref_metadata_2025_split huggingface dataset:
The chromatin landscape of healthy and injured cell types in the human kidney
Authors: Gisch Debora L. , Brennan Michelle , Lake Blue B. , Basta Jeannine , Keller Mark , Ferreira Ricardo Melo , Akilesh Shreeram , Ghag Reetika , Lu Charles , Cheng Ying-Hua , Collins Kimberly S. , Parikh Samir V. , Rovin Brad H. , Robbins Lynn , Conklin Kimberly Y. , Diep Dinh , Zhang Bo , Knoten Amanda , Barwinska Daria , Asghari Mahla , Sabo Angela R. , Ferkowicz Michael J. , Sutton Timothy A , Kelly Katherine J , Boer Ian H. De , Rosas Sylvia E. , Kiryluk Krzysztof , Hodgin Jeffrey B. , Alakwaa Fadhl , Jefferson Nichole , Gaut Joseph P. , Gehlenborg Nils , Phillips Carrie L. , El-Achkar Tarek M. , Dagher Pierre C. , Hato Takashi , Zhang Kun , Himmelfarb Jonathan , Kretzler Matthias , Mollah Shamim ,   Kidney Precision Medicine Project (KPMP), Jain Sanjay , Rauchman Michael , Eadon Michael T. 
Published: June 2023

AbstractThere is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. However, comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measured dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We established a comprehensive and spatially-anchored epigenomic atlas to define the kidney’s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we noted distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network ofELF3,KLF6, andKLF10regulated the transition between health and injury, while in thick ascending limb cells this transition was regulated byNR2F1. Further, combined perturbation ofELF3,KLF6, andKLF10distinguished two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.
A trigger may not be necessary to cause senescence in deciduous broadleaf forests
Authors: Wheeler Kathryn I. , Dietze Michael C. 
Published: June 2023

AbstractPlant phenological changes drive many ecosystem processes and are a key ecological indicator of climate change. Traditional models represent the onset of autumn leaf senescence, or color change, as a threshold response triggered by the accumulation of cold temperatures and declining day lengths, but the physiological mechanisms behind plant thermal memory and chilling thresholds remain elusive. Here we show that we can predict senescence in forest canopies by dynamically modeling daily greenness as the “memoryless” balance between chlorophyll synthesis, linearly-related to daily temperatures and day lengths, and breakdown. Indeed, summer-only data can be used to estimate breakdown and synthesis rates that in many cases successfully predict senescence at both calibration and validation sites. This mechanistic model shows that neither a trigger nor a physiological memory of coldness is necessary for senescence to start. These findings suggest that the start of senescence is not an irreversible transition, but a continuum of decreasing greenness where concurrent environmental conditions determine the rate of initial senescence. Furthermore, this emphasizes that in order to predict how senescence will shift in response to global change we likely need to focus on understanding the impacts on chlorophyll synthesis.Significance statementPlant phenology is a leading ecological indicator of climate change and has wide-ranging ecological and climatological impacts. Our findings here contradict the key assumption that senescence in deciduous broadleaf trees is actively triggered only when a threshold of cumulative cooling in combination of other stressors is reached. Instead we show that canopy greenness can be modeled as a passive process – balancing chlorophyll breakdown and temperature- and photoperiod-controlled synthesis – and still predict a rapid decline in greenness during senescence. This work is particularly important because it emphasizes that in order to understand climate change induced shifts in senescence, we need to focus on impacts on chlorophyll synthesis.
A 3Din vitrocortical tissue model based on dense collagen to study the effects of gamma radiation on neuronal function
Authors: Lojek Neal M. , Williams Victoria A. , Rogers Andrew M. , Sajo Erno , Black Bryan J. , Ghezzi Chiara E. 
Published: June 2023

AbstractStudies on gamma radiation-induced injury have long been focused on hematopoietic, gastrointestinal, and cardiovascular systems, yet little is known about the effects of gamma radiation on the function of human cortical tissue. The challenge in studying radiation-induced cortical injury is, in part, due to a lack of human tissue models and physiologically relevant readouts. Here, we have developed a physiologically relevant 3D collagen-based cortical tissue model (CTM) for studying the functional response of human iPSC derived neurons and astrocytes to a sub-lethal radiation exposure (5 Gy). We quantified cytotoxicity, DNA damage, morphology, and extracellular electrophysiology. We reported that 5 Gy exposure significantly increased cytotoxicity, DNA damage, and astrocyte reactivity while significantly decreased neurite length and neuronal network activity. Additionally, we found that clinically deployed radioprotectant amifostine ameliorated the DNA damage, cytotoxicity, and astrocyte reactivity. The CTM provides a critical experimental platform to understand cell-level mechanisms by which GR affects human cortical tissue and to screen prospective radioprotectant compounds.
Calling Cards: a customizable platform to longitudinally record protein-DNA interactions over time in cells and tissues
Authors: Yen Allen , Mateusiak Chase , Sarafinovska Simona , Gachechiladze Mariam A. , Guo Juanru , Chen Xuhua , Moudgil Arnav , Cammack Alexander J. , Hoisington-Lopez Jessica , Crosby MariaLynn , Brent Michael R. , Mitra Robi D. , Dougherty Joseph D. 
Published: June 2023

ABSTRACTCalling Cards is a platform technology to record a cumulative history of transient protein-DNA interactions in the genome of genetically targeted cell types. The record of these interactions is recovered by next generation sequencing. Compared to other genomic assays, whose readout provides a snapshot at the time of harvest, Calling Cards enables correlation of historical molecular states to eventual outcomes or phenotypes. To achieve this, Calling Cards uses the piggyBac transposase to insert self-reporting transposon (SRT) “Calling Cards” into the genome, leaving permanent marks at interaction sites. Calling Cards can be deployed in a variety ofin vitroandin vivobiological systems to study gene regulatory networks involved in development, aging, and disease. Out of the box, it assesses enhancer usage but can be adapted to profile specific transcription factor binding with custom transcription factor (TF)-piggyBac fusion proteins. The Calling Cards workflow has five main stages: delivery of Calling Card reagents, sample preparation, library preparation, sequencing, and data analysis. Here, we first present a comprehensive guide for experimental design, reagent selection, and optional customization of the platform to study additional TFs. Then, we provide an updated protocol for the five steps, using reagents that improve throughput and decrease costs, including an overview of a newly deployed computational pipeline. This protocol is designed for users with basic molecular biology experience to process samples into sequencing libraries in 1-2 days. Familiarity with bioinformatic analysis and command line tools is required to set up the pipeline in a high-performance computing environment and to conduct downstream analyses.Basic Protocol 1: Preparation and delivery of Calling Cards reagentsBasic Protocol 2: Sample preparationBasic Protocol 3: Sequencing library preparationBasic Protocol 4: Library pooling and sequencingBasic Protocol 5: Data analysis
Identification of dialects and individuals of globally threatened Yellow Cardinals using neural networks
Authors: Bocaccio Hernan , Domínguez Marisol , Mahler Bettina , Reboreda Juan Carlos , Mindlin Gabriel 
Published: June 2023

AbstractAudio-based analysis of bird songs has proven to be a valuable practice for the growth of knowledge in the fields of ethology and ecology. In recent years, machine learning techniques applied to audio field recordings of bird calls have yielded successful results in studying population distributions and identification of individuals for their monitoring in a variety of bird species. This offers promising possibilities in the study of social behavior, biodiversity, and conservation strategies for birds. In this work, we trained deep learning models, directly from the sonograms of audio field recordings, to investigate the statistical properties of vocalizations in the endangered Yellow Cardinal. To our knowledge, this is the first time that this approach has been applied to this threatened species. Our results indicate the presence of vocal signatures that reflect similarities in songs of individuals that inhabit the same region, determining dialects, but which also show differences between individuals. These differences can be exploited by a deep learning classifier to discriminate the bird identities through their songs. Models trained with data labeled by regions showed a good performance in the recognition of dialects with a mean accuracy of (0.84 +/-0.04) significantly higher than accuracy obtained by chance. Precision and recall values also reflected the classifier’s ability to find alike vocal patterns in the songs of neighboring individuals. Models trained with data labeled by individuals showed an accuracy of (0.63 +/-0.03) significantly higher than that obtained by chance. However, the individual discrimination model showed greater confusion with neighboring individuals. This reflects a hierarchical structure in the characteristics of the Yellow Cardinal’s vocalization, where the intra-individual variability is lower than the inter-individual variability, but it is even lower than the variability obtained when individuals inhabit different regions, providing evidence of the existence of dialects. This reinforces the results of previous works but also offers an automated method for characterizing cultural units within the species. Along with genetic data, this method could help better define management units, thereby benefiting the success of reintroduction programmes of recovered individuals of Yellow Cardinal. Moreover, the novelty of individual discrimination using neural networks for the Yellow Cardinal, which has limited data availability, shows promise for non-invasive acoustic monitoring strategies with potentially relevant implications for its conservation.
In silicodiscovery of the myxosortases that process MYXO-CTERM and three novel prokaryotic C-terminal protein-sorting signals that share invariant Cys residues
Authors: Haft Daniel H. 
Published: June 2023

AbstractThe LPXTG protein-sorting signal, found in surface proteins of various Gram-positive pathogens, was the founding member of a growing panel of prokaryotic small C-terminal sorting domains. Sortase A (SrtA) cleaves LPXTG, exosortases (XrtA and XrtB) cleave the PEP-CTERM sorting signal, archaeosortase A (ArtA) cleaves PGF-CTERM, and rhombosortase (RrtA) cleaves GlyGly-CTERM domains. Four sorting signal domains without previously known processing proteases are the MYXO-CTERM, JDVT-CTERM, Synerg-CTERM, and CGP-CTERM domains. These exhibit the standard tripartite architecture of short signature motif, then a hydrophobic transmembrane segment, then an Arg-rich cluster. Each has an invariant cysteine in its signature motif. Computational evidence strongly suggests that each of these four Cys-containing sorting signals is processed, at least in part, by a cognate family of glutamic-type intramembrane endopeptidases, related to eukaryotic type II CAAX-processing protease Rce1. For the MYXO-CTERM sorting signals of different lineages, their sorting enzymes, called myxosortases, include MrtX (MXAN_2755 inMyxococcus xanthus), MrtC, and MrtP, all with radically different N-terminal domains but with a conserved core. Predicted cognate sorting enzymes were identified also for JDVT-CTERM (MrtJ), Synerg-CTERM (MrtS), and CGP-CTERM (MrtA). This work establishes a major new family of protein-sorting housekeeping endopeptidases contributing to surface attachment of proteins in prokaryotes.ImportanceHomologs of the eukaryotic type II CAAX-box protease Rce1, a membrane-embedded endopeptidase found in yeast and human ER and involved in sorting proteins to their proper cellular locations, are abundant in prokaryotes but are not well understood there. This bioinformatics paper identifies several subgroups of the family as cognate endopeptidases for four protein-sorting signals processed by previously unknown machinery. Sorting signals with newly identified processing enzymes include three novel ones, but also MYXO-CTERM, which had been the focus of previous experimental work in the model fruiting and gliding bacteriumMyxococcus xanthus. The new findings will substantially improve our understanding of Cys-containing C-terminal protein-sorting signals and of protein trafficking generally in bacteria and archaea.
Per-ischemic changes in penumbral blood supply and its microscopic distribution
Authors: Iversen Nina K. , Jimenéz Eugenio Gutierréz , Rasmussen Peter Mondrup , Angelys Hugo , Mikkelsen Irene Klærke , Hollyer Tristan R. , Østergaard Leif 
Published: June 2023

AbstractAcute ischemic stroke (AIS) is a frequent cause of death and adult disability. AIS patient management targets theischemic penumbra: Hypoperfused, electrically silent brain tissue, which can be salvaged by restoring blood flow during the first, critical hours after symptom onset. Neuroimaging studies in AIS patients suggest that penumbral tissue is characterized not only by hypoperfusion, but also by microvascular flow disturbances that strongly affect tissue outcome. Here, we demonstrate that microvascular flows become increasingly chaotic in the ischemic penumbra in the hours after middle cerebral artery occlusion in a rat model of AIS. Biophysical models suggest that these disturbances are accompanied by increasing hypoxia in the absence of blood flow changes. Unlike findings in severe ischemia, pericyte constrictions do not appear to occlude penumbral capillaries. We propose that microvascular flow disturbances represent a critical feature of penumbral tissue, and a potential target for neuroprotective therapy after AIS.
KV7 but not dual SK/IK channel openers inhibit the activation of colonic afferents by noxious stimuli
Authors: Bhebhe Charity N , Higham James P , Gupta Rohit A , Raine Tim , Bulmer David C 
Published: June 2023

AbstractIn numerous subtypes of central and peripheral neurons, small and intermediate conductance Ca2+-activated K+(SK and IK, respectively) channels are important regulators of neuronal excitability. Transcripts encoding SK channel subunits, as well as the closely related IK subunit, are co-expressed in the soma of colonic afferent neurons with receptors for the algogenic mediators adenosine triphosphate (ATP) and bradykinin, P2X3and B2, highlighting the potential utility of these channels as drug targets for the treatment of abdominal pain in gastrointestinal diseases such as irritable bowel syndrome. Despite this, pre-treatment with the dual SK/IK channel opener SKA-31 had no effect on the colonic afferent response to ATP, bradykinin or noxious ramp distention of the colon. Inhibition of SK or IK channels with apamin or TRAM-34, respectively, yielded no change in spontaneous baseline afferent activity, indicating these channels are not tonically active. In contrast to its lack of effect in electrophysiological experiments, comparable concentrations of SKA-31 abolished ongoing peristaltic activity in the colonex vivo. Treatment with the KV7 channel opener retigabine blunted the colonic afferent response to all applied stimuli. Our data therefore highlight the potential utility of KV7, but not SK/IK, channel openers as analgesic agents for the treatment of abdominal pain.
Alarm barks of male vervet monkeys as displays of male quality
Authors: Schad Lukas , Dongre Pooja , van de Waal Erica , Fischer Julia 
Published: June 2023

AbstractResearch on the vocal behaviour of non-human primates is often motivated by a desire to understand the origins of semantic communication, which led to a partial separation of this research from ecological-evolutionary approaches. To bridge this gap, we returned to the textbook example of semantic communication in animals, the vervet monkey,Chlorocebus pygerythrus, alarm call system, and investigated whether male alarm barks fulfil a dual function of alarming and indicating male quality. Barks are loud calls, produced by adult males, in response to large carnivores. However, since barks occasionally occur in agonistic interactions, we investigated whether barks may also indicate male quality. We recorded natural barking events over 23 months, sampling individual male participation from 45 individuals in six free-ranging groups at the Mawana Game Reserve, KwaZulu-Natal, South Africa. We hypothesized that barking frequency is under intra-sexual selection and predicted that barking frequency would increase with male rank and the degree of male-male competition. We found that the highest-ranking males were more likely to produce barks than lower-ranking males and that the number of daily barking events increased during the mating season. We advocate studying primate communication in its evolutionary context to achieve a comprehensive understanding of call “meaning”.
Distinctive Whole-brain Cell Types Predict Tissue Damage Patterns in Thirteen Neurodegenerative Conditions
Authors: Pak Veronika , Adewale Quadri , Bzdok Danilo , Dadar Mahsa , Zeighami Yashar , Iturria-Medina Yasser 
Published: June 2023

AbstractFor over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in thirteen neurodegenerative conditions, including early-and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and three clinical variants of frontotemporal lobar degeneration (behavioural variant, semantic and non-fluent primary progressive aphasia) along with associated 3-repeat and 4-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorders pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.
Astrocyte store-operated calcium entry is required for centrally mediated neuropathic pain
Authors: Prokhorenko Mariya A. , Smyth Jeremy T. 
Published: June 2023

AbstractCentral sensitization is a critical step in chronic neuropathic pain formation following acute nerve injury. Central sensitization is defined by nociceptive and somatosensory circuitry changes in the spinal cord leading to dysfunction of antinociceptive gamma-aminobutyric acid (GABA)ergic cells (Li et al., 2019), amplification of ascending nociceptive signals, and hypersensitivity (Woolf, 2011). Astrocytes are key mediators of the neurocircuitry changes that underlie central sensitization and neuropathic pain, and astrocytes respond to and regulate neuronal function through complex Ca2+signaling mechanisms. Clear definition of the astrocyte Ca2+signaling mechanisms involved in central sensitization may lead to new therapeutic targets for treatment of chronic neuropathic pain, as well as enhance our understanding of the complex central nervous system (CNS) adaptions that occur following nerve injury. Ca2+release from astrocyte endoplasmic reticulum (ER) Ca2+stores via the inositol 1,4,5-trisphosphate receptor (IP3R) is required for centrally mediated neuropathic pain (Kim et al, 2016); however recent evidence suggests the involvement of additional astrocyte Ca2+signaling mechanisms. We therefore investigated the role of astrocyte store-operated Ca2+entry (SOCE), which mediates Ca2+influx in response to ER Ca2+store depletion. Using an adultDrosophila melanogastermodel of central sensitization based on thermal allodynia in response to leg amputation nerve injury (Khuong et al., 2019), we show that astrocytes exhibit SOCE-dependent Ca2+signaling events three to four days following nerve injury. Astrocyte-specific suppression of Stim and Orai, the key mediators of SOCE Ca2+influx, completely inhibited the development of thermal allodynia seven days following injury, and also inhibited the loss of ventral nerve cord (VNC) GABAergic neurons that is required for central sensitization in flies. We lastly show that constitutive SOCE in astrocytes results in thermal allodynia even in the absence of nerve injury. Our results collectively demonstrate that astrocyte SOCE is necessary and sufficient for central sensitization and development of hypersensitivity inDrosophila, adding key new understanding to the astrocyte Ca2+signaling mechanisms involved in chronic pain.