bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tricellular junctional protein Ildr2 helps maintain glomerular podocyte architecture
Authors: Gerlach Gary F. , Xiong Yubin , O’Brien Lori L. 
Published: May 2024

AbstractPodocytes are highly specialized epithelial cells of the glomerular filtration barrier essential for maintaining proper kidney function. Their intricate cellular projections, called foot processes, wrap around the capillary endothelium, interdigitate, and connect to one another via slit diaphragm intercellular junctions to form a sieve-like barrier. Compromise to this unique podocyte architecture can lead to altered glomerular function and eventual kidney disease. We previously identified Immunoglobulin-like domain containing receptor 2 (Ildr2) as a component of the podocyte foot process through proteomic analyses. Ildr2 is a tricellular tight junction constituent and localizes to distinct puncta in podocytes that likely represent these specialized junctions. However, the significance of tricellular tight junctions and Ildr2 to podocyte integrity is unknown. To this end, we generated a conditional knockout mouse with podocyte-specific deletion ofIldr2(Podocin-Cretg/+;Ildr2fl/florIldr2PodKO). Kidneys fromIldr2PodKOadult animals show disruptions to podocyte foot process architecture including effacement and the unique formation of electron dense strands connecting subsets of processes. Additionally, the glomerular basement membrane was significantly thicker in conditional knockouts and histological analyses revealed glomerular collagen and glycoprotein accumulation. Surprisingly,Ildr2PodKOanimals displayed no significant albuminuria. WhenIldr2PodKOmice were challenged with a stress to kidney function, immunohistochemistry revealed podocyte loss from a subset of glomeruli with concomitant detection of podocytes in urine, although function was still preserved. Collectively, our data provide novel insights into the function of Ildr2 and suggest tricellular junctions help preserve podocyte architecture but are likely not necessary to maintain proper filtration in no or low stress physiological states.
Desmosomal Cadherin Tension Loss in Pemphigus Vulgaris Mediated by the Inhibition of Active RhoA at Cell-Cell Adhesions
Authors: Jin Xiaowei , Rosenbohm Jordan , Moghaddam Amir Ostadi , Kim Eunju , Seiffert-Sinha Kristina , Leiker Merced , Zhai Haiwei , Baddam Sindora R. , Minnick Grayson , Huo Yucheng , Safa Bahareh Tajvidi , Wahl James K. , Meng Fanben , Huang Changjin , Lim Jung Yul , Conway Daniel E. , Sinha Animesh A. , Yang Ruiguo 
Published: May 2024

SUMMARYBinding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.
Impacts of dietary fat on multi tissue gene expression in the desert-adapted cactus mouse
Authors: Blumstein Danielle M. , MacManes Matthew D. 
Published: May 2024

AbstractUnderstanding the relationship between dietary fat and physiological responses is crucial in species adapted to arid environments where water scarcity is common. In this study, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract, and hypothalamus) and 19 phenotypic measurements, investigating the effects of dietary fat in the desert-adapted cactus mouse (Peromyscus eremicus). We show impacts on immune function, circadian gene regulation, and mitochondrial function for mice fed a lower-fat diet compared to mice fed a higher-fat diet. In arid environments with severe water scarcity, even subtle changes in organismal health and water balance can affect physical performance, potentially impacting survival and reproductive success. The study sheds light on the complex interplay between diet, physiological processes, and environmental adaptation, providing valuable insights into the multifaceted impacts of dietary choices on organismal well-being and adaptation strategies in arid habitats.
Application of Supervised Machine Learning Models for Drug-Action Prediction Towards Nuclear Type I Receptors
Authors: Jaundoo Rajeev , Tuszynski Jack A. , Craddock Travis J.A. 
Published: May 2024

1.AbstractInteractions between drugs can lead to adverse side effects for patients taking combination therapies to treat complex diseases such as cancer. Knowledge of drug-action towards a receptor would allow these drug-drug interactions to be predicted, and in this study, we trained a total of 5 different machine learning models to classify whether a given drug was an agonist (activator), antagonist (blocker), or a decoy (non-binder) to each of the androgen, estrogen, glucocorticoid, and progesterone receptors. The classification performance and efficiency, measured in training time, of the decision tree, naïve Bayes, neural network, random forest, and support vector machine models for each receptor were then compared. The results showed that the decision tree and naïve Bayes models were best suited for drug-action prediction across all receptors while only requiring minutes of training time at most. Future work will focus on increasing the prediction accuracy of antagonist drugs, integrating experimental data during training, and using other targets outside of nuclear type I receptors.
Analysis ofAmblyomma americanummicroRNAs in response toEhrlichia chaffeensis infection and their potential role in vectorial capacity
Authors: Kumar Deepak , Budachetri Khemraj , Rikihisa Yasuko , Karim Shahid 
Published: May 2024

AbstractBackgroundMicroRNAs (miRNAs) represent a subset of small noncoding RNAs and carry tremendous potential for regulating gene expression at the post-transcriptional level. They play pivotal roles in distinct cellular mechanisms including inhibition of bacterial, parasitic, and viral infections via immune response pathways. Intriguingly, pathogens have developed strategies to manipulate the host’s miRNA profile, fostering environments conducive to successful infection. Therefore, changes in an arthropod host’s miRNA profile in response to pathogen invasion could be critical in understanding host-pathogen dynamics. Additionally, this area of study could provide insights into discovering new targets for disease control and prevention. The main objective of the present study is to investigate the functional role of differentially expressed miRNAs uponEhrlichia chaffeensis, a tick-borne pathogen, infection in tick vector,Amblyomma americanum.MethodsSmall RNA libraries from uninfected andE. chaffeensis-infectedAm. americanummidgut and salivary gland tissues were prepared using the Illumina Truseq kit. Small RNA sequencing data was analyzed using miRDeep2 and sRNAtoolbox to identify novel and known miRNAs. The differentially expressed miRNAs were validated using a quantitative PCR assay. Furthermore, a miRNA inhibitor approach was used to determine the functional role of selected miRNA candidates.ResultsThe sequencing of small RNA libraries generated >147 million raw reads in all four libraries and identified a total of >250 miRNAs across the four libraries. We identified 23 and 14 differentially expressed miRNAs in salivary glands, and midgut tissues infected withE. chaffeensis, respectively. Three differentially expressed miRNAs (miR-87, miR-750, and miR-275) were further characterized to determine their roles in pathogen infection. Inhibition of target miRNAs significantly decreased theE. chaffeensisload in tick tissues, which warrants more in-depth mechanistic studies.ConclusionsThe current study identified known and novel miRNAs and suggests that interfering with these miRNAs may impact the vectorial capacity of ticks to harborEhrlichia. This study identified several new miRNAs for future analysis of their functions in tick biology and tick-pathogen interaction studies.
Novel clock neuron subtypes regulate temporal aspects of sleep
Authors: Ma Dingbang , Le Jasmine Quynh , Dai Xihuimin , Díaz Madelen M. , Abruzzi Katharine C. , Rosbash Michael 
Published: May 2024

AbstractCircadian neurons within animal brains orchestrate myriad physiological processes and behaviors, But the contribution of these neurons to the regulation of sleep is not well understood. To address this deficiency, we leveraged single-cell RNA sequencing to generate a new and now comprehensive census of transcriptomic cell types ofDrosophilaclock neurons. We focused principally on the enigmatic DN3s, which constitute about half of the 75 pairs of clock neurons in the fly brain and were previously almost completely uncharacterized. These DN3s are organized into 12 clusters with unusual gene expression features compared to the more well-studied clock neurons. We further show that different DN3 subtypes with distinct projection patterns promote sleep at specific times of the day through a common G protein–coupled receptor,TrissinR. Our findings indicate an intricate regulation of sleep behavior by clock neurons and highlight their remarkable diversity in gene expression, projection patterns and functional properties.
Pneumonia induced rise in glucagon promotes endothelial damage and vascular thrombogenicity
Authors: Rad Pegah Ramezani , Nageswaran Vanasa , Peters Lisa , Reinshagen Leander , Roessler Johann , Simmons Szandor , Asmus Erik , Wittig Corey , Brack Markus C. , Nouailles Geraldine , van der Vorst Emiel P. C. , Maas Sanne L. , Sonnenschein Kristina , Verhaar Barbara , Szulcek Robert , Witzenrath Martin , Landmesser Ulf , Kuebler Wolfgang M. , Haghikia Arash 
Published: May 2024

BackgroundRecent studies have demonstrated a link between respiratory infections and increased short-term risk of cardiovascular disease (CVD). However, the molecular mechanisms underlying the increased cardiovascular risk after respiratory infections are only poorly understood. Here, we aimed to decipher pathophysiological circuits of pneumonia associated CVD in experimental models of bacterial pneumonia and vascular injury.MethodsC57BL/6J mice were exposed to intranasal inoculation with eitherStreptococcus pneumoniae(S. pneumoniae) serotype 4 (pneumonia group) or phosphate buffered saline (PBS) (control group). 24 hourspost infectionem(p.i.) mice were treated with antibiotics until the end of the study. On day 7 p.i. carotid artery injury (CI) was induced by electric stimulation and vascular repair was analyzed 3 days after injury. Plasma proteomic analyses were performed by Olink Bioscience. Primary human aortic endothelial cells (HAECs) were used to study alterations of the endothelial functional properties, bioenergetic state and thrombogenic potentialin vitro. Intravital fluorescence microscopy equipped with video recording was applied to measure thrombus formation in real-time.ResultsBacterial pneumonia impaired repair capacity of the endothelium after vascular injury. Proteomic analyses revealed significantly higher plasma levels of glucagon in mice after recovery from pneumonia relative to controls, which was further confirmed by ELISA detecting glucagon. Mechanistically, we found that glucagon impaired mitochondrial bioenergetics and migratory potential in HAECs and induced an inflammatory response. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to HAECs and accelerated carotid artery thrombus formationin vivo. Acute application of the glucagon-like peptide-1 receptor (GLP1-R) agonist liraglutide to lower blood glucagon levels, restored vascular repair potential and attenuated vascular thrombogenicity in mice with pneumonia.ConclusionsOur findings reveal a novel mechanism that associates elevated circulatory glucagon levels to dysfunctional endothelium and increased vascular thrombogenicity, suggesting glucagon signaling as a potential therapeutic target to prevent pneumonia-induced cardiovascular events.Graphical Abstract
HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma
Authors: Zhao Wencao , Kim Boyoung , Coffey Nathan J , Bowers Schuyler , Jiang Yanqing , Bowman Caitlyn E. , Noji Michael , Jang Cholsoon , Simon M. Celeste , Arany Zoltan , Kim Boa 
Published: May 2024

ABSTRACTClear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, but not in ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by reduced intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 markedly enhances glutaminase activity and promotes cell death under glutamine-deprived conditions. HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growthin vivo. These findings provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2α promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2α inhibition in the treatment of ccRCC.
Playback-aided surveys and acoustic monitoring in the detection of the Endangered Forest OwletAthene blewitti
Authors: Rajan Amrutha , Neema Aditi , Trivedi Pranav G , Worah Sejal , MR Meera , Mukherjee Shomita , Robin V.V. 
Published: May 2024

ABSTRACTLong-term monitoring of populations of rare, endangered species is often challenging. Both the availability of baseline historical datasets and appropriate methods for long-term monitoring are often limited. Anthropogenic climate change and landscape change can impact species distributions significantly, sometimes resulting in a distributional shift of species and, in some cases, driving species to extinction. The Forest Owlet is an endangered bird that was considered extinct but was rediscovered after 113 years in 1997. Since its rediscovery, followed by the description of its calls, there have been regular sightings of the species from newer locations, leading to its down-listing in the IUCN Red List from Critically Endangered to Endangered. One area of interest is the Dang region in Gujarat, India, where there have been no historical records despite previous ornithological studies, but there are several recent records. Through field surveys, we repurpose data from the last three decades (1990, 2000, and 2019) to explore if this bird currently occurs in previous study sites where it was not recorded. The period has seen the rise of acoustic data, and we assess if new survey techniques using playback of its call could increase its detection. Additionally, we examined any changes in landscape and climate in this region across the same period. We also developed an acoustic detection framework for detecting the Forest Owlet from co-occurring sympatric owlets using Automated Recording Units (ARU) and sound-analysis software. We assessed appropriate detection distances from vocalizing birds on the field to design a spacing grid for future surveys of the species. We could locate the Forest Owlet from the resurveys at locations where previous studies three decades ago had not. We also find a significant change in the landscape - loss of native forests and increased agriculture, along with a significant change in climatic variables - mean maximum temperature and mean rainfall. Although the detection of the Forest Owlet is higher when accompanied by playback of its call, there is considerable variation across the landscape. Our acoustic detector comparison led us to a detection strategy for long-term monitoring – different approaches for songs and calls, and an effective detection distance of 300m in its habitat. Although the species responds to climate and habitat change, our study cannot determine the cause of the increased reports of this endangered species. All possibilities remain; the increase in the recent records of the species could be from variable detection or changes in climate and land use. However, we do find increased detections with newer survey techniques with bioacoustics, and we recommend they be used with care for future baseline studies that are urgently required.
Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55α
Authors: Sergienko Nicola M , Trewin Adam J , Kiriazis Helen , Raaijmakers Antonia JA , Donner Daniel G , Garside Victoria C , Smith Kelly A , Bell James R , Mellor Kimberley M , Delbridge Lea MD , McMullen Julie R , Weeks Kate L 
Published: May 2024

1.AbstractProtein phosphatase 2A (PP2A) regulatory subunit B55α has been implicated in the transcriptional regulation of cardiac growth and fibrosis by suppressing HDAC5/MEF2 signalling in cardiomyocytes. We created and characterised two mouse models with global or cardiomyocyte-specific disruption of the gene encoding B55α (Ppp2r2a) to conduct the first detailed exploration of B55α in the heart. Global homozygous B55α knockout mice diedin utero, while heterozygous mice had thinner left ventricular walls at 12 months, an effect more pronounced in males. At 10-12 weeks of age, cardiomyocyte-specific B55α knockout mice displayed normal cardiac morphology with increased left ventricular collagen deposition, identifying B55α as a negative regulator of cardiac fibrosis. Gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male but not female mice, identifying a sexually dimorphic role for B55α in cardiac transcriptional regulation. These findings provide a basis for future work investigating B55α in cardiac stress settings.
An fMRI study of phrase structure and subject island violations
Authors: Matchin William , Almeida Diogo , Hickok Gregory , Sprouse Jon 
Published: May 2024

AbstractIn principle, functional neuroimaging provides uniquely informative data in addressing linguistic questions, because it can indicate distinct processes that are not apparent from behavioral data alone. This could involve adjudicating the source of unacceptability via the different patterns of elicited brain responses to different ungrammatical sentence types. However, it is difficult to interpret brain activations to syntactic violations. Such responses could reflect processes that have nothing intrinsically related to linguistic representations, such as domain-general executive function abilities. In order to facilitate the potential use of functional neuroimaging methods to identify the source of different syntactic violations, we conducted an fMRI experiment to identify the brain activation maps associated with two distinct syntactic violation types: phrase structure (created by inverting the order of two adjacent words within a sentence) and subject islands (created by extracting a wh-phrase out of an embedded subject). The comparison of these violations to control sentences surprisingly showed no indication of a generalized violation response, with almost completely divergent activation patterns. Phrase structure violations seemingly activated regions previously implicated in verbal working memory and structural complexity in sentence processing, whereas the subject islands appeared to activate regions previously implicated in conceptual-semantic processing, broadly defined. We review our findings in the context of previous research on syntactic and semantic violations using event- related potentials. Although our results suggest potentially distinct underlying mechanisms underlying phrase structure and subject island violations, our results are tentative and suggest important methodological considerations for future research in this area.
Divineruncovers hundreds of novel human (and other) exons though comparative analysis of proteins
Authors: Nord Alexander J , Wheeler Travis J 
Published: May 2024

BackgroundEukaryotic genes are often composed of multiple exons that are stitched together bysplicingout the intervening introns. These exons may be conditionally joined in different combinations to produce a collection of related, but distinct, mRNA transcripts. For protein-coding genes, these products ofalternative splicinglead to production of related protein variants (isoforms) of a gene. Complete labeling of the protein-coding content of a eukaryotic genome requires discovery of mRNA encoding all isoforms, but it is impractical to enumerate all possible combinations of tissue, developmental stage, and environmental context; as a result, many true exons go unlabeled in genome annotations.ResultsOne way to address the combinatoric challenge of finding all isoforms in a single organismAis to leverage sequencing efforts for other organisms – each time a new organism is sequenced, it may be under a new combination of conditions, so that a previously unobserved isoform may be sequenced. We presentDiviner, a software tool that identifies previously undocumented exons in organisms by comparing isoforms across species. We demonstrateDiviner’s utility by locating hundreds of novel exons in the genomes of human, mouse, and rat, as well as in the ferret genome. Further, we provide analyses supporting the notion that most of the new exons reported byDivinerare likely to be part of a true (but unobserved) isoform of the containing species.