bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knockout of the V-ATPase interacting protein Tldc2 in B-type kidney intercalated cells impairs urine alkalinization
Authors: Eaton Amity F. , Danielson Elizabeth C. , Tu Leona J. , Brown Dennis , Merkulova Maria 
Published: December 2024

ABSTRACTIntercalated cells (ICs) are acid-base regulatory cells in the kidney collecting duct that excrete either acid or base into the urine in response to systemic cues. A-ICs deliver protons into the tubule lumen via an apical proton pump (V-ATPase) and reabsorb base (bicarbonate) using the AE1 anion exchanger. B-ICs function in the opposite direction. They have basolateral V-ATPase and secrete bicarbonate into the lumen via the anion exchange protein, pendrin. The function of a third IC subtype, the non-A non-B IC which has apical pendrin and apical V-ATPase, is less well understood. We previously reported that members of the TLDc protein family interact with the V-ATPase and may regulate its function. TLDc proteins exhibit a distinct expression pattern in the kidney with RNAseq showing high, differential expression of Tldc2 in B-ICs. Here, we show by RNAscope imaging that Tldc2 is indeed expressed in B-ICs, but also in some non-A, non-B ICs. UsingTldc2knockout (Tldc2-/-) mice, we found that male and females had significantly lower urine pH than wild-type littermates, and their ability to increase urine pH in response to a bicarbonate load was impaired. In addition,Tldc2-/-males developed hyperbicarbonatemia.Tldc2-/-kidneys contained fewer B-ICs than wild-type mice, but more non-A, non-B ICs; therefore their sum and the number of A-ICs were unchanged. Furthermore, there was decreased basolateral accumulation of V-ATPase inTldc2/-/-B-ICs. These findings suggest thatTldc2is a novel gene involved in renal acid-base regulation and in addition, may serve as a differentiation marker for B-ICs.NEW & NOTEWORTHYAcid-base balance in the body is constantly changing but must be tightly controlled to be compatible with life. The kidney contains specialized cells that can excrete excess acid or base (bicarbonate) into the urine to maintain normal blood pH. The key protein involved in this process is called the V-ATPase. Here, we report that a novel V-ATPase interacting protein Tldc2 is critical for kidney bicarbonate secretion and is, therefore, a previously unrecognized acid-base regulatory gene.
Induction of hemodynamic traveling waves by glial-related vasomotion in a rat model of neuroinflammation: implications for functional neuroimaging
Authors: Pereira Mickaël , Droguerre Marine , Valdebenito Marco , Vidal Louis , Marcy Guillaume , Benkeder Sarah , Comte Jean-Christophe , Pascual Olivier , Zimmer Luc , Vidal Benjamin 
Published: December 2024

AbstractCerebral hemodynamics are crucial for brain homeostasis and serve as a key proxy for brain activity. Although this process involves coordinated interaction between vessels, neurons and glial cells, its dysregulation in neuroinflammation is not well understood.We used in vivo mesoscopic functional ultrasound imaging to monitor cerebral blood volume changes during neuroinflammation in rats injected with lipopolysaccharide (LPS) in the visual cortex, under resting-state or visual stimulation, combined to advanced ex vivo techniques for glial cell reactivity analysis.Cortical neuroinflammation induced large oscillatory hemodynamic traveling waves in the frequency band of vasomotion (∼0.1 Hz) in both anesthetized and awake rats. Vasomotor waves traveled through large distances between adjacent penetrating vessels, spanning the entire cortex thickness, and even extending to subcortical areas. Moreover, vasomotion amplitude correlated with microglial morphology changes and was significantly reduced by astrocytic toxins, suggesting that both microglia and astrocytes are involved in the enhancement of vasomotion during neuroinflammation. Notably, functional connectivity was increased under this oscillatory state and functional hyperemia was exacerbated.These findings reveal new spatiotemporal properties and cellular mechanisms of cerebral vasomotion, and suggest that this is a major component of brain hemodynamics in pathological states. Moreover, reactive microglia and astrocytes are participating to increased vasomotion during neuroinflammation. These results call for a reassessment of vasomotion and traveling waves as primary phenomena when imaging brain hemodynamic activity, particularly in conditions associated with neuroinflammation.
Cardiac fibroblasts cellular anisotropy is determined by YAP-dependent cellular contractility and ECM production
Authors: Pereira-Sousa Daniel , Guillamat Pau , Niro Francesco , Vinarský Vladimír , Fernandes Soraia , Cassani Marco , Pagliari Stefania , Trepat Xavier , Rasponi Marco , Oliver-De La Cruz Jorge , Forte Giancarlo 
Published: December 2024

ABSTRACTCardiac fibroblasts (CFbs) determine the topological arrangement and the anisotropy of the heart tissue, features which are essential for maintaining tissue integrity and function, primarily through the production and remodeling of the extracellular matrix (ECM). Under pathological conditions, CFbs can activate into myofibroblasts, which promote maladaptive ECM remodeling, a process which may lead to heart failure. Although the mechanosensitive Yes-Associated Protein (YAP) has been implicated in CFb activation, its role in the organization of CFbs and in their ability to deposit cardiac ECM remains unexplored. We investigated the effects of YAP genetic deletion on cardiac fibroblast phenotype and function by generating CFbs from wild-type (WT) and YAP knockout (KO) human embryonic stem cells (hESCs). We found that YAP depletion impaired CFbs differentiation by reducing the expression of cardiogenic markers. Additionally, we demonstrated that YAP expression is required for monolayer alignment of CFbs. Transcriptomic analysis further revealed that YAP is essential for the regulation of ECM- and contractility-related genes, and that its absence resulted in reduced ECM deposition, diminished anisotropy, and decreased force generation. Pharmacological inhibition of contractility closely mirrored YAP KO phenotype, suggesting that YAP regulates both monolayer organization and ECM structure through its control over contractility. These findings underscore the critical role of the mechanosensor YAP in maintaining the supracellular organization of CFbs and the mechanical integrity of cardiac tissue.
Collective dynamics of DNA methylation during ageing
Authors: Hashtroud Aida , Bonder Marc , Stegle Oliver , von Meyen Ferdinand , Reik Wolf , Rulands Steffen 
Published: December 2024

AbstractAgeing is the decline of physiological function over time. Statistical models termed ageing clocks can predict chronological and biological age from the longitudinal time evolution of DNA methylation. Here, we show that DNA methylation ageing is also manifest in how pairs of genomic loci evolve with respect to each other with age. Using sequencing data from a range of tissues in mouse we show that genomic correlations in DNA methylation during ageing are characterised by an enrichment of correlations between sites that are roughly 500 bp apart. We trace the origin of this behaviour to collective dynamics in the boundaries of CpG islands. We derive a simple, biophysical model that explains the origin due to a tilt in the competition between methylating and demethylating processes and an ensuing wetting-like phenomenon. Using Chip-seq data, we argue for a molecular mechanism based on a PRC2-dependent dilution of H3K27me3 during ageing. Our work gives a new perspective on epigenetic ageing, highlighting the importance of correlative as opposed to longitudinal dynamics.
Joining the Conversation with a Dedicated Medical Education Corpus
Authors: Ow Gregory M. , Stetson Geoffrey V. , Costello Joseph A. , Artino Anthony R. , Maggio Lauren A. 
Published: December 2024

AbstractPROBLEMMedical education scholars struggle to join ongoing conversations in their field due to the lack of a dedicated medical education corpus. Without such a corpus, scholars must either search too widely across thousands of irrelevant journals, or too narrowly by relying on PubMed’s Medical Subject Headings (MeSH). In our tests, MeSH missed 34% of medical education papers.APPROACHWe developed the MEC (Medical Education Corpus), the first dedicated collection of medical education papers, through a three-step process. First, using the Core-Periphery model, we created the MEJ (Medical Education Journals), a collection of three groups of journals based on participation and influence in medical education discourse: the MEJ-Core (formerly the MEJ-24, 24 journals), MEJ-Adjacent (127 journals), and MEJ-Peripheral (a theoretical group). Second, we developed and evaluated a machine learning model, the MEC Classifier, trained on 4,032 manually labeled papers to identify medical education content. Finally, we applied the MEC Classifier to extract medical education papers from the MEJ-Core and MEJ-Adjacent journals.OUTCOMESThe MEC currently contains 119,137 medical education papers from the MEJ-Core (54,927 papers) and MEJ-Adjacent journals (64,210 papers). In our evaluation using 1,358 test papers, the MEC Classifier demonstrated significantly improved sensitivity compared to MeSH (90% vs 66%,p= 0.001), even while maintaining a similar positive predictive value (82% vs 81%).NEXT STEPSThe MEC provides a focused, searchable corpus that enables medical education scholars to more easily join conversations in the field. Scholars can now rely on the MEC when reviewing literature to frame their work, and the MEC also creates opportunities for field-wide analyses and meta-research. The MEC is freely available in the Supplement and is regularly updated on MedEdMentor (mededmentor.org), where we will also incorporate community feedback to further improve and expand the corpus.
Gene age shapes functional and evolutionary properties of theDrosophilaseminal fluid proteome
Authors: Ranz Jose M. , Flacchi Carolina , Hariyani Imtiyaz E. , Civetta Alberto 
Published: December 2024

AbstractSeminal fluid proteins (Sfps) are crucial for animal reproductive success, with most Sfps-encoding genes believed to be evolutionarily young and rapidly evolving. By employing estimates of the phylogenetic origin of eachDrosophila melanogasterSfp gene based on genomic resources that include outgroup species to theDrosophilagenus, we examined the functional attributes and evolutionary characteristics of Sfp genes relative to their evolutionary age. Contrary to common belief, 62% of Sfp genes existed in the genome of the ancestor to such genus. These ancient genes have broadened their expression profiles, expanded their biological roles, and formed a denser network of interactions with non-Sfp genes. This increased pleiotropy has imposed constraints on the rate of sequence evolution in ancient Sfp genes compared to younger ones. Within the Sfp interactome, we identified a fast-evolving core sub-network of younger genes with more restricted tissue expression and functions. Our findings uncover a large, previously unrecognized set of ancient Sfp genes with distinct genomic, functional, and evolutionary characteristics compared to the younger, more commonly studied Sfp genes.
The TRX assay for triplet repeat expansions
Authors: O’Brien Thomas , Salciute Karolina , Kieffer Shaylee , Packil Ponraj Nehaa Kandasamy , Richer Madeleine , Marzec Paulina , Benn Caroline , Monckton Darren G. , Dion Vincent , Lahue Robert S. 
Published: December 2024

AbstractExpansion mutations of triplet repeat sequences cause numerous inherited neurological diseases. In some diseases, affected individuals display somatic expansions in affected tissues which have been linked to accelerated disease onset and progression. There is currently considerable interest in developing therapies to slow somatic repeat expansions to delay or block disease onset.In vitroassays are particularly important to evaluate potential therapeutic interventions. Current assays typically use physical methods to monitor triplet repeat lengths within a population of cells. While useful, most of these assays are relatively slow (∼six weeks) and are somewhat limited in sensitivity to rare events. Here, a new assay, called TRX, is described to monitor CAG•CTG triplet repeat expansions more rapidly and with better sensitivity. TRX uses human tissue culture cells expressing two fluorescent proteins. Red fluorescent protein TagRFP658 is constitutively expressed and serves as an internal control. GFP is expressed in a CAG•CTG repeat length-dependent manner, with longer repeat lengths predicted to give higher green fluorescence intensity. Standard flow cytometry allows quantification of changes in fluorescent signal as a simple readout with <2% sensitivity. Two independently derived cell lines with 63 or 59 CAG repeats yielded similar rates of TRX activity. Cells with increased green fluorescence were observed within one to two weeks of culture, with longer times leading to additional signal. The appearance of green fluorescence was partly dependent on MutSβ, the DNA MSH2-MSH3 complex, based on siRNA knockdown of MSH3. However, physical analysis of the CAG•CTG repeat tracts by MiSeq deep sequencing or capillary electrophoresis showed limited changes in the length of the repeat tracts. We conclude that the TRX assay is a promising new tool for monitoring CAG•CTG repeat expansions but that further development of the assay is needed to make it fully useful.
Detection of triglyceride metabolism in white blood cells using a novel fluorescently labeled long chain fatty acid analogue
Authors: Hara Yasuhiro , Hirano Ken-ichi 
Published: December 2024

Abstract123I-15-(p-iodophenyl)-(R,S)-methyl pentadecanoic acid (123I-BMIPP) is a long-chain fatty acid (LCFA) analog developed to examine myocardial LCFA metabolism and has been used as a tracer for nuclear cardiology. However, its use is limited because of the specialized features of cardiac scintigraphy. In this study, a novel BMIPP-based probe, in which iodine-123 was replaced with a fluorescent compound, was used to extend the application of123I-BMIPP toex vivoanalysis of fatty acid metabolism. To confirm that fluorescently labeled BMIPP-based probe (fluorescent BMPP) is effective for the detection of LCFA metabolismex vivo, we performed fluorescence-activated cell sorting (FACS) analysis for the incorporation of fluorescent BMPP using white blood cells from human peripheral blood. FACS analysis showed that the incorporation of fluorescent BMPP into white blood cells was dose-dependent. Fluorescence intensities of cells incorporating fluorescent BMPP were attenuated after incubation in non-fluorescent BMPP medium, suggesting that these cells could export the probe. Neutrophils from a patient with primary triglyceride deposit cardiomyovasculopathy, a rare type of triglyceride (TG) metabolism disorders, showed lower BMPP export and was ameliorated after treatment with tricaprin. These results suggest that fluorescent BMPP could be imported to and exported from cells through the same mechanism as123I-BMIPP, reflecting the mechanism that occurs for LCFAs during TG metabolism. This study shows that fluorescent BMPP has the potential to be used as a probe for the diagnosis of TG metabolic diseasesex vivo.
Oral and faecal viromes of New Zealand calves on pasture with an idiopathic ill-thrift syndrome
Authors: Grimwood Rebecca M. , Darnley Jessica A. , O’Connell John P. , Hunt Hayley , Taylor Harry S. , Lawrence Kevin E. , Abbott Michaela B. W. , Jauregui Ruy , Geoghegan Jemma L. 
Published: December 2024

AbstractSince 2015, an idiopathic ill-thrift syndrome featuring diarrhoea and, in some cases, gastrointestinal ulceration has been reported in weaned New Zealand dairy calves. Similar syndromes have been described in the British Isles and Australia, but investigations in New Zealand have yet to identify a specific cause. Notably, the viromes of affected calves remain understudied. We conducted metatranscriptomic analyses of oral and faecal viromes in 11 calves from a dairy farm in Taranaki, New Zealand experiencing an outbreak of this syndrome. This included nine symptomatic calves. Our analysis identified 18 bovine-associated viruses across two DNA and three RNA viral families, including five novel species. Oral viromes were dominated byPseudocowpox virus, detected in all calves with oral lesions. Faecal viromes were more diverse, featuring adenoviruses, caliciviruses, astroviruses, and picornaviruses.Bovine bopivirus, from thePicornaviridaefamily and previously unreported in New Zealand, was significantly associated with calves showing oral lesions and diarrhoea, indicating a possible link to disease, though its role remains unclear. The diverse viral communities in the calves complicates identifying a single causative agent. Importantly, no novel viruses were significantly associated with the syndrome, and the viromes closely resembled those found in cattle globally. These findings suggest the syndrome likely has a multifactorial origin involving nutritional, management, and environmental factors rather than being driven primarily by known or novel viruses. Further research across regions and seasons is recommended to clarify the role of viruses in idiopathic ill-thrift among New Zealand calves.
DTPSP: A Deep Learning Framework for Optimized Time Point Selection in Time-Series Single-Cell Studies
Authors: Hijazin Michel , Shi Pumeng , Wang Jingtao , Ding Jun 
Published: December 2024

AbstractTime-series studies are critical for uncovering dynamic biological processes, but achieving comprehensive profiling and resolution across multiple time points and modalities (multi-omics) remains challenging due to cost and scalability constraints. Current methods for studying temporal dynamics, whether at the bulk or single-cell level, often require extensive sampling, making it impractical to deeply profile all time points and modalities. To overcome these limitations, we present DTPSP, a deep learning framework designed to identify the most informative time points in any time-series study, enabling resource-efficient and targeted analyses. DTPSP models temporal gene expression patterns using readily obtainable data, such as bulk RNA-seq, to select time points that capture key system dynamics. It also integrates a deep generative module to infer data for non-sampled time points based on the selected time points, reconstructing the full temporal trajectory. This dual capability enables DTPSP to prioritize key time points for in-depth profiling, such as single-cell sequencing or multi-omics analyses, while filling gaps in the temporal landscape with high fidelity. We apply DTPSP to developmental and disease-associated time courses, demonstrating its ability to optimize experimental designs across bulk and single-cell studies. By reducing costs, enabling strategic multi-omics profiling, and enhancing biological insights, DTPSP provides a scalable and generalized solution for investigating dynamic systems.
Contribution of front-line, standard of care drugs to bactericidal responses, resistance emergence, and cure in murine models of easy- or hard-to-treat tuberculosis disease
Authors: Peroutka-Bigus Nathan , Brooks Elizabeth J. , Ramey Michelle E. , D’Erasmo Hope , Ernest Jacqueline P. , Bauman Allison A. , Woolhiser Lisa K , Savic Radojka M. , Lenaerts Anne J. , Aldridge Bree B. , Sarathy Jansy P. , Robertson Gregory T. 
Published: December 2024

AbstractBy assessing the standard of care regimen for tuberculosis (TB) in BALB/c and C3HeB/FeJ mice, we demonstrate that rifampin, with or without pyrazinamide, is essential to effective bactericidal response and resistance suppression. Potency measurements in anin vitrolipid-rich model and rabbit caseum assay recapitulate the significance of rifampin as a sterilizing agent. These outcomes align with clinical performance, thus emphasizing the value ofin vitropredictive tools and murine TB models with human-like pathology.
Quantum chemical properties of chlorinated polycyclic aromatic hydrocarbons for delta machine learning
Authors: Frolov Dmitry , Ibraev Ilya , Sedov Igor 
Published: December 2024

AbstractPromising Δ-machine learning approaches aim to correct the values of molecular properties obtained with computationally inexpensive methods to the accuracy of higher levels of theory. Training such models requires datasets containing the results of calculations at several different levels of quantum chemical theory. While several large and chemically diverse datasets have been published, studies in many areas require specialized datasets of structurally related molecules. Chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs), the products of incomplete combustion of organic substances and materials, are hazardous pollutants with carcinogenic and mutagenic activity. Quantum chemistry methods are important to understand their formation mechanisms and properties. We describe a dataset, PACHQA, containing the results of quantum chemical calculations including properties, geometries, wavefunctions, and electron densities for 3551 molecules including 3417 Cl-PAHs with up to 6 rings and a different number of chlorine atoms in their structure as well as 134 parent polycyclic aromatic hydrocarbons (PAHs). The major part of these molecules have previously not been included in any quantum chemical datasets. The calculations were performed at three different levels of theory including geometry optimization with GFN2-xTB and r2SCAN-3c methods and single-point energy calculation at ωB97X-D4/def2-TZVP DFT level. The dataset can be useful to develop and validate the computational, machine learning, or experimental, approaches and study the structure-property relationships for Cl-PAHs.
DNMT1 loss leads to hypermethylation of a subset of late replicating domains by DNMT3A
Authors: Kafetzopoulos Ioannis , Taglini Francesca , Davidson-Smith Hazel , Sproul Duncan 
Published: December 2024

AbstractLoss of DNA methylation is a hallmark of cancer that is proposed to promote carcinogenesis through gene expression alterations, retrotransposon activation and induction of genomic instability. Cancer-associated hypomethylation does not occur across the whole genome but leads to the formation of partially methylated domains (PMDs). However, the mechanisms underpinning PMD formation remain unclear. PMDs replicate late in S-phase leading to the proposal that they become hypomethylated due to incomplete re-methylation by the maintenance methyltransferase DNMT1 during cell division. Here we investigate the role of DNMT1 in the formation of PMDs in cancer by conducting whole genome bisulfite sequencing (WGBS), repli-seq and ChIP-seq on DNMT1 knockout HCT116 colorectal cancer cells (DNMT1 KO cells). We find that DNMT1 loss leads to preferential hypomethylation in late replicating, heterochromatic PMDs marked by the constitutive heterochromatic mark H3K9me3 or the facultative heterochromatic mark H3K27me3. However, we also observe that a subset of H3K9me3-marked PMDs gain methylation in DNMT1 KO cells. We find that, in DNMT1 KO cells, these hypermethylated PMDs remain late replicating but gain DNMT3A localisation. This is accompanied by loss of heterochromatic H3K9me3 and specific gain of euchromatic H3K36me2. Our observations suggest that hypermethylated PMDs lose their heterochromatic state, enabling their methylation by DNMT3A and the establishment of a hypermethylated, non-PMD state, despite their late replication timing. More generally, our findings suggest that thede novoDNMTs play a key role in establishing domain level DNA methylation patterns in cancer cells.