bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPV3 channel activity helps cortical neurons stay active during fever
Authors: Shen Yiming , Fiáth Richárd , Ulbert István , Antoine Michelle W. 
Published: September 2024

AbstractFever raises body temperature (Tb) from ∼37°C to beyond 38°C to combat pathogens. While generally well tolerated below 40°C, fevers can induce seizures in 2-5-year-old neurotypical children. This study investigates how neuronal activity is maintained during fever-range temperatures. Recordings of layer (L) 4-evoked spiking in L2/3 mouse somatosensory cortex show that excitatory pyramidal neurons (PNs) may remain inactive, stay active, cease activity, or initiate activity as temperature rises from 30°C (standard in electrophysiology studies) to 36°C (normal Tb) and then to 39°C (fever-range). Similar proportions of neurons cease or initiate spiking. Thus, “STAY” PNs, which remain active across temperatures changes, are crucial for maintaining stable spiking activity. STAY PNs are more prevalent at younger postnatal ages. To sustain spiking during temperature increases, STAY PNs adjust their depolarization levels to match the spike threshold while remaining temperature-insensitive in input resistance. In the striatum, STAY medium-spiny neurons are likely dopamine (D)2-type receptor-expressing and share similar characteristics with STAY PNs. Intracellular blockade of the thermosensitive channelTRPV3, but notTRPV4, significantly decreased the population of STAY PNs and reduced spiking at 39°C. Therefore,TRPV3function may be critical for maintaining cortical activity during fever.
On the specificity of manual triggers of autonomic nervous system responses using osteopathic cranial manipulative medicine
Authors: Keller Micha , Perlitz Volker , Pelz Holger , Borik Stefan , Repik Ines , Geilgens Armin , Cotuk Birol , Müller Gero , Mathiak Klaus , Mayer Johannes 
Published: September 2024

AbstractSignificant autonomic nervous system responses to a specific osteopathic intervention, the cranial vault hold (CVH), have recently been demonstrated in forehead skin blood volume changes, heart rate, and respiration frequencies. The specificity of the CVH-intervention-related autonomic responses yet requires differentiation. Thus, we compared autonomic responses to CVH with responses to compression of the fourth ventricle (CV4) and to two corresponding SHAM conditions. Analysis of frequencies and amplitudes for changes in skin blood volume and respiration in low (LF; 0.05 – 0.12 Hz), intermediate (IM; 0.12 – 0.18 Hz), and high (HF; 0.18 – 0.4 Hz) frequency bands, and metrics of heartrate variability revealed significant decreases in LF range (from 0.12 to 0.10 Hz), increased LF and decreased IM durations, and increased skin blood volume amplitudes in response to CVH, but no significant skin blood volume responses to any of the control interventions. Ratio changes for respiration and skin blood volume frequencies approximately at 3:1 during CVH, remained unchanged in all other interventions. Heart rate decreased across conditions, indicating an increase in parasympathetic tone. This was also indicated by a significant increase in root mean of squared successive difference following CV4. We incurred that rhythmic response patterns in the LF and IM bands only appeared in CVH. This suggests specific physiological responses to CVH warranting further investigation by studying e.g., responses to CVH in physical or mental health disorders with autonomic involvement.
Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function
Authors: Anderson Andrea , Kovilakath Anna , Jamil Maryam , Lambert Johana , Cowart L. Ashley 
Published: September 2024

AbstractCircadian rhythms align biological functions with the 24-hour day-night cycle, but modern artificial light disrupts these patterns, contributing to health issues like obesity and cardiovascular disease. The circadian clock operates through a transcriptional-translational feedback loop involving core components such as BMAL1 and CLOCK. Recent research has shown circadian variations in sphingolipid metabolism, specifically sphingosine-1-phosphate (S1P), which plays crucial signaling roles. This study investigates the sphingolipid enzyme, sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, as a circadian-regulated gene in adipocytes. We find that SphK1 expression and activity follow a circadian rhythm, regulated by BMAL1 and CLOCK binding to its promoter. Adipocyte-specific SphK1 knockout mice exhibit disrupted circadian rhythms, and impaired adipocyte function. Additionally, SphK1 deficiency leads to reduced histone acetylation and altered histone deacetylase (HDAC) localization, affecting gene regulation. These results highlight the critical role of SphK1 in linking lipid metabolism with circadian biology.
QuickEd: High-performance exact sequence alignment based on bound-and-align
Authors: Doblas Max , Lostes-Cazorla Oscar , Aguado-Puig Quim , Iñiguez Cristian , Moreto Miquel , Marco-Sola Santiago 
Published: September 2024

AbstractMotivationPairwise sequence alignment is a core component of multiple sequencing-data analysis tools. Recent advancements in sequencing technologies have enabled the generation of longer sequences at a much lower price. Thus, long-read sequencing technologies have become increasingly popular in sequencing-based studies. However, classical sequence analysis algorithms face significant scalability challenges when aligning long sequences. As a result, several heuristic methods have been developed to improve performance at the expense of accuracy, as they often fail to produce the optimal alignment.ResultsThis paper introduces QuickEd, a sequence alignment algorithm based on a bound-and-align strategy. First, QuickEd effectively bounds the maximum alignment-score using efficient heuristic strategies. Then, QuickEd utilizes this bound to reduce the computations required to produce the optimal alignment. Using QuickEd’s bound-and-align strategy, we reduceO(n2) complexity of traditional dynamic programming algorithms toO(nŝ), wherenis the sequence length andŝis an estimated upper bound of the alignment-score between the sequences. As a result, QuickEd is consistently faster than other state-of-the-art implementations, such as Edlib and BiWFA, achieving performance speedups of 1.6−7.3× and 2.1−2.5×, respectively, aligning long and noisy datasets. In addition, QuickEd maintains a stable memory footprint below 50 MB while aligning sequences up to 1 Mbp.AvailabilityQuickEd code and documentation are publicly available athttps://github.com/maxdoblas/QuickEd.Contactmax.doblas@bsc.es
Transcriptional program-based deciphering of the MET exon 14 skipping regulation network
Authors: Truong Marie-José , Pawlak Geoffrey , Meneboo Jean-Pascal , Sebda Shéhérazade , Fernandes Marie , Figeac Martin , Elati Mohamed , Tulasne David 
Published: September 2024

AbstractThe MET exon 14 skipping mutation (named METex14del) described in lung cancer leads to prolonged activation of signaling pathways and aberrant cell responses, but the link between HGF signaling and cell responses remains unclear. A putative regulatory network of influential regulators of target genes was constructed from the transcriptomes of lung cancer cell lines. Overlaying this reference network with transcriptomic data from METex14del-expressing cells, stimulated or not by HGF, revealed a major regulatory node consisting mainly of the transcription factors ETS1, FOSL1 and SMAD3. HGF activation of METex14del induced the phosphorylation of these master regulators and the expression of their predicted target genes in a RAS-ERK pathway-dependent manner. Furthermore, most of the transcription factors in the regulatory node are known regulators of epithelial-mesenchymal transition, consistent with their involvement in migration and invasion. New modeling with transcriptomic data from MEK inhibitor-treated METex14del cells validated the key role of RAS-ERK pathway regulators and their target genes in METex14del receptor activation. Thus, we report an original strategy to identify key transcriptional nodes associated with specific signaling pathways that may become novel therapeutic targets.
Nanomechanics of cell-derived matrices as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies
Authors: White Tom , López-Márquez Arístides , Badosa Carmen , Jiménez-Mallebrera Cecilia , Samitier Josep , Giannotti Marina I. , Lagunas Anna 
Published: September 2024

AbstractAtomic force microscopy-force spectroscopy (AFM-FS) applied to biological samples can provide information on the micro- and nanoscale mechanical properties of tissues, which are a determinant of cellular behavior. Mechanical properties are largely determined by the structure and composition of the extracellular matrix (ECM), for which severalin vitromodels have been developed, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells, that closely mimic thein vivostromal fiber organization and molecular content.Here we applied AFM-FS to evaluate the nanomechanical properties of CDMs obtained from primary skin fibroblast cultures of patients affected by collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs.The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. We describe differences in the elastic modulus (E) among CDMs deriving from patients with different clinical phenotypes, as well as the restoration ofEin CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
Th17 cells require the DNA repair sensor XPC to control oxidative DNA damage
Authors: Leite Jefferson Antônio , Notaberardino Bos Natalia , Menezes Luísa , Martins Eloísa , da Silva Leandro Giovana , da Silva Patrick , Ranfley Hedden , Oliveira Samuel , Pontes Ferreira Camila , Arimatéia de Oliveira Nery Neto José , Yuji Victor , Cipelli Marcela , Leocata Beatriz , Gonçalves Talita , Gabry da Silveira Anthony , Baroni Sabrina , Weiner Howard L. , Hofmann Thomas , Scheu Stefanie , Machado Colli Leandro , Waisman Ari , Muxel Sandra , Menck Carlos Frederico Martins , Saraiva Câmara Niels Olsen 
Published: September 2024

AbstractTh17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPC’s role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases.
Homeostatic balance of Gut-resident Tregs (GTregs) plays a pivotal role in maintaining bone health under post-menopausal osteoporotic conditions
Authors: Bhardwaj Asha , Sapra Leena , Madan Divya , Ahuja Vineet , Mishra Pradyumna K. , Srivastava Rupesh K. 
Published: September 2024

AbstractOsteoporosis is a skeletal condition characterized by the deterioration of bone tissue. The immune system plays a crucial role in maintaining bone homeostasis and combating the development of osteoporosis. Immunoporosis is the term used to describe the recent convergence of research on the immune system’s role in osteoporosis. Gut harbors the largest component of the immune system and there is growing evidence that intestinal immunity plays a vital role in regulating bone health. Gut-resident regulatory T cells (GTregs) play an essential role in inhibiting immune responses and preventing various inflammatory manifestations. Our findings show that GTregs have a pivotal role in the pathophysiology of post-menopausal osteoporosis (PMO). We investigated the potential of GTregs in regulating the development of bone cellsin vitro. We observed that GTregs significantly enhance osteoblastogenesis with concomitant inhibition of osteoclastogenesis in a cell-ratio-dependent manner. We further report that the deficiency of short-chain fatty acids (SCFAs) in osteoporotic conditions substantially disrupts the composition of GTregs, leading to a loss of peripherally derived Tregs (pTregs) and an expansion of thymus-derived Tregs (tTregs). Moreover, the administration of probioticsLactobacillus rhamnosusandBifidobacterium longummodulated the GTregs compartment in an SCFA-dependent manner to mitigate inflammatory bone loss in PMO. Notably, SCFAs-primed GTregs were found to be significantly more effective in inhibiting osteoclastogenesis compared to unprimed GTregs. Altogether our results, for the first time, highlight the crucial role of GTregs in the pathophysiology of PMO, with potential clinical implications in the near future.Graphical Abstract:A) During normal physiological conditions there is a sufficient proportion of Tregs in the mice intestine with a higher frequency of pTregs compared to the tTregs. Gut-resident Tregs inhibit osteoclastogenesis and therefore prevent bone loss. However post-menopausal condition decreases the Treg population in the intestinal tissues and further perturbs the balance of pTregs and tTregs resulting in bone loss. Probiotics such asLactobacillus rhamnosus(LR) andBifidobacterium longum(BL) induce the development of Tregs from naïve T cells and further restore the balance of pTregs and tTregs in a short chain fatty acid (SCFA) dependent manner. SCFAs primed Tregs are more potent in inhibiting osteoclastogenesis thereby preventing bone loss due to osteoporosis. B) Similar to mice the frequency of Tregs decreases in the human colon of inflammatory bowel disease (IBD) patients with osteopenia or osteoporosis compared to the IBD patients without osteopenia/osteoporosis
Fluorescent pH-sensitive nanosensors enable precise low-volume monitoring in high-throughput bioprocess manufacturing
Authors: Besenyei Greta Csalane , Tang Alison , Aylott Jonathan W , Chauhan Veeren M 
Published: September 2024

Abstract / SummaryBiopharmaceutical manufacturing requires precise pH control during production to ensure product quality and process performance. However, achieving this precision in low-volume, high-throughput automated settings present significant challenges with existing technology, often leading to inefficiencies and inaccuracies. This study introduces fluorescent nanosensors as a novel solution for accurate pH monitoring in micro-scale environments. Employing ratiometric fluorescence measurement, these nanosensors use analyte responsive and reference fluorophores in inert polyacrylamide matrices to perform dynamic measurements over pH 3.5 - 7.5. Nanosensors (35.26 ± 3.66 nm diameter) were synthesised with a neutral or positive surface charge (−5.08 ± 4.05 mV and +12.87 ± 1.25 mV, respectively). An automated workflow, using sacrificial and at line sample analysis, was developed by integrating the nanosensors with a TECAN™ automated liquid handling platform and a fluorescence spectrophotometer. The method was verified using in-process samples obtained from a monoclonal antibody purification, to highlight the compatibility of the nanosensors to different buffer systems in a typical biopharmaceutical manufacturing process. We show that pH-sensitive nanosensors can effectively monitor pH through the various stages of purification, demonstrating high accuracy (pH ± 0.23-0.40) even in sample volumes as low as 12.5 μL. The application of nanosensors represents a significant advancement in high-throughput scale-down bioprocess development by enabling precise, automated pH adjustment. This study improves the understanding of biopharmaceutical manufacturing, through the application of fluorescent nanosensors, paving-the-way for optimisations in low-volume and high-throughput product production.Graphical Abstract
Multiplexed spatial mapping of chromatin features, transcriptome, and proteins in tissues
Authors: Guo Pengfei , Mao Liran , Chen Yufan , Lee Chin Nien , Cardilla Angelysia , Li Mingyao , Bartosovic Marek , Deng Yanxiang 
Published: September 2024

AbstractThe phenotypic and functional states of a cell are modulated by a complex interactive molecular hierarchy of multiple omics layers, involving the genome, epigenome, transcriptome, proteome, and metabolome. Spatial omics approaches have enabled the capture of information from different molecular layers directly in the tissue context. However, current technologies are limited to map one to two modalities at the same time, providing an incomplete representation of cellular identity. Such data is inadequate to fully understand complex biological systems and their underlying regulatory mechanisms. Here we present spatial-Mux-seq, a multi-modal spatial technology that allows simultaneous profiling of five different modalities, including genome-wide profiles of two histone modifications and open chromatin, whole transcriptome, and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We applied this technology to generate multi-modal tissue maps in mouse embryos and mouse brains, which discriminated more cell types and states than unimodal data. We investigated the spatiotemporal relationship between histone modifications, chromatin accessibility, gene and protein expression in neuron differentiation revealing the relationship between tissue organization, function, and gene regulatory networks. We were able to identify a radial glia spatial niche and revealed spatially changing gradient of epigenetic signals in this region. Moreover, we revealed previously unappreciated involvement of repressive histone marks in the mouse hippocampus. Collectively, the spatial multi-omics approach heralds a new era for characterizing tissue and cellular heterogeneity that single modality studies alone could not reveal.
Toxoplasma gondiichronic infection decreases visceral nociception through peripheral opioid receptor signaling
Authors: Audibert Alexis , Mas-Orea Xavier , Rey Léa , Belloy Marcy , Bassot Emilie , Marodon Gilles , Masson Frederick , Cenac Nicolas , Dietrich Gilles , Bonnart Chrystelle , Blanchard Nicolas 
Published: September 2024

AbstractBy eliciting immune activation in the digestive tract, intestinal pathogens may perturb gut homeostasis. Some gastrointestinal infections can indeed increase the risk of developing post-infectious irritable bowel syndrome (PI-IBS). Intriguingly, the prevalent foodborne parasiteToxoplasma gondiihas not been linked to the development of PI-IBS and the impact of this infection on colon homeostasis remains ill-defined. We show in a mouse model that latentT. gondiidecreases visceral nociceptive responses in an opioid signaling-dependent manner. Despite the accumulation of Th1 and cytotoxic T cells in the colon of latently infected mice, the selective invalidation of enkephalin gene in T cells ruled out the involvement of T cell-derived enkephalins in hypoalgesia. These findings provide clues about how this widespread infection durably shapes the gut immune landscape and modifies intestinal physiological parameters. They suggest that in contrast to other gut microbes,T. gondiiinfection could be negatively associated with abdominal pain.TeaserLatent toxoplasmosis decreases gut nociception in the mouse, suggesting a negative association with abdominal pain in humans
Chromosomal instability increases radiation sensitivity
Authors: Cosper Pippa F. , Paracha Maha , Jones Kathryn M. , Hrycyniak Laura , Henderson Les , Bryan Ava , Eyzaguirre Diego , McCunn Emily , Boulanger Elizabeth , Wan Jun , Nickel Kwangok P. , Horner Vanessa , Hu Rong , Harari Paul M. , Kimple Randall J. , Weaver Beth A. 
Published: September 2024

AbstractContinuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities.Statement of SignificanceCancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.