bluuebunny/crossref_metadata_2025_split huggingface dataset:
Varying selection pressure for a Na+sensing site in epithelial Na+channel subunits reflect divergent roles in Na+homeostasis
Authors: Wang Xue-Ping , Srinivasan Priyanka , Hamdaoui Mustapha El , Grytz Rafael , Kashlan Ossama B. 
Published: February 2024

AbstractThe epithelial Na+channel (ENaC) emerged early in vertebrates and has played a role in Na+and fluid homeostasis throughout vertebrate evolution. We previously showed that proteolytic activation of the channel evolved at the water to land transition of vertebrates. Sensitivity to extracellular Na+, known as Na+self-inhibition, reduces ENaC function when Na+concentrations are high and is a distinctive feature of the channel. A fourth ENaC subunit, δ, emerged in jawed fishes from an α subunit gene duplication. Here, we analyzed 846 α and δ subunit sequences and found that a key Asp in a postulated Na+binding site was nearly always present in the α subunit, but frequently lost in the δ subunit (e.g., human). Analysis of site evolution and codon substitution rates provide evidence that the ancestral α subunit had the site and that purifying selection for the site relaxed in the δ subunit after its divergence from the α subunit, coinciding with a loss of δ subunit expression in renal tissues. We also provide evidence that the proposed Na+binding site in the α subunit is a bona fide site by conferring novel function to channels comprising human δ subunits. Together, our findings provide evidence that ENaC Na+self-inhibition improves fitness through its role in Na+homeostasis in vertebrates.
Evidence for a transfer-to-trap mechanism of fluorophore concentration quenching in lipid bilayers
Authors: Meredith Sophie A. , Kusunoki Yuka , Evans Stephen D. , Morigaki Kenichi , Connell Simon D. , Adams Peter G. 
Published: February 2024

ABSTRACTIt is important to understand the behaviours of fluorescent molecules because, firstly, they are often utilized as probes in biophysical experiments and, secondly, they are crucial cofactors in biological processes such as photosynthesis. A phenomenon called ‘fluorescence quenching’ occurs when fluorophores are present at high concentrations but the mechanisms for quenching are debated. Here, we used a technique called ‘in-membrane electrophoresis’ to generate concentration gradients of fluorophores within a supported lipid bilayer (SLB), across which quenching was expected to occur. Fluorescence lifetime imaging microscopy (FLIM) provides images where the fluorescence intensity in each pixel is correlated to fluorescence lifetime: the intensity provides information about the location and concentration of fluorophores and the lifetime reveals the occurrence of energy-dissipative processes. FLIM was used to compare the quenching behaviour of three commonly-used fluorophores: Texas Red (TR), nitrobenzoaxadiazole (NBD) and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). FLIM images provided evidence of quenching in regions where the fluorophores accumulated but the degree of quenching varied between the different fluorophores. The relationship between quenching and concentration was quantified and the ‘critical radius for trap formation’, representing the relative quenching strength, was calculated as 2.70, 2.02 and 1.14 nm, for BODIPY, TR and NBD, respectively. The experimental data supports the theory that quenching takes place via a ‘transfer-to-trap’ mechanism which proposes, firstly, that excitation energy is transferred between fluorophores and may reach a ‘trap site’ resulting in immediate energy dissipation and, secondly, that trap sites are formed in a concentration-dependent manner. Some previous work suggested that quenching occurs only when fluorophores aggregate, or form long-lived dimers, but our data and this theory argues that traps may be ‘statistical pairs’ of fluorophores that exist only transiently. Our findings should inspire future work to assess whether these traps can be charge-transfer states, excited state dimers or something else.
Epigenetic repression of cFos supports sequential formation of distinct spatial memories
Authors: Franzelin Andreas , Lamothe-Molina Paul J. , Gee Christine E. , Formozov Andrey , Schreiter Eric R. , Morellini Fabio , Oertner Thomas G. 
Published: February 2024

AbstractExpression of the immediate early gene cFos modifies the epigenetic landscape of activated neurons with downstream effects on synaptic plasticity. The production of cFos is inhibited by a long-lived isoform of another Fos family gene, ΔFosB. It has been speculated that this negative feedback mechanism may be critical for protecting episodic memories from being overwritten by new information. Here, we investigate the influence of ΔFosB inhibition on cFos expression and memory. Hippocampal neurons in slice culture produce more cFos on the first day of stimulation compared to identical stimulation on the following day. This downregulation affects all hippocampal subfields and requires histone deacetylation. Overexpression of ΔFosB in individual pyramidal neurons effectively suppresses cFos, indicating that accumulation of ΔFosB is the causal mechanism. Water maze training of mice over several days leads to accumulation of ΔFosB in granule cells of the dentate gyrus, but not in CA3 and CA1. Because the dentate gyrus is thought to support pattern separation and cognitive flexibility, we hypothesized that inhibiting the expression of ΔFosB would affect reversal learning, i.e., the ability to successively learn new platform locations in the water maze. The results indicate that pharmacological HDAC inhibition, which prevents cFos repression, impairs reversal learning, while learning and memory of the initial platform location remain unaffected. Our study supports the hypothesis that epigenetic mechanisms tightly regulate cFos expression in individual granule cells to orchestrate the formation of time-stamped memories.
The Representation of Decision Variables in Orbitofrontal Cortex is Longitudinally Stable
Authors: Zhang Manning , Livi Alessandro , Carter Mary , Schoknecht Heide , Burkhalter Andreas , Holy Timothy E. , Padoa-Schioppa Camillo 
Published: February 2024

AbstractThe computation and comparison of subjective values underlying economic choices rely on the orbitofrontal cortex (OFC). In this area, distinct groups of neurons encode the value of individual options, the binary choice outcome, and the chosen value. These variables capture both the input and the output of the choice process, suggesting that the cell groups found in OFC constitute the building blocks of a decision circuit. Here we show that this neural circuit is longitudinally stable. Using two-photon calcium imaging, we recorded from mice choosing between different juice flavors. Recordings of individual cells continued for up to 20 weeks. For each cell and each pair of sessions, we compared the activity profiles using cosine similarity, and we assessed whether the cell encoded the same variable in both sessions. These analyses revealed a high degree of stability and a modest representational drift. A quantitative estimate indicated this drift would not randomize the circuit within the animal’s lifetime.
Interplay between Mg2+and Ca2+at multiple sites of the ryanodine receptor
Authors: Nayak Ashok R. , Rangubpit Warin , Will Alex H. , Hu Yifan , Castro-Hartmann Pablo , Lobo Joshua J. , Dryden Kelly , Lamb Graham D. , Sompornpisut Pornthep , Samsó Montserrat 
Published: February 2024

AbstractRyR1 is an intracellular Ca2+channel important in excitable cells. Ca2+activates it at low concentrations and inhibits it at high concentrations. Mg2+is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg2+-mediated inhibition, the molecular-level mechanisms remain unclear. We determined two cryo-EM structures of RyR1 with Mg2+up to 2.8 Å resolution, identifying multiple Mg2+binding sites. Mg2+inhibits at the known Ca2+activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg2+inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg2+inhibition is overcome during excitation.
Sequence-based genome-wide association studies reveal the polygenic architecture ofVarroa destructorresistance in Western honey beesApis mellifera
Authors: Eynard Sonia E. , Mondet Fanny , Basso Benjamin , Bouchez Olivier , Le Conte Yves , Dainat Benjamin , Decourtye Axel , Genestout Lucie , Guichard Matthieu , Guillaume François , Labarthe Emmanuelle , Locke Barbara , Mahla Rachid , de Miranda Joachim , Neuditschko Markus , Phocas Florence , Tabet Kamila , Vignal Alain , Servin Bertrand 
Published: February 2024

AbstractHoney bees,Apis mellifera, have experienced the full impacts of globalisation, including the recent invasion by the parasitic miteVarroa destructorwhich has become one of the main causes of colony losses worldwide. Despite its lethal effects, some colonies have developed defence strategies conferring colony resistance and, assuming non-null heritability, selective breeding of naturally resistant bees could be a sustainable way to fight infestations. Here we report on the largest genome-wide association study performed on honey bees to understand the genetic basis of multiple phenotypes linked to varroa resistance. This study was performed on whole genome sequencing of more than 1,500 colonies belonging to different ancestries and combined in a meta-analysis. Results show that varroa resistance is polygenic. A total of 60 genetic markers were identified as having a significant impact in at least one of the tested populations pinpointing several regions of the honey bee genome. Our results also support strategies for genomic selection in honey bee breeding.
Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism
Authors: Gu Xueqing , Kang Hanyujie , Cao Siyu , Tong Zhaohui , Song Nan 
Published: February 2024

AbstractPulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte- derived macrophages. Blockade of TREM2 by gene knock-out or soluble TREM2 administration can both attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found thatTrem2deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such asCcl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.
Comparative analyses of adsorbed circulating proteins in the PMMA and PES hemodiafilters in patients on predilution online hemodiafiltration
Authors: Islam Md. Shoriful , Ema Shingo , Nabi Md. Mahamodun , Rahman Md. Muedur , Waliullah A.S.M. , Yan Jing , Ferdous Rafia , Sakamoto Takumi , Takahashi Yutaka , Kato Akihiko , Sato Tomohito , Kahyo Tomoaki , Setou Mitsutoshi 
Published: February 2024

AbstractAcute and chronic inflammation are common in patients with end-stage kidney disease (ESKD). So, the adsorption of pro-inflammatory cytokines by the hollow fiber has been expected to modify the inflammatory dysregulation in ESKD patients. However, it remains to be determined in detail what molecules of fiber materials can preferably adsorb proteins from the circulating circuit. We aimed this study to analyze directly the adsorbed proteins in the polymethyl methacrylate (PMMA) and polyethersulfone (PES) membranes in patients on predilution online hemodiafiltration (OL-HDF). To compare the adsorbed proteins in the PMMA and PES hemodiafilters membrane, we initially performed predilution OL-HDF using the PES (MFX-25Seco) membrane while then switched to the PMMA (PMF™-A) membrane under the same condition in three patients. We extracted proteins from the collected hemodiafilters by extraction, then SDS-PAGE of the extracted sample, protein isolation, in-gel tryptic digestion, and nano-LC MS/MS analyses. The concentrations of adsorbed proteins from the PMMA and PES membrane extracts were 35.6±7.9 µg/µL and 26.1±9.2 µg/µL. SDS-PAGE analysis revealed distinct variations of adsorbed proteins mainly in the molecular weight between 10 to 25 kDa. By tryptic gel digestion and mass spectrometric analysis, the PMMA membrane exhibited higher adsorptions of β2 microglobulin, dermcidin, retinol-binding protein-4, and lambda-1 light chain than those from the PES membrane. In contrast, amyloid A-1 protein was adsorbed more potently in the PES membrane. Western blot analyses revealed that the PMMA membrane adsorbed interleukin-6 (IL-6) approximately 5 to 118 times compared to the PES membrane. These findings suggest that PMMA-based OL-HDF therapy may be useful in controlling inflammatory status in ESKD patients.
The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: Metformin, Enalapril, caffeic acid phenethyl ester, green tea extract, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride
Authors: Jiang Nisi , Gelfond Jonathan , Liu Qianqian , Strong Randy , Nelson James F. 
Published: February 2024

AbstractThe National Institute on Aging Interventions Testing Program (ITP) has so far identified 12 compounds that extend the lifespan of genetically heterogeneous mice using the log-rank test. However, the log-rank test is relatively insensitive to any compound that does not uniformly reduce mortality across the lifespan. This test may thus miss compounds that only reduce mortality before midlife, for example, a plausible outcome if a compound only mitigates risk factors before midlife or if its efficacy is reduced at later ages. We therefore reanalyzed all data collected by the ITP from 2004-2022 using the Gehan test, which is more sensitive to mortality differences earlier in the life course and does not assume a uniformly reduced mortality hazard across the lifespan. The Gehan test identified 5 additional compounds, metformin, enalapril, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), caffeic acid phenethyl ester (CAPE), and green tea extract (GTE), which significantly increased survival but were previously missed by the log-rank test. Three (metformin, enalapril, and 17-DMAG) were only effective in males and two (CAPE and GTE) were only effective in females. In addition, 1,3-butanediol, which by log-rank analysis increased survival in females but not males, increased survival in males by the Gehan test. These results suggest that statistical tests sensitive to non-uniformity of drug efficacy across the lifespan should be included in the standard statistical testing protocol to minimize overlooking geroprotective interventions.
An explanation for the sister repulsion phenomenon in Patterson’s f-statistics
Authors: Atağ Gözde , Waldman Shamam , Carmi Shai , Somel Mehmet 
Published: February 2024

AbstractPatterson’s f-statistics are among the most heavily utilized tools for analysing genome-wide allele frequency data for demographic inference. Beyond studying admixture,f3andf4statistics are also used for clustering populations to identify groups with similar histories. However, previous studies have noted an unexpected behaviour of f-statistics: multiple populations from a certain region systematically show higher genetic affinity to a more distant population than to their neighbours, a pattern that is mismatched with alternative measures of genetic similarity. We call this counter-intuitive pattern “sister repulsion”. We first present a novel instance of sister repulsion, where genomes from Bronze Age East Anatolian sites show higher affinity towards Bronze Age Greece rather than each other. This is observed both usingf3- andf4-statistics, contrasts with archaeological/historical expectation, and also contradicts genetic affinity patterns captured using PCA or MDS on genetic distances. We then propose a simple demographic model to explain this pattern, where sister populations receive gene flow from a genetically distant source. We calculatef3- andf4-statistics using simulated genetic data with varying population genetic parameters, confirming that low-level gene flow from an external source into populations from one region can create sister repulsion in f-statistics. Unidirectional gene flow between the studied regions (without an external source) can likewise create repulsion. Meanwhile, similar to our empirical observations, MDS analyses of genetic distances still cluster sister populations together. Overall, our results highlight the impact of low-level admixture events when inferring demographic history using f-statistics.
Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics
Authors: Sokolowski Eishani Kumar , Kursawe Romy , Selvam Vijay , Bhuiyan Redwan M. , Thibodeau Asa , Zhao Chi , Spracklen Cassandra N. , Ucar Duygu , Stitzel Michael L. 
Published: February 2024

ABSTRACTEndoplasmic reticulum (ER) and inflammatory stress responses are two pathophysiologic factors contributing to islet dysfunction and failure in Type 2 Diabetes (T2D). However, how human islet cells respond to these stressors and whether T2D-associated genetic variants modulate these responses is unknown. To fill this knowledge gap, we profiled transcriptional (RNA-seq) and epigenetic (ATAC-seq) remodeling in human islets exposed toex vivoER (thapsigargin) or inflammatory (IL-1β+IFN-γ) stress. 5,427 genes (∼32%) were associated with stress responses; most were stressor-specific, including upregulation of genes mediating unfolded protein response (e.g.DDIT3, ATF4) and NFKB signaling (e.g.NFKB1, NFKBIA) in ER stress and cytokine-induced inflammation respectively. Islet single-cell RNA-seq profiling revealed strong but heterogeneous beta cell ER stress responses, including a distinct beta cell subset that highly expressed apoptotic genes. Epigenetic profiling uncovered 14,968 stress-responsivecis-regulatory elements (CREs; ∼14%), the majority of which were stressor-specific, and revealed increased accessibility at binding sites of transcription factors that were induced upon stress (e.g. ATF4 for ER stress, IRF8 for cytokine-induced inflammation). Eighty-six stress-responsive CREs overlapped known T2D-associated variants, including 20 residing within CREs that were more accessible upon ER stress. Among these, we linked the rs6917676 T2D risk allele (T) to increasedin vivoaccessibility of an islet ER stress-responsive CRE and allele-specific beta cell nuclear factor bindingin vitro. We showed thatMAP3K5,the only ER stress-responsive gene in this locus, promotes beta cell apoptosis. Consistent with its pro-apoptotic and putative diabetogenic roles,MAP3K5expression inversely correlated with beta cell abundance in human islets and was induced in beta cells from T2D donors. Together, this study provides new genome-wide insights into human islet stress responses and putative mechanisms of T2D genetic variants.
Targeting CD19 for the treatment of autoimmune with a novel T cell engager
Authors: Yuan Andy Qingan , Zhao Likun , Bai Lili , Wang Yang , Yang Isabella , Yuan Ray Qirui , Meng Qingwu , Dai Xuning 
Published: February 2024

AbstractAutoimmune disorder, affecting more than twenty million in United States and billions of people worldwide, occurs when human immune system mistakenly attacks its own body. Autoreactive B cells, particularly the autoantibodies they produce, play a critical role in the etiology, progress, prognosis, and pathogenesis of multiple autoimmune diseases. While targeting B cells medicines, such as anti-CD19 or anti-CD20 monoclonal antibodies have produced promise in both pre-clinic models and some clinic practices, many patients failed to respond, ended less satisfactory outcome, or relapsed to monoclonal antibody therapies. Novel therapies are desperately needed to fight this challenge. In this study, based upon a symmetrical format, namely fusion of IgG and scFv technology (FIST), an anti-CD19xCD3 T cell engager (TCE) YK012, developed to treat B-cell malignancies such as precursor pre-B acute lymphatic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL), was expanded to explore the treatment of autoimmune diseases by bringing T cells to CD19 positive B cells, including autoreactive B cell populations. Even as bivalent binding to CD3, YK012 has so significantly reduced binding affinity to TCR compared to other TCEs that, free YK012 alone does activate T cells at all. In contrast, in the presence of CD19-expressing Raji target cells and mediated by YK012, T cells can be activated in a dose-dependent manner, measured by upregulation of NFAT-reporter, CD25, IFN-γ and granzyme B expression. Crosslinking of B cell with T cell by YK012, the conjugation elicited T cell-mediated potent but mild cytotoxicity only to CD19-positive Raji cells. Additionally, YK012 elicited much reduced cytokines releasein vitrocompared to that of Blincyto®biosimilar, implying a potentially me-better therapeutics replacement in clinics for B-cell related diseases. In twoin vivopharmacological studies, YK012 alleviated the pathology symptoms of a collagen-induced arthritis model and almost completely depleted the peripheral B cell in human stem cell-transplanted murine model. In summary, this study demonstrated that YK012, a FIST platform designed TCE, has the potential to treat B cell-mediated diseases including autoimmune indications with possible better efficacy and less side effects in clinical practices.