bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased TGF β /Activin-Smad2 signaling is associated with pancreatic β -cell dysfunction and glucose intolerance in gestational diabetes mellitus
Authors: Boronat-Belda Talía , Ferrero Hilda , Soriano Sergi , Ribes-García Elena , Betoret-Gustems Rubén , Martínez-Bañón Daniel , Serrano-Selva Mónica , Martínez-Pinna Juan , Nadal Ángel , Quesada Iván , Magdalena Paloma Alonso- 
Published: February 2025

AbstractBackgroundGestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and offspring. GDM management provides a window of opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are poorly defined. In this study, we explore the potential involvement of transforming growth factor beta (TGF-β) signaling in GDM as this pathway has been reported to affect pancreatic β-cell development, proliferation and identity.MethodsWe developed a GDM animal model. Serum circulating levels of TGFβ family ligands were measured in mice and human GDM. Pancreatic TGFβ signaling was investigated at the level of gene and protein expression.ResultsOur GDM animal model recapitulates the main pathophysiological features of human GDM including glucose intolerance, decreased insulin sensitivity and pancreatic β-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased β-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGFβ/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic β-cell function and regeneration capacity of β-cells.ConclusionsOur data disclose that disruption of pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway could represent a putative therapeutic target for GDM.HighlightsHigh fat diet just before and during pregnancy leads to gestational diabetes in mice.Activin and inhibin serum levels are increased in human and mice gestational diabetes.Enhanced pancreatic Smad2 signaling contributes to inadequate insulin secretion in gestational diabetes.Inhibition of Smad2 signaling improves pancreatic β-cell function and proliferation.
Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation
Authors: Kaas Mathias , Chofflet Nicolas , Bicer Deniz , Skeldal Sune , Duan Jinjie , Feller Benjamin , Vilstrup Joachim , Groth Rosa , Sivagurunathan Suganya , Dashti Hesam , Pedersen Jan Skov , Werge Thomas , Børglum Anders D. , Cimini Beth A. , Jones Thouis R. , Claussnitzer Melina , Madsen Peder , Takahashi Hideto , Demontis Ditte , Thirup Søren , Glerup Simon 
Published: February 2025

AbstractThe leukocyte common antigen related receptor (LAR) is a member of the LAR receptor protein tyrosine phosphatase (RPTP) family of synaptic adhesion molecules that contribute to the proper alignment and specialization of synaptic connections in the mammalian brain. LAR-RPTP members have been genetically associated with neuropsychiatric disorders, but the molecular consequences of genetic perturbations of LAR remain unstudied. Using exome sequencing data from psychiatric patients and controls, we identify rare missense variants of LAR that render the extracellular domain (ECD) unstable and susceptible to proteolytic cleavage. Using recombinant and cellular systems, we describe three variants that cause disruption of the LAR:NGL-3 interaction, which results in loss of transcellular adhesion and synaptogenic effects. Furthermore, we show that overexpression of two of these variants elicit altered morphological phenotypes in an imaging-based morphological profiling assay compared to wild type LAR, suggesting that destabilization of the LAR ECD has broad effects on LAR function. In conclusion, our study identifies three rare, missense variants in LAR that could provide insights into LAR involvement with psychiatric pathobiology.
Molecular Mechanism of pH Sensing and Activation in GPR4 Reveals Proton-Mediated GPCR Signaling
Authors: You Chongzhao , Guo Shimeng , Zhang Tianwei , He Xinheng , Gao Tianyu , Xin Wenwen , Zhu Zining , Lu Yujie , Xu Youwei , Li Zhen , Zhang Yumu , Cheng Xi , Jiang Yi , Xie Xin , Xu H. Eric 
Published: February 2025

AbstractMaintaining pH homeostasis is critical for cellular function across all living organisms. Proton-sensing G protein-coupled receptors (GPCRs), particularly GPR4, play a pivotal role in cellular responses to pH changes, yet the molecular mechanisms underlying their proton sensing and activation remain incompletely understood. Here we present high-resolution cryo-electron microscopy structures of GPR4 in complex with G proteins under physiological and acidic pH conditions. Our structures expose an intricate proton-sensing mechanism driven by a sophisticated histidine network in the receptor’s extracellular domain. Upon protonation of key histidines under acidic conditions, a remarkable conformational cascade is initiated, propagating from the extracellular region to the intracellular G protein-coupling interface. This dynamic process involves precise transmembrane helix rearrangements and conformational shifts of conserved motifs, mediated by strategically positioned water molecules. Notably, we discovered a bound bioactive lipid, lysophosphatidylcholine, which has positive allosteric effects on GPR4 activation. These findings provide a comprehensive framework for understanding proton sensing in GPCRs and the interplay between pH sensing and lipid regulation, offering insights into cellular pH homeostasis and potential therapies for pH-related disorders.
The T Cell-Specific miRNA–Target Network in Psoriasis: A Systematic Review
Authors: Madaan Priyanka , Tyagi Nipanshi , Tyagi Sourabh , Kushwaha Hemant Ritturaj , Jain Manju 
Published: February 2025

AbstractPsoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation, involving T cells as the major players in the manifestation of lesional and systemic inflammation. With the extensive exploration of keratinocyte dysfunctionality, T cell-centric deregulation has gained much focus in the context of disease etiology. miRNAs, the molecular switches known to drive disease manifestation via altering keratinocyte biology, have not been much studied in the context of T cell alterations, with only a few reports. This study aims to explore T cell-associated miRNAs and their target signaling networks to understand their role in modulating psoriasis-specific T cell changes. miRNAs with altered expression in psoriatic T cells were identified through a meta-analysis of the existing literature and datasets. These miRNAs were then used to identify cognate targets and T cell signaling pathways to elucidate T cell-specific cascades influenced by miRNAs, potentially explaining miRNA driven T cell dysregulation in psoriasis. The study identified 14 miRNAs with altered expression in psoriatic T cells and 256 downstream targets involved in 15 T cell-associated signaling pathways. The miRNA-driven targets and pathways identified may dysregulate T cell activation, proliferation, survival, and subset differentiation. These findings suggest multiple miRNA–target signaling axes that require experimental validation to better understand T cell-mediated disease etiology.
Effects of Drought on Inflorescence Yield, and Secondary Metabolites inCannabis sativaL.
Authors: Shenhar Itamar , Ifrach Idan , Barkan Ohad , Guberman Ohad , Kerem Zohar , Taler Dvir , Meiri David , Moshelion Menachem 
Published: February 2025

SummaryThe use of medical products derived fromCannabis sativaL. has increased significantly in recent years. While drought is known to negatively affect the yields of many crops, growers often recommend controlled periods of drought for cannabis cultivation to increase concentrations of secondary metabolites. This is especially pertinent when considering the relationship between medicinal effects and the secondary-metabolite profile.We examined the effects of tightly controlled drought treatments on biochemical (111 phytocannabinoids and 132 terpenoids), physiological, and anatomical responses of three Type-I chemotype cultivars, specifically the THCA-dominant cultivars ‘Odem’, ‘MVA’, and ‘187’.Our results revealed strong correlations between inflorescence and phytocannabinoid yields, on the one hand, and cumulative transpiration on the other (0.96 <r2< 0.99). Drought treatment reduced canopy conductance, with inflorescence weight decreasing by 40% and total fresh weight decreasing by 48%. The concentrations of the major phytocannabinoids, THCA and CBGA, decreased over increasing levels of drought stress (by 26% and 61%, respectively). Interestingly, terpene concentrations showed greater stress-induced variation, and that variation was genotype-dependent.Our findings suggest that the decreases in inflorescence weight and concentrations of major phytocannabinoids under drought conditions are mainly due to a lack of biochemical-production processes, as opposed to metabolic degradation.
Cytb6/fComplex Fine-Tunes PSI Stability and Photosynthetic Capacity Under Fluctuating Light
Authors: Kono Masaru , Kodama Hiromasa , Tanigawa Keiichiro , Terashima Ichiro , Yamori Wataru 
Published: February 2025

AbstractPlants encounter dynamic light fluctuations in natural habitats, requiring robust mechanisms to protect Photosystem I (PSI) against photoinhibition. The cytochrome (Cyt)b6/fcomplex plays a pivotal role in regulating electron flow and ensuring PSI stability under fluctuating light. However, its precise role in balancing PSI protection and photosynthetic capacity remains unclear. In this study, transgenic tobacco (Nicotiana tabacumL. ‘W38’) with reduced Cytb6/fcontent was used to examine PSI tolerance to photoinhibition and photosynthetic performance under fluctuating light. Notably, the reduced Cytb6/fcontent conferred significant protection of PSI against photoinhibition induced by fluctuating light, albeit at the expense of the electron transport capacity. Remarkably, PSI stability was maintained even under extreme fluctuating light conditions in the plants with lowest Cytb6/fcontents, highlighting a trade-off between photoprotection and photosynthetic capacity. These findings reveal that a reduction in Cytb6/fcontent enhances PSI protection while adjusting electron transport capacity, making plants more adaptable in environments dominated by low light and transient sunflecks. This study provides new insights into the adaptive strategies of plants under dynamic light environments and underscores the potential of targeting Cytb6/ffor enhancing crop tolerance to fluctuating light conditions.
Iterative Multiscale Molecular Dynamics: Accelerating Conformational Sampling of Biomolecular Systems by Iterating All-Atom and Coarse-Grained Molecular Dynamics Simulations
Authors: Do Hung N. , Gnanakaran S. 
Published: February 2025

AbstractAll-atom molecular dynamics (AA MD) simulations remain the gold standard for simulating biomolecular dynamics at an atomistic level for decades. However, they often cannot attain the time scales required to sufficiently sample the many biological processes of interest, especially those that involve large biomolecular systems with high energy barriers. Here, we combine the strengths of all-atom (AA) and coarse-grained (CG) MD simulations to develop the iterative multiscale MD (iMMD) simulation workflow in OpenMM by iterating between AA and CG MD simulations to enhance the sampling of biomolecular conformations. The AA-CG-AA iterations are repeated over multiple cycles, facilitating the accelerated sampling of biomolecular conformations at a CG level, while the finer atomistic interactions are refined with AA simulators. We demonstrate the enhanced sampling ability of iMMD over multiple AA-CG-AA iterations on four representative systems, including two globular proteins (fast-folding variant of Trpcage and Z-matrix protein of Mammarenavirus lassaense (LASV)) and two membrane proteins (Torpedo nicotinic acetylcholine receptor (nAChR) and REGN7663 Fab binding to the CXCR4 receptors in a heterogeneous cholesterol/phosphatidylcholine membrane lipid bilayer). In particular, iMMD captures the folding of the fast-folding Trpcage and Z-protein of LASV starting from their extended conformations as well as the binding of the REGN7663 Fab binding to the CXCR4s and dimerization of the CXCR4 receptors within the heterogenous membrane, within few AA-CG-AA iterations. The development of iMMD should allow for unprecedented simulations of biomolecules at much longer biological timescales to explore the biological processes of interest.
Cold-induced nucleosome dynamics linked to silencing of ArabidopsisFLC
Authors: Montez Miguel , Zhu Danling , Huertas Martin Jan , Maristany Maria Julia , Rutjens Bas , Nielsen Mathias , Collepardo-Guevara Rosana , Dean Caroline 
Published: February 2025

AbstractTemperature influences nucleosome dynamics, and thus chromatin, to regulate gene expression. Such mechanisms underlie the epigenetic silencing of ArabidopsisFLOWERING LOCUS C(FLC) by prolonged cold. Here, we show a temperature-dependent transition in local chromatin structure at the H3K27me3 nucleation region, from a modality active for transcription to a state that can be Polycomb silenced.In vivochromatin measurements and coarse-grained simulations at near-atomistic resolution show the active transcription state is characterized by a highly dynamic nucleosome arrangement that exposes theFLCTSS. Cold exposure then changes the chromatin structure by reducing nucleosome dynamics and re-positioning the +1 nucleosome, leading to transcriptional repression. This local chromatin transition partially depends on VRN1, a non-sequence-specific DNA-binding protein. Loss of VRN1 results in hyperaccumulation of H2A.Z, more dynamic nucleosomes and an inability to accumulate H2Aub and H3K27me3. Our work highlights how local nucleosome dynamics link to chromatin structure transitions to integrate temperature inputs into epigenetic switching mechanisms in plants.
Strong Association between Infectious Mononucleosis and Cardiac Allograft Vasculopathy Studying Risk Factors and Viral Infections
Authors: Movahed Mohammad Reza , Namazi Mohammad Javad , Rezasoltani Mahsa , Hashemzadeh Mehrtash 
Published: February 2025

AbstractBackgroundCardiac Allograft vasculopathy (CAV) is a significant cause of late transplant failure. Using a large database, the study’s objective was to assess traditional and infectious risk factors linked to the occurrence and severity of CAV.MethodUsing the large inpatient sample database (NIS), we evaluated any association between CAV and risk factors and infectious viral agents. Additionally, we assessed the severity of CAV based on the occurrence of revascularizations.ResultsA total of 78,330 heart transplant recipients were identified. CAV was diagnosed in 1,015 patients overall. Patients with CAV had a higher mortality rate (4.4% vs 2.1%, OR: 2.09 CI 1.08-4.03 p=0.03). All known traditional risk factors and baseline characteristics, including gender, race, hypertension, hyperlipidemia, diabetes mellitus, and smoking, were not linked to the existence of CAV, except for being younger (mean age 56 vs 59 years). Furthermore, a history of infectious mononucleosis strongly correlated with CAV (OR:8.9 CI 2.68–29.6 p<0.001). Being younger not only increases the possibility of the development of CAV but also increases the probability of undergoing coronary bypass surgery after a heart transplant. Influenza and other forms of viral infections, such as Cytomegalovirus, did not correlate with the presence of CAV.ConclusionYounger age was associated with CAV but no other traditional risk factors. Infectious mononucleosis, the only infectious agent correlating with CAV, had a very high association with CAV, warranting further investigation.
Ligand Screening and Discovery using Cocktail Soaking and Automated MicroED
Authors: Lin Jieye , Gallenito Marc J. , Hattne Johan , Gonen Tamir 
Published: February 2025

AbstractCocktail soaking using single-crystal X-ray diffraction (SC-XRD) has previously allowed high-throughput crystallographic screening of ligands against protein targets. However, protein microcrystals are not amenable to this approach if they are too small to yield strong diffraction patterns. In this study, we developed a workflow integrating cocktail soaking with automated microcrystal electron diffraction (MicroED) to allow rapid ligand screening, structure determination, and binding analysis directly from microcrystals. This can improve the successful hit rate, because binding is often more efficient when smaller crystals are soaked in the ligand. The approach was validated with known ligands of thermolysin and identified novel binding interactions for ligands of proteinase K. The structures of multiple protein-ligand complexes, including ligands with weak binding affinities, could be solved quickly. Their estimated relative binding affinities are in good agreement with previous work and independent microscale thermophoresis (MST) measurements.
The association of gut microbiome composition with musculoskeletal features in middle-aged and older adults: a two-cohort joint study
Authors: Li Ruolin , Okoro Paul C. , Zillikens M. Carola , Vasan Ramachandran S. , Sahni Shivani , Rivadeneira Fernando , Kiel Douglas P. , Medina-Gomez Carolina 
Published: February 2025

AbstractBackgroundBones and muscles are connected anatomically, and functionally. Preliminary evidence has shown the gut microbiome influences the aging process of bone and muscle in animal studies. However, such evidence in humans is still scarce. This study aimed to assess the microbiome-bone and microbiome-muscle associations in two cohorts of community-dwelling older adults.MethodsWe leveraged information from two large population-based cohorts, i.e., the Rotterdam Study (mean age 62.7 ± 5.6 years; n=1,249) and the Framingham Heart Study (mean age 55.2 ± 9.1 years; n=1,227). For individuals included in this study, gut microbiome 16S rRNA sequencing, musculoskeletal phenotyping derived from DXA images, lifestyle and socioeconomic data, and medication records were available. Per cohort, the 16S rRNA sequencing data, derived from stool, were processed with the DADA2 pipeline and taxonomies were assigned using the SILVA reference database. In addition, the microbiome functional potential was obtained with PICRUSt2. Further, we investigated the association between the human gut microbiome (alpha diversity, genera and predicted functional pathways) and appendicular lean mass (ALM), femoral neck bone mineral density (FN-BMD) and trabecular bone score (TBS) using multilinear regression models controlling for multiple confounders, and performed a joint analysis from both cohorts. Sex-stratified analyses were also conducted.ResultsThe gut microbiome alpha diversity was not associated with either tested phenotype after accounting for multiple-testing (P>1.67e-02). In the joint analysis, lower abundance ofOscillibacter(beta= −.51, 95%CI [−0.74, −.29]),Anaerotruncus(beta=-0.41, 95%CI [−0.61, - 0.21]),Eisenbergiella(beta=-0.39, 95%CI [−0.59, −.19]) and higher abundance ofAgathobacter(beta=0.40, 95%CI [0.20, 0.60]) were associated with higher ALM (P<2.0e-04). Lower abundance ofAnaerotruncus(beta=-0.32, 95%CI [−0.45, −.19]),Hungatella(beta=-0.26, 95%CI [−0.38, −.15]) andClostridiales bacterium DTU089(beta=-0.37, 95%CI [−0.55, −.19]) was associated with higher ALM only in females (P< 2.0e-04). Moreover, thebiotin biosynthesis IIpathway was positively associated with ALM (beta=0.44, 95% CI [0.24, 0.64]) (P<1.90e-04) in females while no associations were observed in males. We did not observe any robust association of bone traits with gut microbiome features.ConclusionOur results indicate that specific genera are associated with ALM in middle-aged and older adults and these associations can present in a sex-specific manner. Overall, our study suggests that the gut microbiome is linked to muscle aging in middle-aged and older adults. However, larger sample sizes are still needed to underpin the specific microbiome features involved.
An evolutionarily conserved role for separase in the regulation of nuclear lamins
Authors: Cipressa Francesca , Pennarun Gaëlle , Bosso Giuseppe , Rosignoli Serena , Tullo Liliana , Nadia Schiralli , Borghi Chiara , Paiardini Alessandro , Goldberg Michael Lewis , Bertrand Pascale , Cenci Giovanni 
Published: February 2025

ABSTRACTSeparase is a well conserved endopeptidase that facilitates sister chromatid separation at the metaphase-anaphase transition by cleaving cohesins. Beyond its role in chromosome segregation, Separase also participates in various biological processes, including chromatin organization and replication, centrosome disengagement and duplication, cytokinesis, and telomere capping. Here, we report that the loss ofDrosophilaseparase (Sse) function induces significant changes in global protein expression and affects the protein levels of both A/C-type lamin C (LamC) and B-type lamin Dm0 (Dm0). We further demonstrate that SSE physically interacts with lamins and colocalizes with them at the nuclear envelope during interphase. Additionally, loss of SSE activity disrupts nuclear organization in larval muscles and impairs locomotion in adult flies. Notably, similar to SSE in flies, depletion of human separase (ESPL1) in SV40 fibroblasts leads to misshapen nuclei and increased levels of lamin A. Moreover, we show that ESPL1 interacts with lamin A in human fibroblasts, suggesting that the functional interaction between Separase and lamins is evolutionarily conserved across different organisms.
Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration
Authors: Hou Junjie , Song Yabing , Xiao Chenglu , Sun Yuanyuan , Shen Jie , Ma Xiaokai , Zhou Qinchao , Chiu Shih-Ching , Xu Yang , Huang Yanyi , Chen Ye-Guang , Zhu Xiaojun , Wang Jianbin , Xiong Jing-Wei 
Published: February 2025

SummaryZebrafish has full capacity of heart regeneration, but little is known about how blood cells, especially platelets, are involved in this regenerative process. Here we report thatcloche/npas4lis a pro-regenerative platelet factor for heart regeneration. We found that haploinsufficiency ofnpas4ldisrupted cardiomyocyte (CM) and endothelial cell (EC) proliferation and heart regeneration after injury. A single-cell transcriptomic atlas revealed thatnpas4lwas dynamically expressed in platelets after heart injury and regulated robust interactions between platelets-CMs or -ECs. Decreasing platelets by either nitroreductase-mediated platelet depletion or platelet-deficient mutantmplimpaired CM and EC proliferation, and over-expression ofnpas4lin platelets sufficiently induced CM and EC proliferation in uninjured hearts, as well as rescued CM and EC proliferation defects inclochemutants. Mechanistically, Npas4l positively regulated a panel of ligands expression includingbmp6in platelets to fine-tune CM proliferation and heart regeneration. Therefore, this work unveils a novel platelet Npas4l signaling and presents mechanisms on how platelets modulate CM/EC proliferationvialigand-receptor network during zebrafish heart regeneration.