bluuebunny/crossref_metadata_2025_split huggingface dataset:
Off-target prediction of SGLT2 inhibitors: an integrative bioinformatics approach to uncover structural mechanisms
Authors: Yang Hsin-Ju , Chen Yun-Ti , Hsu Zi-Chun , Yang Jinn-Moon 
Published: January 2025

AbstractGliflozin is known to inhibit sodium glucose transporter 2 (SGLT2) inhibitors (SGLT2i). They have been approved for the treatments of diabetes mellitus, cardiovascular diseases, and chronic kidney disease in recent years. However, the mechanisms for the multifunction remain unclear. We here propose a hypothesis of other protein targets for gliflozins. Additionally, the multistage of the protein, the specificity of the drugs, along with the structural data shortage have posed a hindrance to disclose gliflozin and its binding environment (BE).Considering the difficulties on the issue, this thesis provides an approach to uncover protein off-targets and to find the underlying pathways. We predicted pyranose was a critical substructure from > 1,500 SGLT2i. Hierarchical clustering on atom-based interaction, combined with propensity, revealed key interaction among 1,572 pyranose BEs. The other criterium presented was the concept of compound spanning space via protein pocket size. Binding sites (BSs) from proteins like SGLT2 were able to provide similar pockets, approximating the occupied space of the ligands. Finally, gliflozin binding pockets prefer (1) aromatic residues for van der Waals force, (2) aspartate or asparagine as hydrogen bond providers, and (3) protein pocket size ≧442 Å2. These criteria were integrated into a scoring function STand predicted several possible proteins.This research presents a pipeline for target identification of emerging drug agents and proteins with crystallographic difficulties. The study provides an innovative computational methodology on extraction of binding features on transmembrane proteins and further pharmaceutical development.
Epidermal Cell Dynamics Regulates Rice Lamina Joint Morphogenesis and Leaf Angle Formation throughOsZHD1andOsZHD2Regulation
Authors: Xu Yiru , Zhou Heng , Wu Xiaojiang , Cui Wuyu , Xu Shouling , He Xi , Xiang Dan , Zhou Ming , Hong Lilan 
Published: January 2025

AbstractThe lamina joint is a critical determinant of leaf angle and crop architecture. While epidermal cells play a fundamental role in organ morphogenesis, influencing the overall shape and function of plants, their impact on lamina joint morphology has been largely overlooked. Here, we tracked the cellular dynamics of the rice lamina joint epidermis during leaf angle formation. We found that the asymmetric elongation between the lateral and medial edges, determined by spatial differences in the longitudinal elongation and number of epidermal cells, was a key factor in leaf angle formation. Mutations in the homeobox genesOsZHD1andOsZHD2disrupted the growth patterns of epidermal cells in the lamina joint, resulting in a decreased leaf angle. RestoringOsZHD1expression in the epidermis reverted the reduced leaf angle phenotype ofoszhd1 oszhd2, highlighting the importance of epidermis development for lamina joint morphogenesis. Transcriptome data suggested thatOsZHD1andOsZHD2were involved in auxin synthesis, which modulates leaf angle by inhibiting the growth of lamina joint epidermal cells. This study underscores the significance of epidermal cells in shaping the lamina joint and elucidates the critical role ofOsZHD1andOsZHD2in regulating epidermal cell behavior and leaf angle formation.
Integrative multi-layer workflow for quantitative analysis of post-translational modifications
Authors: Devesa Cristina A. , Barrero-Rodríguez Rafael , Laguillo-Gómez Andrea , Guerrero-Sánchez Victor M. , del Río-Aledo David , Mena Diego , Jorge Inmaculada , Núñez Estefanía , Calvo Enrique , López Juan Antonio , Marín-Vicente Consuelo , Martínez-Val Ana , Camafeita Emilio , Ibáñez Borja , Enríquez José Antonio , Martín-Ventura José Luis , Rodríguez Jose Manuel , Vázquez Jesús 
Published: January 2025

AbstractNovel algorithms based on ultratolerant database searching have paved the way for comprehensive analysis of all possible post-translational modifications (PTM) that can be detected by mass spectrometry-based proteomics, obviating their prior knowledge. These tools together with novel quantitative statistical models allow hypothesis-free approaches to study the role and impact of PTM on biological systems. However, interpretation of this information from a pathophysiological perspective is challenging due to the huge amounts of PTM data, the existence of chemical, structural, and statistical artifacts and the lack of dedicated tools for their analysis.Here we propose a novel integrative workflow that automatically captures several layers of PTM-related information, including variations in trypsin efficiency, zonal changes, specific PTM changes and hypermodified regions, allowing advanced control of artefacts and coherent and comprehensive interpretation of PTM data. We show the performance of the new workflow by reanalyzing proteomics data from animal models of mitochondrial heteroplasmy and ischemia/reperfusion, revealing relevant PTM information not previously detectable, including consistent detection of novel oxidative modifications in Met and Cys residues from raw proteomics data. The workflow is available through the application PTM-compass.
Selection of pre-leukemic hematopoietic stem cells driven by distinct extracellular matrix molecules
Authors: Jassinskaja Maria , Bode Daniel , Gonka Monika , Roumeliotis Theodoros I , Hogg Alexander J , Rubio Lara Juan A , Bennett Ellie , Milek Joanna , Theeuwes Bart , Vijayabaskar M S , Cosme Lilia Cabrera , Che James L C , MacDonald Sandy , Ahmed Sophia , Hall Benjamin A , Vasey Grace , Kooi Helena , Belmonte Miriam , Shepherd Mairi S , Brackenbury William J , Kucinski Iwo , Yamazaki Satoshi , Holding Andrew N , Cull Alyssa H , Wilson Nicola K , Göttgens Berthold , Choudhary Jyoti , Kent David G 
Published: January 2025

SummaryDespite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), there is a relative paucity of studies at the protein level. Here, we perform a deep, multi-omic characterization (epigenome, transcriptome and proteome) of HSCs carrying a loss-of-function mutation inTet2, a key driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile wildtype (WT) and TET2-deficient (Tet2-/-) HSCs and show that the proteome captures previously unrecognized molecular processes which define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of WT andTet2-/-HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as novel points of dysregulation upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion ofTet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization ofTet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
Adiponectin exerts sex-dependent effects on lipid, amino acid, and glucose metabolism during caloric restriction
Authors: Ikushima Yoshiko M , Chen Kuan-Chan , Sulston Richard J. , Mattiucci Domenico , Brain Eleanor J. , Fung Xin Zi Stefanie A , Suchacki Karla J. , Thomas Benjamin J. , Lovdel Andrea , Bennett Matthew , Kobayashi Hiroshi , Whitfield Phillip D. , Takubo Keiyo , Baker Andrew H. , Morton Nicholas M. , Semple Robert K. , Cawthorn William P. 
Published: January 2025

ABSTRACTAdiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed eitherad libitum(AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both on fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency in the context ofad libitumdiet (AL) or obesity, and occurred without changes in insulin secretion or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance under CR. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilisation that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. Together, our findings suggest that adiponectin tunes glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. The widely reported functions of adiponectin in pathological states, including obesity and insulin resistance, thus differ sharply from its roles during CR, with marked sexual dimorphism apparent for many of these functions.
Spatial pattern of serology against Borrelia and tick-borne encephalitis virus in roe deer(Capreolus capreolus), Northern France, 2019-2022
Authors: Métras Raphaëlle , Bastien Matthieu , Ollivier Valentin , Poisson Armelle , Combes Benoit , Gonzalez Gaëlle , Helle Teheipuaura , Migné Camille , Suhanda Ilona Eveline , Kim Younjung , Verheyden Hélène , Boulinier Thierry 
Published: January 2025

SummaryBackgroundLyme borreliosis and tick-borne encephalitis (TBE) are tick-borne zoonoses of public health importance, transmitted in Western Europe by the same tick vectorIxodes ricinus. Roe deer (Capreolus capreolus) is a widespread feeding host forI. ricinusstages. Here, we explored the spatial extent of both pathogens in the wild in Northern France by assessing serological status in roe deer.MethodsWe collected 3,147 blood samples (2019-2022), and searched antibodies against both pathogens using ELISA tests. We fitted logistic models to investigate exposure to both or either pathogens, and explored spatial patterns using Kulldorf clustering scan tests.ResultsThe overall ELISA IgG prevalence was 23.24% (95%CI [21.77-34.72]) for Borrelia and 8.64% (95%CI [7.45-9.86]) for TBEV. The median Borrelia seroprevalence varied from 4% to 42% between departments, with two high-risk clusters of exposure identified. TBEV seroprevalence did not show any spatial pattern, and positives by seroneutralisation tests were reported in eight departments.DiscussionOur findings suggest the presence of both pathogens over large areas. Wider spatial sampling including areas at lower risk and improved serological methods would be beneficial to further validate those estimates.
Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury
Authors: Schuermans Sara , Quanico Jusal , Kestens Caine , Vandendriessche Sofie , Slowikowski Emily , Crijns Maria-Laura , Pörtner Noëmie , Berghmans Nele , Baggerman Geert , Mattos Matheus Silvério , Proost Paul , Marques Pedro Elias 
Published: January 2025

ABSTRACTNecrotic cell death causes loss of membrane integrity, release of intracellular contents and deposition of necrotic cell debris. Effective clearance of this debris is crucial for resolving inflammation and promoting tissue recovery. While leukocyte phagocytosis plays a major role, soluble factors in the bloodstream also contribute to debris removal. Our study examined whether enzymatic degradation or disassembly of necrotic debris enhances clearance and improves outcomes in a mouse model of drug-induced liver injury. Using intravital microscopy and proteomic profiling, we demonstrated that necrotic debris is more complex than anticipated, containing DNA, filamentous actin, histones, complement C3, fibrin(ogen) and plasmin(ogen), among many other components. DNase 1 treatment facilitated recovery significantly by enhancing the clearance of DNA from necrotic areas, reducing circulating nucleosomes and actin, and lowering the associated inflammatory response. However, its effect on actin and other damage-associated molecular patterns in necrotic regions was limited. Treatment with short synthetic peptides, specifically 20-amino acid-long positively charged PLK and negatively charged PLE, which displace histones from debrisin vitro,did not inhibit liver injury or promote recovery. Moreover, activating plasmin to disrupt fibrin encapsulation via tissue plasminogen activator (tPa) led to increased circulating actin levels and worsening of injury parameters. These findings suggest that fibrin encapsulation is important for containing necrotic debris and that enzymatic degradation of necrotic debris is a more effective strategy to enhance tissue recovery than targeting debris disassembly.GRAPHICAL ABSTRACT
Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane
Authors: Puschmann J. , Steffes G. , Froese J. , Manikowski D. , Ehring K. , Wittke J. , Garbers C. , Wegner S.V. , Grobe K. 
Published: January 2025

SummaryHedgehog (Hh) morphogens are essential regulators of growth and patterning at considerable distances from their source, despite being produced as double lipidated proteins that attach to the outer plasma membrane (PM) leaflet of producing cells. While mechanisms to overcome this limitation include the 12-pass transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, proteolytic processing of lipidated peptide termini, and soluble lipoproteins (LPPs) acting as Hh acceptors and transporters, the molecular interplay of these release factors for effective Hh solubilization from the PM remains controversial. In this work, we used in vivo functional knockdown together with in vitro experiments to show that A Disintegrin and Metalloproteinase 10, Scube2 and Disp act synergistically to remove Hh from the PM and transfer it to LPP acceptors. We also show that Scube2 requirement for Hh transfer depends on LPP acceptor levels: low LPP levels in media require Scube2 for efficient Hh release, whereas increasing LPP levels render Scube2 function increasingly dispensable. Biochemical analysis explained this observation by showing that Scube2 binds high-density LPP (HDL) via its 9 EGF domains and associates with the PM via interactions with cell surface heparan sulfate (HS), revealing a previously unknown role for Scube2 in bridging low-abundance soluble carriers for Hh with HS-rich Hh release sites.
Parameterization of intraoperative human microelectrode recordings: Linking action potential morphology to brain anatomy
Authors: Baker Matthew R. , Klassen Bryan T. , Jensen Michael A. , Valencia Gabriela Ojeda , Heydari Hossein , Ince Nuri F. , Müller Klaus-Robert , Miller Kai J. 
Published: January 2025

AbstractDeep brain stimulation (DBS) is a targeted manipulation of brain circuitry to treat neurological and neuropsychiatric conditions. Optimal DBS lead placement is essential for treatment efficacy. Current targeting practice is based on preoperative and intraoperative brain imaging, intraoperative electrophysiology, and stimulation mapping. Electrophysiological mapping using extracellular microelectrode recordings aids in identifying functional subdomains, anatomical boundaries, and disease-correlated physiology. The shape of single-unit action potentials may differ due to different biophysical properties between cell-types and brain regions. Here, we describe a technique to parameterize the structure and duration of sorted spike units using a novel algorithmic approach based on canonical response parameterization, and illustrate how it may be used on DBS microelectrode recordings. Isolated spike shapes are parameterized then compared using a spike similarity metric and grouped by hierarchical clustering. When spike morphology is associated with anatomy, we find regional clustering in the human globus pallidus. This method is widely applicable for spike removal and single-unit characterization and could be integrated into intraoperative array-based technologies to enhance targeting and clinical outcomes in DBS lead placement.Author summaryWe developed a new algorithmic approach to capture the structure of single neuron electrophysiology from microelectrode recordings during deep brain stimulation surgery. This method has broad applications for spike characterization, clustering, removal from the background field potential, and comparison across recording sites. Using this technique, we illustrate regional clustering of spike morphologies in the human globus pallidus.
A Shared Neural Network for Highly Liked and Disliked Music
Authors: Ripollés Pablo , Belfi Amy M. , Kasdan Anna , Vessel Edward A. , Halpern Andrea R. , Rowland Jess , Hopkins Robert , Starr G. Gabrielle , Poeppel David 
Published: January 2025

ABSTRACTMusic research has increasingly focused on neural responses to naturalistic stimuli. The neural correlates of music-induced peak moments of pleasure (e.g., chills) have been well-studied; data on other types of aesthetic responses, such as judgments ofbeauty, goodness, or likingare sparse. Among these,likingis of particular interest given its complex nature and its ubiquity in everyday—and musical—experiences. In this functional magnetic resonance imaging (fMRI) study, 26 participants listened to musical excerpts while continuously rating how much theylikedthe music. In addition, subjects provided an overall liking judgment at the end of each musical piece. Participants’ musical preferences manifested remarkably early and were sustained over time, with the value of the continuous rating at the end of each piece showing the strongest correlation with the overall ratings. At the neural level, highly liked and disliked musical pieces activated a shared neural network previously associated with the processing of both positive and negative emotional stimuli. This network encompassed the anterior cingulate cortex, limbic system, basal ganglia, and precuneus. These activations reflected individual differences, such that participants with greater trait-level responsiveness to artistic stimuli showed stronger engagement of this network while listening to music. Finally, the default-mode network was associated with the slope of the continuous ratings, suggesting that the faster participants liked a musical excerpt, the more disengaged this network became. In linking behavior and brain function to better characterize the way humans make aesthetic judgments of music the data support a model in which preferences and aesthetic choices are modulated by brain circuits associated with emotion and reward.
VCAM1-expressing T cells and systemic autoimmunity in Regnase-1 deficiency
Authors: Cuchet-Lourenço Delphine , Conte Matilde I. , Chang Sooyeon , Ten Nika , Eletto Davide , Papapietro Olivier , Plagnol Vincent , de Kok Mike , Hashim Ilie , Ceron-Gutierrez Lourdes , van den Braber Marlous , Curtis James , Groom Harriet C. T. , Maes Mailis , Doffinger Rainer , Garcia Vallejo Juan , Dominguez Conde Cecilia , Farela Neves Joao , Nejentsev Sergey 
Published: January 2025

SummaryAutoimmunity develops as a result of a breakdown in immune tolerance and activation of autoreactive immune cells. Most of the common autoimmune diseases are polygenic1suggesting dysregulation in multiple signalling pathways. By contrast, in monogenic Inborn Errors of Immunity (IEI), which also can result in autoimmunity, the disease is triggered by a single genetic defect. Therefore, the discovery of causative mutations in IEI allows tracing the molecular mechanisms leading to autoimmunity in humans from a defect in the function of a specific gene to patients’ clinical and immunological phenotype. Here, we discovered an IEI patient with systemic autoimmunity caused by a private homozygous protein-truncating mutation in geneZC3H12Aleading to deficiency of Regnase-1, a regulatory RNase2–5. Flow cytometry, bulk T cell transcriptome analysis and single-cell RNA sequencing demonstrated expansion of γδ T cells expressing VCAM-1 and IFNγ genes. We show that Regnase-1 directly targets 3’UTR ofVCAM1and the coding sequence ofIFNGmRNAs. These findings highlight a new autoimmunity mechanism in humans, where Regnase-1 deficiency causes expansion ofVCAM1+IFNG+ T cells and their interaction with integrin α4β1-expressing B cells, which showed upregulation of IFN-response genes and activation, leading to systemic autoimmunity. Furthermore, we show thatVCAM1+T cells are present in organs of donors and are expanded in the blood of patients with systemic lupus erythematosus, a common autoimmune disease characterised by systemic autoimmunity.
Fusion oncoproteins and cooperating mutations define disease phenotypes inNUP98-rearranged leukemia
Authors: Umeda Masayuki , Hiltenbrand Ryan , Michmerhuizen Nicole L. , Barajas Juan M. , Thomas Melvin E. , Arthur Bright , Walsh Michael P , Song Guangchun , Ma Jing , Westover Tamara , Kumar Amit , Pölönen Petri , Mecucci Cristina , Giacomo Danika Di , Locatelli Franco , Masetti Riccardo , Bertuccio Salvatore N. , Pigazzi Martina , Pruett-Miller Shondra M. , Pounds Stanley , Rubnitz Jeffrey , Inaba Hiroto , Papadopoulos Kyriakos P. , Wick Michael J. , Iacobucci Ilaria , Mullighan Charles G. , Klco Jeffery M. 
Published: January 2025

AbstractLeukemias withNUP98rearrangements exhibit heterogeneous phenotypes correlated to fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the sameNUP98fusions, such asNUP98::KDM5Aacute megakaryocytic leukemia withRB1loss or T-cell acute lymphoblastic leukemia withNOTCH1mutations. CUT&RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Usingin vitromodels, we showRB1loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereasWT1frameshifts skew differentiation toward dormant lympho-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells. NUP98::KDM5A models withRB1orWT1alterations have different sensitivities to menin inhibition, suggesting cellular differentiation stage-specific resistant mechanism against menin inhibitors with clinical implications forNUP98-rearranged leukemia.