bluuebunny/crossref_metadata_2025_split huggingface dataset:
An integrin centered complex coordinates ion transport and pH to regulate f-actin organization and cell migration in breast cancer
Authors: Capitani Chiara , Iorio Jessica , Lastraioli Elena , Duranti Claudia , Bagni Giacomo , Chioccioli Altadonna Ginevra , Colasurdo Rossella , Scarpellino Giorgia , Fraser Scott P. , Becchetti Andrea , Djamgoz Mustafa B. A. , Arcangeli Annarosa 
Published: July 2024

ABSTRACTReciprocal signaling between the Tumor Microenvironment (TME) and cancer cells regulates abnormal proliferation, migration and pro-metastatic behavior. Major player in such interaction is integrin-mediated cell adhesion to the Extracellular Matrix (ECM). Integrin receptors organize signaling hubs constituted by multiprotein membrane complexes often comprising ion channels and transporters. We studied whether and how integrin-centered multiprotein complexes control cell behavior in Breast Cancer (BCa) cell populations with different molecular characteristics. BCa cells were cultured onto the ECM protein fibronectin (FN), to trigger β1 integrin activation. Through biochemical, immunofluorescence and electrophysiological experiments we provide evidence of a novel signaling pathway that involves a β1 integrin-centered plasma membrane complex formed by different transport proteins: the hERG1 K+channel, the neonatal form of the Na+channel NaV1.5 (nNaV1.5) and the Na+/H+antiporter NHE1. The NHE1/hERG1/β1/nNaV1.5 complex was found on the plasma membrane of BCa cells, and particularly of Triple Negative Breast Cancer (TNBCa). When engaged by cell adhesion to FN, such membrane complex recruited the cytoskeletal actin-binding protein a-actinin1 and stimulated NHE1-mediated cytoplasmic alkalinization. Thus, the multiprotein complex activation affected TNBCa migration and invasiveness by stimulating f-actin organization directly (through α-actinin1) and indirectly (by intracellular alkalinization). The contribution of both hERG1 and nNaV1.5 was essential, as the adhesion-dependent signaling pathway and its functional consequences were inhibited by blocking either channel with, respectively, E4031 and TTX, or by applying RNA silencing procedures. The contribution of hERG1 to the structural integrity of the membrane complex appeared to be critical, as the adhesion-dependent signals were hampered by harnessing the hERG1/β1 integrin complex with a single chain bispecific antibody (scDb-hERG1-β1) which disrupts the macromolecular complex without blocking the K+current, as well as by E4031, which impairs the complex formation by blocking the channel in the open state.In conclusion, we revealed that integrin-centered macromolecular complexes in BCa cells recruit a battery of ion transport proteins that cooperate in modulating different aspects of the downstream signals that lead to malignant behavior. This complex could be targeted to develop novel therapeutic strategies for one of the most difficult-to-treat cancers, i.e. TNBCa.
FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis
Authors: Yorek Matthew , Jiang Xingshan , Liu Shanshan , Hao Jiaqing , Yu Jianyu , Avellino Anthony , Liu Zhanxu , Curry Melissa , Keen Henry , Shao Jianqiang , Kanagasabapathy Anand , Kong Maiying , Xiong Yiqin , Sauter Edward R. , Sugg Sonia L. , Li Bing 
Published: July 2024

AbstractA high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migrationin vitroand metastasisin vivo. Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.Graphic AbstractHighlightsUnlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophagesDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophagesFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis
Step Forward Cross Validation for Bioactivity Prediction: Out of Distribution Validation in Drug Discovery
Authors: Saha Udit Surya , Vendruscolo Michele , Carpenter Anne E. , Singh Shantanu , Bender Andreas , Seal Srijit 
Published: July 2024

AbstractRecent advances in machine learning methods for materials science have significantly enhanced accurate predictions of the properties of novel materials. Here, we explore whether these advances can be adapted to drug discovery by addressing the problem of prospective validation - the assessment of the performance of a method on out-of-distribution data. First, we tested whether k-fold n-step forward cross-validation could improve the accuracy of out-of-distribution small molecule bioactivity predictions. We found that it is more helpful than conventional random split cross-validation in describing the accuracy of a model in real-world drug discovery settings. We also analyzed discovery yield and novelty error, finding that these two metrics provide an understanding of the applicability domain of models and an assessment of their ability to predict molecules with desirable bioactivity compared to other small molecules. Based on these results, we recommend incorporating a k-fold n-step forward cross-validation and these metrics when building state-of-the-art models for bioactivity prediction in drug discovery.
Disruption of the PGE2synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice
Authors: Ricciotti Emanuela , Tang Soon Yew , Mrčela Antonijo , Das Ujjalkumar S. , Lordan Ronan , Joshi Robin , Ghosh Soumita , Aoyama Justin , McConnell Ryan , Yang Jianing , Grant Gregory R. , FitzGerald Garret A. 
Published: July 2024

AbstractImmune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs.Prostaglandin (PG) E2, formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE2synthesis /response pathway – global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4 – on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr-/-) mice.All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE2biosynthesis, reflected by its major urinary metabolite, PGE2biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4-/-mice was impaired. Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.
The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice
Authors: Wingfield Kelly K. , Misic Teodora , Jain Kaahini , McDermott Carly S. , Abney Nalia M. , Richardson Kayla T. , Rubman Mia B. , Beierle Jacob A. , Miracle Sophia A. , Sandago Emma J. , Baskin Britahny M. , Lynch William B. , Borrelli Kristyn N. , Yao Emily J. , Wachman Elisha M. , Bryant Camron D. 
Published: July 2024

ABSTRACTRationaleOpioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.ObjectivesWe sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.MethodsWe employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.ResultsOn P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.ConclusionsWe identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.
Mutations in theStaphylococcus aureusGlobal Regulator CodY Confer Tolerance to an Interspecies Redox-Active Antimicrobial
Authors: Martini Anthony M. , Alexander Sara A. , Khare Anupama 
Published: July 2024

ABSTRACTBacteria often exist in multispecies communities where interactions among different species can modify individual fitness and behavior. Although many competitive interactions have been characterized, molecular adaptations that can counter this antagonism and preserve or increase fitness remain underexplored. Here, we characterize the adaptation ofStaphylococcus aureusto pyocyanin, a redox-active interspecies antimicrobial produced byPseudomonas aeruginosa, a co-infecting pathogen frequently isolated from wound and chronic lung infections withS. aureus. Using experimental evolution, we identified mutations in a conserved global transcriptional regulator, CodY, that confer tolerance to pyocyanin and thereby enhance survival ofS. aureus. The transcriptional response of a pyocyanin tolerant CodY mutant to pyocyanin indicated a two-pronged defensive response compared to the wild type. Firstly, the CodY mutant strongly suppressed metabolism, by downregulating pathways associated with core metabolism, especially translation-associated genes, upon exposure to pyocyanin. Metabolic suppression via ATP depletion was sufficient to provide comparable protection against pyocyanin to the wild-type strain. Secondly, while both the wild-type and CodY mutant strains upregulated oxidative stress response pathways, the CodY mutant overexpressed multiple stress response genes compared to the wild type. We determined that catalase overexpression was critical to pyocyanin tolerance as its absence eliminated tolerance in the CodY mutant and overexpression of catalase was sufficient to impart tolerance to the wild-type strain. Together, these results suggest that both transcriptional responses likely contribute to pyocyanin tolerance in the CodY mutant. Our data thus provide new mechanistic insight into adaptation toward interbacterial antagonism via altered regulation that facilitates multifaceted protective cellular responses.
Induction of ectopic external gills and tetrapodomorph-like skeletal elements through homeotic transformations in the salamander branchial region
Authors: Vintr Jan , Soukup Vladimír 
Published: July 2024

AbstractHomeotic transformations are morphological changes associated with alterations of identities of segments in serially repeated systems and these changes may be a source of modifications in body plan evolution. Retinoic acid (RA) signaling has previously been shown to induce homeotic transformations in the vertebral column, although its role in other vertebrate segmented systems remains unexplored.Here, we use pharmacological inhibition of RA receptors to study homeotic transformations in the larval salamander branchial region. This region normally contains three pairs of external gills supported by the underlying skeleton, however upon treatments we observe induction of ectopic outgrowths in the posterior portion of the apparatus. We characterize these outgrowths as ectopically induced fourth external gills on the position of the otherwise gill-free segment. This induction is further associated with transformations and appearance of cartilaginous elements that phenocopy similar elements in fossil stem amphibians and tetrapodomorphs.These experimentally instigated morphological changes qualify as homeotic transformations in the branchial region and present re-emergence of features that were lost prior to the origin of modern tetrapods. More broadly, our results point to RA signaling as a potent driver regulating the number and composition of pharyngeal segments and thus controlling the evolution of the vertebrate pharyngeal apparatus.
Memantine Inhibits Calcium-Permeable AMPA Receptors
Authors: Carrillo Elisa , Romero Alejandra Montaño , Gonzalez Cuauhtemoc U. , Turcu Andreea L. , Chen Shao-Rui , Chen Hong , Pan Hui-Lin , Vázquez Santiago , Twomey Edward C. , Jayaraman Vasanthi 
Published: July 2024

AbstractMemantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimer’s. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.
LinkR: an open source, low-code and collaborative data science platform for healthcare data analysis and visualization
Authors: Delange Boris , Popoff Benjamin , Séité Thibault , Lamer Antoine , Parrot Adrien 
Published: July 2024

AbstractBackgroundThe development of Clinical Data Warehouses (CDWs) has greatly increased access to big data in medical research. However, the lack of standardization among different data models hampers interoperability and, consequently, the research potential of these vast data resources. Moreover, data manipulation and analysis require advanced programming skills, a skill set that healthcare professionals often lack.MethodsTo address these issues, we created an open source, low-code and collaborative data science platform for manipulating, visualizing and analyzing healthcare data using graphical tools alongside an advanced programming interface. The software is based on the OMOP common data model.ResultsLinkR enables users to generate studies using data imported from multiple sources. The software organizes the studies into two main sections: individual and population data sections. In theindividual data section, user-friendly graphical tools allow users to customize data presentation, recreating the equivalent of a medical record, according to the needs of their study. Thepopulation data sectionis designed for conducting statistical analyses through both graphical and programming interfaces. The application also incorporates collaborative features, such as a messaging page and an integrated Git module. These features facilitate efficient collaboration and shared data analysis efforts across different research centers.ConclusionLinkR is a low-code data science platform that democratizes access, manipulation, and analysis of data from clinical data warehouses and facilitates collaborative work on healthcare data, using an open science approach.
"Stroke Patient and Stakeholder Engagement (SPSE): Concepts, Definitions, Models, Implementation Strategies, Indicators, and Frameworks - A Systematic Scoping Review"
Authors: Khankeh Hamidreza , Guyatt Gordon , Shirozhan Shima , Roudini Juliet , Rackoll Torsten , Dirnagl Ulrich 
Published: July 2024

AbstractBackgroundInvolving stroke patients in clinical research through patient engagement aims to ensure that studies are patient-centered, and may help ensure they are feasible, ethical, and credible, ultimately leading to enhanced trust and communication between researchers and the patient community. In this study, we have conducted a scoping review to identify existing evidence and gaps in SPSE.MethodsThe five-step approach outlined by Arksey and O’Malley, in conjunction with the Preferred Reporting Items for Scoping Reviews (PRISMA-ScR) guidelines, provided the structure for this review. To find relevant articles, we searched PubMed, Web of Science, and Embase databases up to February 2024. Additionally, the review team conducted a hand search using Google Scholar, key journals, and references of highly relevant articles. Reviewers conducted primary and secondary screening, ultimately selecting English-language articles with available full texts that met the eligibility criteria. Reviewers extracted data from these articles into a table designed and tested by the research team.ResultsOf 1,002 articles initially identified, 21 proved eligible. Stakeholder engagement primarily occurred during the design phase of studies and within the studies using qualitative methodologies. Although the engagement of stakeholders in the research process is increasing, practice regarding terminology and principles of implementation remains variable. Researchers have recognized the benefits of stakeholder engagement, but have also faced numerous challenges that often arise during the research process.ConclusionThe current study identifies stakeholder groups and the benefits and challenges researchers face in implementing their engagement. Given existing challenges and limited specific models or frameworks, it is recommended to explore applied recommendations for stakeholder engagement in future studies, that may enhance stakeholder engagement, overcome obstacles, and unify researchers’ understanding of engagement and implementation.
Contrastive Self-supervised Learning for Neurodegenerative Disorder Classification
Authors: Gryshchuk Vadym , Singh Devesh , Teipel Stefan , Dyrba Martin ,   ADNI, AIBL, FTLDNI study groups
Published: July 2024

AbstractNeurodegenerative diseases such as Alzheimer’s disease (AD) or frontotemporal lobar degeneration (FTLD) involve specific loss of brain volume, detectable in vivo using T1-weighted MRI scans. Supervised machine learning approaches classifying neurodegenerative diseases require diagnostic-labels for each sample. However, it can be difficult to obtain expert labels for a large amount of data. Self-supervised learning (SSL) offers an alternative for training machine learning models without data-labels. We investigated if the SSL models can applied to distinguish between different neurodegenerative disorders in an interpretable manner. Our method comprises a feature extractor and a downstream classification head. A deep convolutional neural network trained in a contrastive self-supervised way serves as the feature extractor, learning latent representation, while the classifier head is a single-layer perceptron. We used N=2694 T1-weighted MRI scans from four data cohorts: two ADNI datasets, AIBL and FTLDNI, including cognitively normal controls (CN), cases with prodromal and clinical AD, as well as FTLD cases differentiated into its sub-types. Our results showed that the feature extractor trained in a self-supervised way provides generalizable and robust representations for the downstream classification. For AD vs. CN, our model achieves 82% balanced accuracy on the test subset and 80% on an independent holdout dataset. Similarly, the Behavioral variant of frontotemporal dementia (BV) vs. CN model attains an 88% balanced accuracy on the test subset. The average feature attribution heatmaps obtained by the Integrated Gradient method highlighted hallmark regions, i.e., temporal gray matter atrophy for AD, and insular atrophy for BV. In conclusion, our models perform comparably to state-of-the-art supervised deep learning approaches. This suggests that the SSL methodology can successfully make use of unannotated neuroimaging datasets as training data while remaining robust and interpretable.