bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maspin/SerpinB5 is a cytoskeleton-binding protein that regulates epithelial cell shape
Authors: da Silva Luiz E. , Paim Lia M.G. , Menezes Ana P. J. , da Cunha Julia P. C. , Bechstedt Susanne , Cella Nathalie 
Published: September 2024

AbstractMaspin/SerpinB5 is an abundant and pleiotropic protein mostly expressed by epithelia. Initially described as a tumor suppressor, it has been reported as a regulator of cell adhesion, migration, and invasion. How intracellular Maspin orchestrates these processes is poorly understood. In this study, we utilized Affinity purification-Mass spectrometry (AP/MS) alongsidein vitroreconstitution assays to establish that Maspin directly interacts with microtubules and microfilaments. Additionally, CRISPR/Cas9-mediated GFP tagging of endogenous Maspin, combined with immunostaining, revealed its localization at the cortical cytoskeleton and the mitotic spindle. Depletion of Maspin by RNAi and CRISPR/Cas9 in three distinct epithelial cell lines disrupts cell-cell adhesion, reorganizes the cytoskeleton and results in upregulation of mesenchymal markers during interphase. In mitotic cells, loss of Maspin induces abnormal cell rounding and rearrangement of cortical F-actin. Moreover, Maspin suppresses microtubule growthin vitroand in cells. Collectively, these results demonstrate that Maspin acts at the interface between the cytoskeleton and adhesion sites, directly modulating cell shape and preventing epithelial-mesenchymal transition.SummaryDa Silva et al. report that the non-inhibitory serpin Maspin (SerpinB5), which has long been implicated in the regulation of cell adhesion, migration, invasion and metastasis, directly binds to microfilaments and microtubulesin vitroand in cells, acting at the interface between the cytoskeleton and adhesion sites.
Calcium Binding Affinity in the Mutational Landscape of Troponin-C: Free Energy Calculation, Coevolution Modeling and Machine Learning
Authors: Pooja  , Bandyopadhyay Pradipta 
Published: September 2024

AbstractMutation in calcium-binding proteins (CBPs) can significantly influenceCa2+binding affinity (BA), resulting in substantial impairment in the signaling process and leading to several lethal diseases. The knowledge behind the changes in the binding affinity can help in understanding the signaling process and designing inhibitors for therapeutic usage. However, accurate prediction of BA for a large number of mutations has been elusive. In this work, for an important calcium binding protein, cardiac Troponin-C, we have developed an integrative modeling approach that combines molecular dynamics (MD)-based binding free energy calculations, prediction of plausible mutants using evolutionary information, and an interpretable machine learning model to predictCa2+BA for a large number of mutations (seventy-six in all). For the binding free energy calculation, we have used a charge-scaling based MD simulation that considers the polarization in the system, which is critical for divalent ion binding with proteins. The well-known molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was used for the binding free energy calculations. The calculated results for twenty-four disease mutants, which are associated with different cardiomyopathies and have experimental binding affinity, are in close agreement with the experimental results. To study other plausible mutations, we have probed the evolutionary landscape of cardiac Troponin-C and used the EVmutation method of Hopfet al.(Nature biotechnology 2017, 35, 128–135) to generate sixty-one additional mutants. Finally, a Support vector regression model was developed for both observed and plausible mutations. Our machine learning model used simple structure and sequence-based descriptors along with MD-based descriptors and gave a mean squared error (MSE) of only 0.16 kcal/mol. Assessment of the contribution of each descriptor shows that the number of water molecules within theCa2+binding site, type of amino acid substitution (e.g. polar to hydrophobic reduces the binding affinity), and the distance of mutation withCa2+are the most important factors in determining the binding affinity. This integrative modeling can be used for other CBPs and can lay the path for modeling the complex and astronomically large mutational landscape of Calcium-binding proteins.
Reactive Oxygen species dependent increase in H3K27 acetylation by intermittent hypoxia is regulated by H3S28 phosphorylation
Authors: Wang Ning , Hildreth Matthew , Prabhakar Nanduri R. , Nanduri Jayasri 
Published: September 2024

ABSTRACTHistones play a crucial role in regulating gene expression through post –translational modifications (PTMS) which include acetylation, methylation and phosphorylation. We have previously identified histone 3 acetylation (H3Kac) and methylation (H3Kme) as an early epigenetic mechanism associated with intermittent hypoxia (IH), a hallmark feature of sleep apnea. The goal of the present study was to determine the molecular mechanisms underlying IH increased H3 acetylation. IH-induced H3 acetylation was blocked by an antioxidant. Conversely, reactive oxygen species (ROS) mimetics, increased H3 acetylated protein expression similar to IH, suggesting a role for ROS. Trichostatin A (TSA), an HDAC (histone deacetylase) inhibitor mimicked IH-induced H3 acetylation under normoxic conditions, while pharmacological blockade of p300/CBP (HAT, histone acetylase) with CTK7A abolished IH-induced H3 acetylation. These results suggest that interplay between HATs and HDACs regulate ROS-dependent H3 acetylation by IH. Lysine 27 (H3K27) on H3 was one of the lysines specifically acetylated by IH and this acetylation was associated with dephsophorylation of H3 at serine 28 (H3S28). Inhibition of S28 dephosphorylation by protein phosphatase inhibitors (PIC or Calyculin A), prevented H3K27 acetylation by IH. Conversely, inhibiting K27 acetylation with CTK7A, increased S28 phosphorylation in IH-exposed cells. These findings highlight the intricate balance between H3 acetylation and phosphorylation in response to IH, shedding light on epigenetic mechanism regulating gene expression. (Supported by NIH-PO1-HL90554).
Cell-type-specific splicing of transcription regulators andPtbp1byRbfox1/2/3in the developing neocortex
Authors: Ruan Xiangbin , Hu Kaining , Yang Yalan , Yang Runwei , Tseng Elizabeth , Kang Bowei , Kauffman Aileen , Zhong Rong , Zhang Xiaochang 
Published: September 2024

AbstractHow master splicing regulators crosstalk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq of the developing neocortex uncover that transcription regulators are enriched for differential splicing, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glia progenitors induces neuronal splicing events preferentially in transcription regulators such asMeis2andTead1. Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon inPtbp1. Simultaneous ablation ofRbfox1/2/3in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform ofMeis2promotesTgfb3transcription, while theMeis2neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex.
Novel Pannexin 1 isoform is increased in cancer
Authors: O’Donnell Brooke L. , Stefan Dan , Chiu Yu-Hsin , Zeitz Michael J. , Tang Justin , Johnston Danielle , Leighton Stephanie E. , Van Kessel Carlijn , Barr Kevin , Gyenis Laszlo , Freeman Taylor J. , Kelly John J. , Sayedyahossein Samar , Isakson Brant E. , Litchfield David W. , Roth Kathryn , Smyth James W. , Hebb Matthew , Ronald John , Bayliss Douglas A. , Penuela Silvia 
Published: September 2024

ABSTRACTPannexin 1 (PANX1) is upregulated in many cancers, where its channel activity and signalling promote tumorigenic properties. Here, we report that potential internal translation start sites exist in mouse and human PANX1 which have implications in trafficking and protein interaction. Using mouse PANX1 constructs for each internal methionine (M) we saw that the shorter PANX1 isoforms were glycosylated, able to traffic to the cell surface and PANX1-M37 formed channels which could be activated by C-terminus cleavage or α1-adrenoceptor stimulation. Furthermore, we report a novel ∼25 kDa isoform of human PANX1 (hPANX1-25K) which lacks the N-terminus and was detected in several human cancer cell lines including melanoma, osteosarcoma, breast cancer, and glioblastoma multiforme. This isoform was increased uponhPANX1CRISPR/Cas9 deletion targeting the first exon near M1, and using Expasy PeptideCutter we did not find any evidence of hPANX1 cleavage sites which would produce a 25 kDa fragment, suggesting a potential alternative translation initiation site as the source of hPANX1-25K. hPANX1-25K was confirmed to be a hPANX1 isoform via mass spectrometry, can be N-linked glycosylated at multiple sites including the canonical N255 and novel N338 and N394 residues, and can interact with both β-catenin and full length hPANX1. Using cell surface biotinylation and immunocytochemistry, we also determined hPANX1-25K exhibits a predominantly intracellular localization. hPANX1-25K is prevalent throughout melanoma progression, and its levels are increased in squamous cell carcinoma cells and patient-derived tumours, compared to keratinocytes and patient-matched normal skin, indicating that it may be differentially regulated in normal and cancer cells.
Obstructive sleep apnea mediates genetic risk of Diabetes Mellitus: The Hispanic Community Health Study/Study of Latinos
Authors: Hrytsenko Yana , Spitzer Brian W. , Wang Heming , Bertisch Suzanne M. , Taylor Kent , Garcia-Bedoya Olga , Ramos Alberto R , Daviglus Martha L. , Gallo Linda C , Isasi Carmen , Cai Jianwen , Qi Qibin , Alcantara Carmela , Redline Susan , Sofer Tamar 
Published: September 2024

AbstractObjectiveWe sought to evaluate whether obstructive sleep apnea (OSA), and other sleep disorders, increase genetic risk of developing diabetes mellitus (DM).Research Design and MethodsUsing GWAS summary statistics from the DIAGRAM consortium and Million Veteran Program, we developed multi-ancestry Type 2 Diabetes (T2D) polygenic risk scores (T2D-PRSs) useful in admixed Hispanic/Latino individuals. We estimated the association of the T2D-PRS with cross-sectional and incident DM in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We conducted a mediation analysis with T2D-PRSs as an exposure, incident DM as an outcome, and OSA as a mediator. Additionally, we performed Mendelian randomization (MR) analysis to assess the causal relationship between T2D and OSA.ResultsOf 12,342 HCHS/SOL participants, at baseline, 48.4% were normoglycemic, 36.6% were hyperglycemic, and 15% had diabetes, and 50.9% identified as female. Mean age was 41.5, and mean BMI was 29.4. T2D-PRSs was strongly associated with baseline DM and with incident DM. At baseline, a 1 SD increase in the primary T2D-PRS had DM adjusted odds ratio (OR) = 2.67, 95% CI [2.40; 2.97] and a higher incident DM rate (incident rate ratio (IRR) = 2.02, 95% CI [1.75; 2.33]). In a stratified analysis based on OSA severity categories the associations were stronger in individuals with mild OSA compared to those with moderate to severe OSA. Mediation analysis suggested that OSA mediates the T2D-PRS association with DM. In two-sample MR analysis, T2D-PRS had a causal effect on OSA, OR = 1.03, 95% CI [1.01; 1.05], and OSA had a causal effect on T2D, with OR = 2.34, 95% CI [1.59; 3.44].ConclusionsOSA likely mediates genetic effects on T2D.
Co-infection dynamics of SARS-CoV-2 and respiratory viruses in the 2022/2023 respiratory season in the Netherlands
Authors: Carstens Gesa , Kozanli Eva , Bulsink Kirsten , McDonald Scott , Elahi Mansoer , de Bakker Jordy , Schipper Maarten , van Gageldonk-Lafeber Rianne , van den Hof Susan , van Hoek Albert Jan , Eggink Dirk 
Published: September 2024

AbstractObjectivesEvaluation of the presence and effect of SARS-CoV-2 co-infections on disease severity.MethodsWe collected both symptom data and nose- and throat samples from symptomatic people during the 2022/2023 respiratory season in a large participatory surveillance study in the Netherlands, and tested these for 18 respiratory viruses including SARS-CoV-2. We compared reported health status, symptoms and odds of having a mono respiratory viral infection or co-infection with SARS-CoV-2 and another respiratory virus.ResultsIn total 4,655 samples were included with 22% (n=1,017) testing SARS-CoV-2 positive. Of these 11% (n=116) also tested positive for a second respiratory virus. The most frequently occurring co-infections in SARS-CoV-2 positive participants were with rhinovirus (59%; n=69), seasonal coronaviruses (15%; n=17) and adenovirus (7%; n=8). Participants with a co-infection with one of these three viruses did not report more severe disease compared to those with a SARS-CoV-2 mono-infection. The odds of experiencing SARS-CoV-2 co-infection with seasonal coronavirus or rhinovirus were lower compared to the odds of the respective non-SARS-CoV-2 mono-infection (OR: 0.16, CI 95%: 0.10 – 0.24; OR: 0.21 CI 95%: 0.17 – 0.26; respectively).ConclusionsSARS-CoV-2 co-infections with rhinovirus, seasonal coronavirus and adenovirus are frequently observed in the general population, but are not associated with more severe disease compared to SARS-CoV-2 mono-infections. Furthermore, we found indications for inter-virus interaction with rhinovirus and seasonal coronavirus, possibly decreasing risk of co-infection.HighlightsOur study showed viral co-infections in 11% of the SARS-CoV-2 positive participantsSARS-CoV-2 mono-infections led to more severe symptoms than the common cold mono-infections with seasonal coronavirus or rhinovirusSARS-CoV-2 co-infections with common cold viruses did not lead to worse health status compared to SARS-CoV-2 mono-infectionsOdds for mono-infection with common cold virus were higher than for co-infection with SARS-CoV-2 and the respective common cold virus
FishPi: a bioinformatic prediction tool to link piRNA and transposable elements
Authors: Godden Alice M. , Rix Benjamin , Immler Simone 
Published: September 2024

AbstractBackgroundPiwi-interacting RNAs (piRNA)s are non-coding small RNAs that post-transcriptionally affect gene expression and regulation. Through complementary seed region binding with transposable elements (TEs), piRNAs protect the genome from transposition. A tool to link piRNAs with complementary TE targets will improve our understanding of the role of piRNAs in genome maintenance and gene regulation. Existing tools such asTEsmallcan process sRNA-seq datasets to produce differentially expressed piRNAs, andpiRScandeveloped for nematodes can link piRNAs and TEs but it requires knowledge about the target region of interest and works backwards.ResultsWe have therefore developedFishPito predict the pairings between piRNA and TEs for available genomes from zebrafish, medaka and tilapia, with full user customisation of parameters including orientation of piRNA, mismatches in the piRNA seed binding to TE and scored output lists of piRNA-TE matches.FishPiworks with individual piRNAs or a list of piRNA sequences in fasta format. The software focuses on the piRNA-TE seed region and analyses reference TEs for piRNA complementarity. TE type is examined, counted and stored to a dictionary, with genomic loci recorded. Any updates to piRNA-TE binding rules can easily be incorporated by changing the seed-region options in the graphic user-interface.FishPiprovides a graphic interface usingtkinterfor the user to input piRNA sequences to generate comprehensive reports on piRNA-TE interactions.FishPican easily be adapted to genomes from other species and taxa opening the interpretation of piRNA functionality to a wide community.ConclusionsUsers will gain insight into genome mobility andFishPiwill help further our understanding of the biological role of piRNAs and their interaction with TEs in a similar way that public databases have improved the access to and the understanding of the role of small RNAs.
Lessons learned during the journey of data: from experiment to model for predicting kinase affinity, selectivity, polypharmacology, and resistance
Authors: de Castro Raquel López-Ríos , Rodríguez-Guerra Jaime , Schaller David , Kimber Talia B. , Taylor Corey , White Jessica B. , Backenköhler Michael , Payne Alexander , Kaminow Ben , Pulido Iván , Singh Sukrit , Kramer Paula Linh , Pérez-Hernández Guillermo , Volkamer Andrea , Chodera John D. 
Published: September 2024

AbstractRecent advances in machine learning (ML) are reshaping drug discovery. Structure-based ML methods use physically-inspired models to predict binding affinities from protein:ligand complexes. These methods promise to enable the integration of data for many related targets, which addresses issues related to data scarcity for single targets and could enable generalizable predictions for a broad range of targets, including mutants. In this work, we report our experiences in building KinoML, a novel framework for ML in target-based small molecule drug discovery with an emphasis on structure-enabled methods. KinoML focuses currently on kinases as the relative structural conservation of this protein superfamily, particularly in the kinase domain, means it is possible to leverage data from the entire superfamily to make structure-informed predictions about binding affinities, selectivities, and drug resistance. Some key lessons learned in building KinoML include: the importance of reproducible data collection and deposition, the harmonization of molecular data and featurization, and the choice of the right data format to ensure reusability and reproducibility of ML models. As a result, KinoML allows users to easily achieve three tasks: accessing and curating molecular data; featurizing this data with representations suitable for ML applications; and running reproducible ML experiments that require access to ligand, protein, and assay information to predict ligand affinity. Despite KinoML focusing on kinases, this framework can be applied to other proteins. The lessons reported here can help guide the development of platforms for structure-enabled ML in other areas of drug discovery.
Enterprise risk management in supply chain operation: a fuzzy risk prioritization approach
Authors: Mukherjee Swarup , De Anupam , Roy Supriyo 
Published: September 2024

PurposeTraditional risk prioritization methods in Enterprise Risk Management (ERM) rely on precise data, which is often not available in real-world contexts. This study addresses the need for a robust model that can handle uncertain and imprecise information for more accurate risk assessment.Design/methodology/approachWe propose a group decision-making approach using fuzzy numbers to represent risk attributes and preferences. These are converted into fuzzy risk scores through defuzzification, providing a reliable method for risk ranking.FindingsThe proposed fuzzy risk prioritization framework improves decision-making and risk awareness in businesses. It offers a more accurate and robust ranking of enterprise risks, enhancing control and performance in supply chain operations by effectively representing uncertainty and accommodating multiple decision-makers.Practical implicationsThe adoption of this fuzzy risk prioritization framework can lead to significant improvements in enterprise risk management across various industries. By accommodating uncertainty and multiple decision-makers, organizations can achieve more reliable risk assessments, ultimately enhancing operational efficiency and strategic decision-making. This model serves as a guide for firms seeking to refine their risk management processes under conditions of imprecise information.Originality/valueThis study introduces a novel weighted fuzzy Risk Priority Number method validated in the risk management process of an integrated steel plant. It is the first to apply this fuzzy approach in the steel industry, demonstrating its practical effectiveness under imprecise information. The results contribute significantly to risk assessment literature and provide a benchmarking tool for improving ERM practices.
Ownership concentration and SME IPO underpricing in India – moderating impact of board monitoring and resource provision role
Authors: Arora Nischay , Singh Balwinder 
Published: September 2024

PurposeThe study aims to explore how the monitoring and resource provision function of board of directors impact the association between ownership concentration and small- and medium-sized enterprise (SME) initial public offering (IPO) underpricing in the context of an emerging economy like India.Design/methodology/approachThe sample comprises 390 SME IPOs listed on Bombay Stock Exchange SME platform and National Stock Exchange EMERGE (EMERGE is the NSE new initiative for SMEs to raise the funds from investors) in India. To test the moderating impact of the board monitoring role and resource provision role, the study employs hierarchical moderated regression subject to the fulfillment of assumptions.FindingsThe findings divulge that ownership concentration significantly reduces underpricing, hinting towards the operationalization of alignment of interest hypothesis. With regards to moderating relationship, the study found that while board resource providing role negatively moderates the relationship between ownership concentration and SME IPO underpricing, board monitoring function fails to cast any significant impact on the relationship between ownership concentration and SME IPO underpricing.Research limitations/implicationsThe present study ignores larger firms listed on the main platform which have complex decision-making than smaller firms. Besides, it is confined to only a single country, i.e. India. Extending the study to other countries with similar institutional characteristics would have validated the findings. Furthermore, the moderating impact of other organizational factors like firm age, lifecycle of firm and change in technology would form an interesting avenue for future research.Practical implicationsThe findings of the study have practical implications for managers in designing the adequate board structure that significantly reduces underpricing. It thus further advices the issuers on focusing more on strengthening the resource provision role of board of directors for achieving higher rewards. The findings are helpful to policymakers in framing such policies that enhance the resource-oriented role of board of directors and resource accessibility for SMEs. Furthermore, the results advise the investors to be relatively assured about the SMEs whose board exercises its resource provision role emphatically. Accordingly, findings are helpful to investors in making investment decisions in alternative market settings characterized by the concentrated ownership structure.Originality/valueThe study furthers the debate on the importance of two prominent roles played by board as a moderating variable in the underexplored context of IPO underpricing of small and medium-sized firms in India.