bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of Thermal Proteome Profiling with phosphoproteomic and transcriptomic data via mechanistic network models decodes the molecular response to PARP inhibition
Authors: Burtscher Mira L , Gade Stephan , Garrido-Rodriguez Martin , Rutkowska Ania , Werner Thilo , Eberl H Christian , Petretich Massimo , Knopf Natascha , Zirngibl Katharina , Grandi Paola , Bergamini Giovanna , Bantscheff Marcus , Fälth-Savitski Maria , Saez-Rodriguez Julio
Published: August 2023

The deregulation of complex diseases often spans multiple molecular processes. A multimodal functional characterization of these processes can shed light on the disease mechanisms and the effect of drugs. Thermal Proteome Profiling (TPP) is a mass-spectrometry based technique assessing changes in thermal protein stability that can serve as proxies of functional changes of the proteome. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a framework for causal integration of multi-omics, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover known mechanistic consequences of PARP inhibition in ovarian cancer cells on cell cycle and DNA damage response in detail and to uncover new insights into drug response mechanisms related to interferon and hippo signaling. We found that TPP complements the other omics data and allowed us to obtain a network model with higher coverage of the main underlying mechanisms. These results illustrate the added value of TPP, and more generally the power of network models to integrate the information provided by different omics technologies. We anticipate that this strategy can be used to broadly integrate functional proteomics with other omics to study complex molecular processes.

Graphical abstract
Non-uniform contextual interactions in the visual cortex place fundamental limits on spatial vision
Authors: Morton Mitchell P. , Denagamage Sachira , Hudson Nyomi V. , Nandy Anirvan S.
Published: August 2023

A prevailing assumption in our understanding of how neurons in the primary visual cortex (V1) integrate contextual information is that such processes are spatially uniform. Conversely, perceptual phenomena such as visual crowding, the impaired ability to accurately recognize a target stimulus among distractors, suggest that interactions among stimuli are distinctly non-uniform. Prior studies have shown flankers at specific spatial geometries exert differential effects on target perception. To resolve this discrepancy, we investigated how flanker geometry impacted the representation of a target stimulus in the laminar microcircuits of V1. Our study reveals flanker location differentially impairs stimulus representation in excitatory neurons in the superficial and input layers of V1 by tuned suppression and untuned facilitation of orientation responses. Mechanistically, this effect can be explained by asymmetrical spatial kernels in a normalization model of cortical activity. Strikingly, these non-uniform modulations of neural representation mirror perceptual anisotropies. These results establish the non-uniform spatial integration of information in the earliest stages of cortical processing as a fundamental limitation of spatial vision.
Predicting human microbe-drug associations via graph attention network with multiple kernel fusion
Authors: Shi Sairu , Kong Shu , Zhang Qingwei , Zhang Ji
Published: August 2023

Microbial dysregulation may lead to the occurrence of diseases, and using microbe and drug data to infer the microbe-drug association has attracted extensive attention. There have been many studies to build association prediction models, but most of them are through biological experiments, which are time-consuming and expensive. Therefore, it is necessary to develop a computational method focusing on microbe-drug spatial information to predict the microbe-drug associations. In this work, we use the biological information to construct heterogeneous networks of drugs and microbes. We propose a new method based on Multiple Kernel fusion on Graph Attention Network (GAT) to predict human microbe-drug associations, called GATMDA. Our method extracts multi-layer features based on GAT which can learn the embedding of microbes and drugs on each layer and achieve the purpose of extracting multiple information. We further fuse multiple kernel matrices based on average weighting method. Finally, combined kernel in the microbe space and drug space are used to infer microbe-drug associations. Compared with eight state-of-the-art methods, our method receives the highest AUC and AUPR on MDAD and aBiofilm dataset. Case studies for Human immunodeficiency virus 1 (HIV-1) and adenovirus further confirm the effectiveness of GATMDA in identifying potential microbe-drug associations.
Auxin Exposure Disrupts Feeding Behavior and Fatty Acid Metabolism in AdultDrosophila
Authors: Fleck Sophie A. , Biswas Puja , DeWitt Emily D. , Knuteson Rebecca L. , Eisman Robert C. , Nemkov Travis , D’Alessandro Angelo , Tennessen Jason M. , Rideout Elizabeth J. , Weaver Lesley N.
Published: August 2023

The ease of genetic manipulation inDrosophila melanogasterusing theGal4/UASsystem has been beneficial in addressing key biological questions. Current modifications of this methodology to temporally induce transgene expression require temperature changes or exposure to exogenous compounds, both of which have been shown to have detrimental effects on physiological processes. The recently described auxin-inducible gene expression system (AGES) utilizes the plant hormone auxin to induce transgene expression and is proposed to be the least toxic compound for genetic manipulation, with no obvious effects onDrosophiladevelopment and survival in one wild-type strain. Here we show that auxin delays larval development in another widely-used fly strain, and that short- and long-term auxin exposure in adultDrosophilainduces observable changes in physiology and feeding behavior. We further reveal a dosage response to adult survival upon auxin exposure, and that the recommended auxin concentration for AGES alters feeding activity. Furthermore, auxin fed male and female flies exhibit a significant decrease in triglyceride levels and display altered transcription of fatty acid metabolism genes. Although fatty acid metabolism is disrupted, auxin does not significantly impact adult female fecundity or progeny survival, suggesting AGES may be an ideal methodology for studying limited biological processes. These results emphasize that experiments using temporal binary systems must be carefully designed and controlled to avoid confounding effects and misinterpretation of results.
Automating an insect biodiversity metric using distributed optical sensors: an evaluation across Kansas, USA cropping systems
Authors: Rydhmer Klas , Eckberg James O. , Lundgren Jonathan G. , Jansson Samuel , Still Laurence , Quinn John E. , Washington Ralph , Lemmich Jesper , Nikolajsen Thomas , Sheller Nikolaj , Michels Alex M. , Bredeson Michael M. , Rosenzweig Steven T. , Bick Emily N.
Published: August 2023

Global ecosystems and food supply depend on insect biodiversity for key functions such as pollination and decomposition. High-resolution, accurate data on invertebrate populations and communities across scales are critical for informing conservation efforts. However, conventional data collection methodologies for invertebrates are expensive, labor intensive, and require substantial taxonomic expertise, limiting researchers, practitioners, and policymakers. Novel optical techniques show promise for automating such data collection across scales as they operate unsupervised in remote areas. In this work, optical insect sensors were deployed in 20 agricultural fields in Kansas, USA. Measurements were compared to conventional assessments of insect diversity from sweep nets and Malaise traps. Species richness was estimated on optical insect data by applying a clustering algorithm to the optical insect sensor’s signal features of wing-beat frequency and body-to-wing ratio. Species richness correlated more strongly between the optical richness estimate and each of the conventional methods than between the two conventional methods, suggesting sensors can be a reliable indicator of invertebrate richness. Shannon- and Simpson indices were calculated for all three methods but were largely uncorrelated including between conventional methods. Although the technology is relatively new, optical sensors may provide next-generation insight into the spatiotemporal dynamics of invertebrate biodiversity and their conservation.

Significance Statement

The implications of this research extend from the field level to the regional level. Much of what scientists understand about the decline of invertebrates comes from a small number of long-term studies that can be coarse and correlational in nature. High-resolution biodiversity data sets on fields to landscapes may provide the insight needed for the successful management and accounting of biodiversity by practitioners and policymakers. Such high-resolution data has the potential to support global efforts and coordination of biodiversity conservation.
In vitro toxicity of LiTFSI on Human Renal and Hepatoma Cells
Authors: Zhang Xing , Sands Mia , Lin Mindy , Guelfo Jennifer , Irudayaraj Joseph
Published: August 2023

We evaluate the cytotoxicity, intracellular redox conditions, apoptosis, and methylation of DNMTs/TETs upon exposure to LiTFSI, a novel PFAS compound commonly found in lithium-ion batteries, on human renal carcinoma cells (A498) and hepatoma cells (HepG2). The MTT assay showed both PFOS and LiTFSI had a dose-dependent effect on A498 and HepG2, with LiTFSI being less toxic. Intracellular redox conditions were assessed with a microplate reader and confocal, which showed a significant decrease in ROS levels and an increase in SOD content in both cells. Exposure to LiTFSI enhanced cell apoptosis, with HepG2 being more susceptible than A498. Quantitative analysis of mRNA expression levels of 19 genes associated with kidney injury, methylation, lipid metabolism and transportation was performed. LiTFSI exposure impacted kidney function by downregulating Acta2 and upregulating Tgfb1, Bcl2l1, Harvcr1, Nfe2l2, and Hes1 expression. LiTFSI exposure also affected the abundance of transcripts associated with DNA methylation by the expression of TET and DNMT genes. Furthermore, LiTFSI exposure induced an increase in lipid anabolism and alterations in lipid catabolism in HepG2. Our results provide new insight on the potential role of a new contaminant, LiTFSI in the regulation of oxidative stress, apoptosis and methylation in human renal carcinoma and hepatoma cells.
Hypoxia-inducible-factors differentially contribute to clinical disease and viral replication during RSV infection
Authors: Morris Dorothea R. , Qu Yue , Haas de Mello Aline , Jones-Hall Yava L. , Liu Tianshuang , Weglarz Meredith , Ivanciuc Teodora , Garofalo Roberto P. , Casola Antonella
Published: August 2023

Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to activate this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previousin vitrostudies, we found that respiratory syncytial virus (RSV), a leading cause of respiratory illness, stabilizes HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α (PT2385) inhibitors in RSV-infected BALB/c mice. We found that inhibition of HIF-1α worsen clinical disease parameters, while simultaneously improving lung inflammation and airway function. Additionally, blocking HIF-1α resulted in significantly reduced viral titer at early and peak time points of RSV replication. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, enhanced immune responses and reduced early and peak lung viral replication. Analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of the compounds that are currently in use or under therapeutic consideration.
Predicting host-based, synthetic lethal antiviral targets from omics data
Authors: Staheli Jeannette P. , Neal Maxwell L. , Navare Arti , Mast Fred D. , Aitchison John D.
Published: August 2023

Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be selectively eliminated by targeting synthetic lethal (SL) partners of proteins disrupted by viral infection. Thus, we hypothesized that genes depleted in CRISPR KO screens of virus-infected cells may be enriched in SL partners of proteins altered by infection. To investigate this, we established a computational pipeline predicting SL drug targets of viral infections. First, we identified SARS-CoV-2-induced changes in gene products via a large compendium of omics data. Second, we identified SL partners for each altered gene product. Last, we screened CRISPR KO data for SL partners required for cell viability in infected cells. Despite differences in virus-induced alterations detected by various omics data, they share many predicted SL targets, with significant enrichment in CRISPR KO-depleted datasets. Comparing data from SARS-CoV-2 and influenza infections, we found possible broad-spectrum, host-based antiviral SL targets. This suggests that CRISPR KO data are replete with common antiviral targets due to their SL relationship with virus-altered states and that such targets can be revealed from analysis of omics datasets and SL predictions.
Dissecting tumor transcriptional heterogeneity from single-cell RNA-seq data by generalized binary covariance decomposition
Authors: Liu Yusha , Carbonetto Peter , Willwerscheid Jason , Oakes Scott A. , Macleod Kay F. , Stephens Matthew
Published: August 2023

Profiling tumors with single-cell RNA sequencing (scRNA-seq) has the potential to identify recurrent patterns of transcription variation related to cancer progression, and produce new therapeutically relevant insights. However, the presence of strong inter-tumor heterogeneity often obscures more subtle patterns that are shared across tumors, some of which may characterize clinically relevant disease subtypes. Here we introduce a new statistical method, generalized binary covariance decomposition (GBCD), to address this problem. We show that GBCD can help decompose transcriptional heterogeneity into interpretable components — including patient-specific, dataset-specific and shared components relevant to disease subtypes — and that, in the presence of strong inter-tumor heterogeneity, it can produce more interpretable results than existing methods. Applied to data from three studies on pancreatic cancer adenocarcinoma (PDAC), GBCD produces a refined characterization of existing tumor subtypes (e.g., classical vs. basal), and identifies a new gene expression program (GEP) that is prognostic of poor survival independent of established prognostic factors such as tumor stage and subtype. The new GEP is enriched for genes involved in a variety of stress responses, and suggests a potentially important role for the integrated stress response in PDAC development and prognosis.
Effect of Ambient Temperature on Diabetes Patient Visits at Primary and Referral Healthcare Services in Yogyakarta Province, Indonesia: An Analysis of Indonesian National Health Insurance Data 2021
Authors: Ramadona Aditya Lia , Qaimamunazzala Hayu , Kusnanto Hari , Lazuardi Lutfan , Danawati Cornelia Wahyu , Fuad Anis , Tetra Dewi Fatwa Sari
Published: August 2023

The global incidence of diabetes mellitus is on the rise, posing a significant health challenge worldwide. Recent evidence indicates a possible link between diabetes mellitus and temperature. This study aimed to examine the effect of temperature on diabetes patient visits in Yogyakarta Province, Indonesia, which is currently experiencing a high burden of diabetes and an increasingly aging population. Daily temperature data for 2021 were obtained from the Indonesian Meteorological, Climatological, and Geophysical Agency (BMKG). The number of diabetes patient visits was gathered from BPJS Health data samples for primary and referral healthcare facilities in the province. The relationship between temperature and diabetes patient visits was explored through data visualization, Pearson correlation, and Poisson regression models. We found a short-term correlation between higher temperatures and an increase in patient visits daily. However, observations on Sundays and holidays may not reflect the delayed effect of temperature on patient visits since not all primary and referral care providers offer services on these days. Nonetheless, including the observations on these days is necessary to assess the overall impact of temperature on patient visits weekly and monthly. The regression analysis revealed that for each additional 1°C increase in the average monthly temperature, the estimated number of patients for primary care increased by 15% and 14% for referral care services.
Unmet need for family planning and associated factors among currently married women in Nepal: A further analysis of Nepal Demographic and Health Survey - 2022
Authors: KC Saugat Pratap , Adhikari Bikram , Pandey Achyut Raj , Pandey Merina , Kakchapati Sampurna , Giri Santosh , Sharma Shreeman , Lamichhane Bipul , Gautam Ghanshyam , Joshi Deepak , Dulal Bishnu Prasad , Regmi Shophika , Baral Sushil Chandra
Published: August 2023

Introduction

Family planning (FP) is crucial for improving maternal and newborn health outcomes, promoting gender equality, and reducing poverty. Unmet FP needs persist globally, especially in South Asia and Sub-Saharan Africa leading to unintended pregnancies, unsafe abortions, and maternal fatalities. Nepal, despite efforts, faces significant unmet FP needs, particularly among specific groups. This study aims to identify the determinants of unmet needs for FP from a nationally representative survey.

Methods

We analyzed the data from nationally representative Nepal Health Demographic Survey 2022. There was a total of 14,845 participants in the survey selected through systematic random sampling technique. Weighted analysis using R statistical software was conducted binary and multinomial logistic regression were performed to assess associations between independent variables and unmet FP needs.

Results

The total unmet FP need was 20.8% (95%CI: 19.7, 21.9) accounting 13.4% (95%CI: 12.5, 14.4) for unmet need for limiting and 7.4% (95%CI: 6.8, 8.0) for unmet for spacing. In multivariable regression model, age, ethnicity, religion, participants and partners education level, province, occupation, wealth quintile, parity and desire for child were statistically associated with total unmet need of FP. Lower odds of total unmet need for FP were present in 20-34 years and 35-49 years compared to <20 years, women belonging to Madhesi ethnic group(AOR: 0.79, 95% CI:0.65, 0.97) compared to brahmin/Chhetri, women from richest (AOR: 0.73, 95% CI:0.59, 0.90) and middle wealth quintile (AOR: 0.83, 95% CI:0.70, 0.99) group compared poorest wealth quintile and women belonging to rural area (AOR: 0.89, 95%CI: 0.80, 0.99) compared to urban area. Whereas higher odds of total unmet need for FP were present in non-Hindu women (AOR: 1.30, 95% CI:1.10, 1.53) compared to Hindu women and women belonging to Madhesh, Lumbini and Sudurpaschim province compared to Bagmati province.

Conclusion

Nepal faces relatively high unmet FP needs across various socio-demographic strata. Addressing these needs requires targeted interventions focusing on age, ethnicity, religion, education, and socio-economic factors to ensure universal access to FP services.
Neural network emulation of the human ventricular cardiomyocyte action potential: a tool for more efficient computation in pharmacological studies
Authors: Grandits Thomas , Augustin Christoph M. , Haase Gundolf , Jost Norbert , Mirams Gary R. , Niederer Steven A. , Plank Gernot , Varró András , Virág László , Jung Alexander
Published: August 2023

Abstract

Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.21 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies.
Overlapping Neural Correlates Underpin Theory of Mind and Semantic Cognition: Evidence from a Meta-Analysis of 344 Functional Neuroimaging Studies
Authors: Balgova Eva , Diveica Veronica , Jackson Rebecca L. , Binney Richard J.
Published: August 2023

Key unanswered questions for cognitive neuroscience include whether social cognition is underpinned by specialised brain regions and to what extent it simultaneously depends on more domain-general systems. Until we glean a better understanding of the full set of contributions made by various systems, theories of social cognition will remain fundamentally limited. In the present study, we evaluate a recent proposal that semantic cognition plays a crucial role in supporting social cognition. While previous brain-based investigations have focused on dissociating these two systems, our primary aim was to assess the degree to which the neural correlates are overlapping, particularly within two key regions, the anterior temporal lobe (ATL) and the temporoparietal junction (TPJ). We focus on activation associated with theory of mind (ToM) and adopt a meta-analytic activation likelihood approach to synthesise a large set of functional neuroimaging studies and compare their results with studies of semantic cognition. As a key consideration, we sought to account for methodological differences across the two sets of studies, including the fact that ToM studies tend to use nonverbal stimuli while the semantics literature is dominated by language-based tasks. Overall, we observed consistent overlap between the two sets of brain regions, especially in the ATL and TPJ. This supports the claim that tasks involving ToM draw upon more general semantic retrieval processes. We also identified activation specific to ToM in the right TPJ, bilateral anterior mPFC, and right precuneus. This is consistent with the view that, nested amongst more domain-general systems, there is specialised circuitry that is tuned to social processes.
Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling
Authors: Vitali Halie E. , Kuschel Bryce , Sherpa Chhiring , Jones Brendan W. , Jacob Nisha , Madiha Syeda A. , Elliott Sam , Dziennik Eddie , Kreun Lily , Conatser Cora , Bhetwal Bhupal P. , Sharma Bikram
Published: August 2023

Background

Coronary vessels in embryonic mouse heart arises from multiple progenitor population including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is shown to regulate coronary growth from SV pathway within the subepicardium, whereas VEGF-A/VEGF-R2 pathways is implicated to regulate coronary growth from endocardium pathway. Our previous study show hypoxia as a potential signaling cue to stimulate overall coronary growth and expansion within the myocardium. However, the role of hypoxia and its downstream signaling pathways in the regulation of coronary vessel development is not known. In this study, we investigated the role of hypoxia in coronary vessel development and have identified SOX17- and VEGF-R2-mediated signaling as a potential downstream pathway of hypoxia in the regulation of coronary vessel development.

Results

We show that hypoxia gain-of-function in the myocardium through upregulation of HIF-1α disrupts the normal pattern of coronary angiogenesis in developing mouse hearts and displays phenotype that is reminiscent of accelerated coronary growth. We show that VEGF-R2 expression is increased in coronary endothelial cells under hypoxia gain-of-functionin vivoandin vitro. Furthermore, we show that SOX17 expression is upregulated in developing mouse heart under hypoxia gain-of-function conditions, whereas SOX17 expression is repressed under hypoxia loss-of-function conditions. Furthermore, our results show that SOX17 loss-of-function disrupts normal pattern of coronary growth.

Conclusion

Collectively, our data provide strong phenotypic evidence to show that hypoxia might regulate coronary growth in the developing mouse heart potentially through VEGF-R2- and SOX17-mediated downstream signaling pathways.
High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus
Authors: Wang Qiang , Kim Taehyeung , Martínez-Bonet Marta , Aguiar Vitor R. C. , Sim Sangwan , Cui Jing , Sparks Jeffrey A. , Chen Xiaoting , Todd Marc , Wauford Brian , Marion Miranda C. , Langefeld Carl D. , Weirauch Matthew T. , Gutierrez-Arcelus Maria , Nigrovic Peter A.
Published: August 2023

Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (IKZF1), thereby modulating expression ofIKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKε. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a new regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.
Conformational transitions of the HIV-1 Gag polyprotein upon multimerization and gRNA binding
Authors: Banerjee Puja , Voth Gregory A.
Published: August 2023

During the HIV-1 assembly process, the Gag polyprotein multimerizes at the producer cell plasma membrane, resulting in the formation of spherical immature virus particles. Gag-gRNA interactions play a crucial role in the multimerization process, which is yet to be fully understood. We have performed large-scale all-atom molecular dynamics simulations of membrane-bound full-length Gag dimer, hexamer, and 18-mer. The inter-domain dynamic correlation of Gag, quantified by the heterogeneous elastic network model (hENM) applied to the simulated trajectories, is observed to be altered by implicit gRNA binding, as well as the multimerization state of the Gag. The lateral dynamics of our simulated membrane-bound Gag proteins, with and without gRNA binding, agree with prior experimental data and help to validate our simulation models and methods. The gRNA binding is observed to impact mainly the SP1 domain of the 18-mer and the MA-CA linker domain of the hexamer. In the absence of gRNA binding, the independent dynamical motion of the NC domain results in a collapsed state of the dimeric Gag. Unlike stable SP1 helices in the six-helix bundle, without IP6 binding, the SP1 domain undergoes a spontaneous helix-to-coil transition in the dimeric Gag. Together, our findings reveal conformational switches of Gag at different stages of the multimerization process and predict that the gRNA binding reinforces an efficient binding surface of Gag for multimerization, as well as regulates the dynamic organization of the local membrane region itself.

Significance

Gag(Pr55Gag) polyprotein orchestrates many essential events in HIV-1 assembly, including packaging of the genomic RNA (gRNA) in the immature virion. Although various experimental techniques, such as cryo-ET, X-ray, and NMR, have revealed structural properties of individual domains in the immature Gag clusters, structural and biophysical characterization of a full-length Gag molecule remains a challenge for existing experimental techniques. Using atomistic molecular dynamics simulations of the different model systems of Gag polyprotein, we present here a detailed structural characterization of Gag molecules in different multimerization states and interrogate the synergy between Gag-Gag, Gag-membrane, and Gag-gRNA interactions during the viral assembly process.
Cell cycle progression mechanisms: slower cyclin-D/CDK4 activation and faster cyclin-E/CDK2
Authors: Zhang Wengang , Liu Yonglan , Jang Hyunbum , Nussinov Ruth
Published: August 2023

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the short G1/S phase transition. We consider the experimentally established high-level bursting of cyclin-E, and sustained duration of elevated cyclin-D expression in the cell, available experimental cellular and structural data, and comprehensive explicit solvent molecular dynamics simulations to provide the mechanistic foundation of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. Importantly, we determine the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses the compelling cell cycle regulation question and illuminates the distinct activation speeds in the G1 versus G1/S phases, which are crucial for cell function.

Statement

Our work provides an unprecedented mechanistic understanding of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in cell cycle regulation, underpinning the slower activation of cyclin-D/CDK4 in the more extended G1 phase and the rapid activation of cyclin-E/CDK2 in the brief G1/S transition. Our findings address a long-standing question in cell cycle biology and suggest the design of targeted CDK4 inhibitors.
Oxytocin alleviated colitis and colitis-associated colorectal tumorigenesis by targeting fucosylated MUC2
Authors: Wang Xia , chen Dawei , guo MengNan , Ning Yao , Guo Jing , Gao Jiahui , Xie Xiaoran , Zhao Dong , Li Lixiang , Li Shiyang , Li Yanqing , Zuo Xiuli , Li Jingxin
Published: August 2023

Colon cancer is commonly regarded as hormone-independent. However, there have been reports suggesting the involvement of sex hormones in colon cancer development. Nevertheless, the role of hormones from the hypothalamus-hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both colitis and CAC patients. To investigate further, we generated mice with an intestinal epithelium cell (IEC)-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and DSS/Azoxymethane (AOM)-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate MUC2 maturation through B3GNT7-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the administration of oxytocin significantly alleviated tumor burden. Hence, our study unveils oxytocin’s promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.
Crystal structure studies and Hirshfeld surface analysis of 4-(dimethylazaniumyl)-2-hydroxyanilinium dichloride monohydrate at 90 K
Authors: Anil Kumar Haleyur G. , Mohan Kumar Thaluru M. , Divakara Thayamma R. , Geetha Doreswamy , Yathirajan Hemmige S. , Parkin Sean
Published: August 2023

The crystal structure and a Hirshfeld surface analysis of the substituted anilinium salt 4-(dimethylazaniumyl)-2-hydroxyanilinium dichloride monohydrate, C8H14N2O+·2Cl−·H2O, at low temperature (90 K) are presented. The organic cation is essentially planar: the r.m.s. deviation of its non-hydrogen atoms (aside from the two methyl groups) is 0.0045 Å. The methyl carbons are 1.3125 (12) Å and 1.1278 (12) Å either side of the mean plane. The crystal packing involves extensive hydrogen bonding of types O—H...Cl, N—H...Cl, N—H...OW, and OW—HW...Cl (where W = water), which arrange into chains of R
2
4(12) motifs that combine to form corrugated layers parallel to (10\overline{1}). Atom–atom contacts for the cation primarily involve hydrogen, leading to the most abundant coverage percentages being 51.3% (H...H), 23.0% (H...Cl), 12.9% (H...O), and 9.7% (C...H).
Exploring financial inclusion in MENA countries: an entropy weight approach
Authors: Ramaian Vasantha Naveenan , Liew Chee Yoong , Kijkasiwat Ploypailin
Published: August 2023

Purpose

Research on financial inclusion (FI) in Islamic countries has evolved and gained prominence. This study aims to construct an extensive multidimensional FI index to ascertain the level of inclusion and trends in the Middle East/North Africa (MENA) countries. Additionally, this study examines the potential role of Islamic finance in improving access to financial services.

Design/methodology/approach

Data for the study were collected from databases covering MENA countries for the period 2010–2020. An inclusion index has been constructed using the entropy method.

Findings

Key findings indicate that the overall FI has improved in Islamic countries. However, it should be noted that all MENA countries fall within the low or medium levels of the inclusion index. It was observed that insurance access and penetration savings were poor in the Islamic MENA countries.

Social implications

The authors recommend that policymakers focus on insurance access and saving behaviour in their respective countries. Based upon these observations, policymakers should promote the economic benefits of Islamic finance, which will help improve FI and economic development in Islamic countries. This study emphasises the necessity of policy framework reform to provide Islamic financial services to the poorest in society at low or no cost for better economic benefits.

Originality/value

Most studies tend to overlook important indicators such as insurance, savings and credit penetration while calculating the index. These indicators add value to the existing literature. The majority of prior studies used United Nation Development Programme methodology or principal component analysis for Inclusion Index measurements. The adoption of the entropy weighting method is the novelty of this study.
How big data features drive financial accounting and firm sustainability in the energy industry
Authors: Azzam Mohsen Ebied Abdelghafar Younis , Alsayed Marwa Saber Hamoda , Alsultan Abdulaziz , Hassanein Ahmed
Published: August 2023

Purpose

This study aims to scrutinize the relationship between the perception of big data (BD) features and the primary outcomes of financial accounting. Likewise, it explores whether financial accounting practices moderate the relationship between BD features and firm sustainability.

Design/methodology/approach

The study used a questionnaire survey based on the Likert scale for two distinct groups of participants: academic scholars and industry practitioners operating in the BD era within the energy sector.

Findings

The results reveal significant positive associations between BD features and firm performance, reporting quality, earnings determinants, fair value measurements, risk management, firm value, the efficiency of the decision-making process, narrative disclosure and firm sustainability. Besides, the path analysis indicates an indirect impact of BD on firm sustainability via financial accounting practices. The results suggest that energy firms should consider incorporating BD analysis into their financial accounting processes to improve their sustainability performance and create long-term value for their stakeholders.

Practical implications

The findings are particularly interesting to academics in accounting and business to improve the accounting curriculums to fit the technological revolution, especially in the field of BD analytics. Practitioners within energy industries must also refine their skills and knowledge to meet the challenges of BD in the foreseeable future. The results provide important implications for policy setters to revise current financial accounting standards to cope with technological innovation.

Originality/value

The study makes a valuable contribution by critically examining the impact of BD on various financial accounting practices neglected in prior research. It highlights the transformative power of BD in the domain of financial accounting and provides insights into its potential implications for energy firms.
Revitalizing reference services and fostering information literacy: Google Bard’s dynamic role in contemporary libraries
Authors: Adetayo Adebowale Jeremy , Oyeniyi Wosilat Omolara
Published: August 2023

Purpose

This paper aims to explore the transformative potential of Google Bard, an artificial intelligence (AI)-powered chatbot, in reshaping contemporary library reference services and advancing information literacy.

Design/methodology/approach

In this perspective piece, a qualitative research approach is used to explore the capabilities of Google Bard within library contexts. Real-world case studies and insights are used to critically examine Bard’s evolving role as a virtual assistant, its impact on enhancing information literacy and the multifaceted challenges it introduces, including biases and privacy concerns.

Findings

The research reveals that Google Bard, leveraging natural language processing and machine learning, engages users in dynamic conversational interactions. It provides contextually relevant responses and personalized guidance, leading to an enriched library experience. The symbiotic relationship between AI-driven technology and traditional librarian expertise is highlighted, contributing to interactive knowledge exploration and collaborative learning.

Originality/value

This study contributes to the literature by exploring the multifaceted impact of Google Bard on library services and information literacy. It uncovers novel insights into the integration of AI-powered chatbots in traditional library settings.
Modeling drivers and barriers of climate change mitigation strategies in Indian iron and steel industry: a TISM-based approach
Authors: Singh Puja , Pradhan Vishal Suresh , Patil Yogesh B.
Published: August 2023

Purpose

The main purpose of this paper is to investigate drivers and barriers of climate change mitigation strategies (CCMS), their linkages and impact in Indian Iron and Steel Industry (IISI) in light of ninth sustainable development goal (building resilient infrastructure, promote sustainable industrialization and foster innovation).

Design/methodology/approach

To identify relevant drivers and barriers, a thorough literature review and opinions of industry experts were obtained. Utilizing Total Interpretive Structural Modeling (TISM), the selected drivers and barriers were modeled separately along with Cross Impact Matrix-multiplication Applied to Classification (MICMAC).

Findings

Pragmatic and cost-effective technology, less supply chain complexity, robust policy and legal framework were found to have the highest driving power over all the other drivers. Findings suggest political pressure as the most critical barrier in this study. The results from TISM and MICMAC analysis have been used to elucidate a framework for the understanding of policymakers and achieve top management commitment.

Practical implications

This paper will help researchers, academicians, industry analysts and policymakers in developing a systems approach in prioritizing CCMS in energy-intensive (coal dependent) iron and steel plants. The model outcomes of this work will aid operational research to understand the working principles in other industries as well.

Originality/value

To the best of authors' knowledge, there is paucity of reported literature for the drivers and barriers of CCMS in iron and steel industry. This paper can be considered a unique, first attempt to use data from developing nations like India to develop a model and explain relationships of the existing drivers and barriers of CCMS.
Examining the effect of brand coolness on communal brand connection and brand commitment: a mediation and moderation perspective
Authors: Amenuvor Fortune Edem , Akasreku Frank , Mensah Kobby A.
Published: August 2023

Purpose

The purpose of this study, which draws on the stimulus organism response (S-O-R) theory, is to empirically examine the effect of brand coolness on communal brand connection and brand commitment, while assessing how the latter fosters brand trust and loyalty among smartphone users.

Design/methodology/approach

Data are collected from 410 smartphone users in Ghana and analyzed with Smart-PLS utilizing the structural equations modeling technique.

Findings

The study's findings show that consumers' perceptions of brand coolness have a positive influence on their communal brand connection and brand commitment. The study also discovers that brand commitment influences brand loyalty, whereas communal brand connection influences brand commitment, loyalty and trust, respectively. Similarly, brand commitment and communal brand connection are identified as important mediating variables in the relationship between brand coolness and both brand loyalty and brand trust.

Practical implications

The study underlines the significance of developing cool brand images and communicating same effectively to current and prospective customers, along with other stakeholders.

Originality/value

The study highlights the fact that properly creating cool brands can lead to increased communal brand connection, brand commitment, and, consequently, brand trust and loyalty.
Training and development in the hybrid workplace
Authors: Suravi Swati
Published: August 2023

Purpose

This paper aims to discuss innovations in the training and development practices of companies and delineate a new approach to training and development in the context of the hybrid workplace using the ADDIE and Kirkpatrick training models.

Design/methodology/approach

This paper discusses innovations in training and development in modern times and builds on the instructional training design approach or the ADDIE Model and the Kirkpatrick Model of training evaluation.

Findings

The paper presents new approaches to training and development in the context of the hybrid work model applying the ADDIE Model and the Kirkpatrick Model. These new approaches are both necessitated and also made possible due to the technological advancements of modern times.

Originality/value

With the rapid transition of companies to the hybrid model of work in recent times, several human resource management practices need to be transformed to suit the requirements of the new work model. Training and development is one function that needs to change in the hybrid work model to ensure its effectiveness. This paper analyses innovations in the training and development practices of companies and discusses new approaches while applying existing training models, the ADDIE and Kirkpatrick Models, to adapt to the changes associated with the hybrid work model.
Perceived value of recommended product and consumer e-loyalty: an expectation confirmation perspective
Authors: Ampadu Seth , Jiang Yuanchun , Gyamfi Samuel Adu , Debrah Emmanuel , Amankwa Eric
Published: August 2023

Purpose

The purpose of this study is to examine the effect of perceived value of recommended product on consumer’s e-loyalty, based on the proposition of expectation confirmation theory. Vendors’ reputation is tested as the mediator in the perceived value of recommended product and e-loyalty relationship, whereas shopping enjoyment is predicted as the moderator that conditions the perceived value of recommended product and e-loyalty relationship through vendors reputation.

Design/methodology/approach

Data were collected via an online survey platform and through a QR code. Partial least squares analysis, confirmatory factor analysis and structural equation modeling were used to verify the research proposed model.

Findings

The findings revealed that the perceived value of recommended product had a significant positive effect on E-loyalty; in addition, the perceived value of the recommended product and e-loyalty link was partly explained by e-shopper’s confidence in vendor reputation. Therefore, the study established that the direct and indirect relationship between the perceived value of the recommended product and e-loyalty was sensitive and profound to shopping enjoyment.

Originality/value

This study has established that the perceived value of a recommended product can result in consumer loyalty. This has successively provided the e-shop manager and other stakeholders with novel perspectives about why it is necessary to understand consumers’ pre- and postacquisition behavior before recommending certain products to the consumer.