bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking inP. falciparumMalaria
Authors: Chahine Z , Abel S , Hollin T , Chung JH , Barnes GL , Daub ME , Renard I , Choi JY , Pratap V , Pal A , Alba-Argomaniz M , Banks CAS , Kirkwood J , Saraf A , Camino I , Castaneda P , Cuevas MC , De Mercado-Arnanz J , Fernandez-Alvaro E , Garcia-Perez A , Ibarz N , Viera-Morilla S , Prudhomme J , Joyner CJ , Bei AK , Florens L , Ben Mamoun C , Vanderwal CD , Le Roch KG 
Published: November 2023

ABSTRACTHere we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and-resistantP. falciparumstrains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective againstP. knowlesiandP. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses inP. falciparumrevealed that a mutation inPfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189in vitroandin vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.Editor’s SummaryHere we report the mode of action and mechanism of resistance of a pan-antimalarial agent, MED6-189, which disrupts apicoplast function and vesicular trafficking inP. falciparum.
Insights into Intestinal P-glycoprotein Function using Talinolol: A PBPK Modeling Approach
Authors: Mallol Beatrice Stemmer , Grzegorzewski Jan , Tautenhahn Hans-Michael , König Matthias 
Published: November 2023

ABSTRACTTalinolol is a cardioselective beta-blocker that was previously used to treat heart failure and myocardial infarction. Following the development of new, more effective beta-blockers with better study results, talinolol is now only used clinically for the treatment of arterial hypertension. In basic science, talinolol continues to be used as a test substance due to its pharmacokinetics. Its intestinal absorption is determined by uptake by the organic anion transporting polypeptide 2B1 (OATP2B1) and efflux via P-glycoprotein (P-gp). Talinolol can be taken up via OATP1B1 in the liver, where it enters the enterohepatic circulation. Talinolol is excreted unchanged in the urine and feces. Talinolol is widely used as a probe drug for the intestinal efflux transporter P-gp, which plays a critical role in protecting against potentially toxic substances and facilitating the elimination of xenobiotics. In this work, an extensive database of talinolol pharmacokinetics was established and used to develop and validate a physiologically based pharmacokinetic (PBPK) model of talinolol for P-gp phenotyping. The model was used to investigate the influence of several factors on talinolol pharmacokinetics: (i) inhibition of P-gp via drug-drug interaction; (i) genetic polymorphisms of P-gp; (iii) activity of OATP2B1 and OATP1B1; (iv) effect of comorbidity, namely hepatic and renal impairment; and (v) site-specific distribution of P-gp and OATP2B1 in the intestine. The model accurately predicts the concentration-time profile of talinolol after oral or intravenous administration of single and multiple dosing. Furthermore, the model accurately describes the effect of genetic variants of P-gp on the pharmacokinetics of talinolol, the effect of inhibition of P-gp, the effect of renal impairment, as well as site-specific infusion of talinolol in the intestine. The detailed description of the intestinal absorption of talinolol and the predictions of talinolol pharmacokinetics as a function of hepatorenal impairment provide valuable clinical insights for metabolic phenotyping with talinolol. Both the model and the database are freely available for reuse.
Systematic characterization of the local evolutionary space available to human PKR and vaccinia virus K3
Authors: Chambers Michael J. , Scobell Sophia , Sadhu Meru J. 
Published: November 2023

AbstractThe interfaces between host and viral proteins can be dynamic spaces in which genetic variants are continually pursued, giving rise to evolutionary arms races. One such scenario is found between the mammalian innate immunity protein PKR (protein kinase R) and the poxvirus antagonist K3. Once activated, PKR phosphorylates the natural substrate eIF2α, which halts protein synthesis within the cell and prevents viral replication. K3 acts as a pseudosubstrate antagonist against PKR by directly antagonizing this halt in protein synthesis, enabling poxviruses to replicate in the cell. Exploring the impact of genetic variants in both PKR and K3 is necessary not only to highlight residues of evolutionary constraint and opportunity but also to elucidate the mechanism by which human PKR is able to subvert a rapidly evolving viral antagonist. To systematically explore this dynamic interface, we have generated a combinatorial library of PKR and K3 missense variants to be co-expressed and characterized in a high-throughput yeast selection assay. This assay allows us to characterize hundreds of thousands of unique PKR-K3 genetic combinations in a single pooled experiment. Our results highlight specific missense variants available to PKR that subvert the K3 antagonist. We find that improved PKR variants are readily available at sites under positive selection, with limited opportunity at sites interfacing with K3 and eIF2α. Additionally, we find many variants that improve and disable K3 antagonism, suggesting a pliable interface. We reason that this approach can be leveraged to explore the evolutionary plasticity of many other host-virus interfaces.
BARtab & bartools: an integrated Nextflow pipeline and R package for the analysis of synthetic cellular barcodes in the genome and transcriptome
Authors: Holze Henrietta , Talarmain Laure , Fennell Katie A. , Lam Enid Y. , Dawson Mark A. , Vassiliadis Dane 
Published: November 2023

AbstractCellular barcoding using heritable synthetic barcodes coupled to high throughput sequencing is a powerful technique for the accurate tracing of clonal lineages in a wide variety of biological contexts. Recent studies have integrated cellular barcoding with a single-cell transcriptomics readout, extending the capabilities of these lineage tracing methods to the single-cell level. However there remains a lack of scalable and standardised open-source tools to pre-process and visualise both population-level and single-cell level cellular barcoding datasets. To address these limitations, we developedBARtab, a portable and scalable Nextflow pipeline that automates upstream barcode extraction, quality control, filtering and enumeration from high throughput sequencing data; andbartools, an open-source R package that streamlines the analysis and visualisation of population and single-cell level cellular barcoding datasets.BARtabcontains additional methods for the extraction and annotation of transcribed barcodes from single-cell RNA-seq and spatial transcriptomics experiments, thus extending this analytical toolbox to also support novel expressed cellular barcoding methodologies. We showcase the integratedBARtabandbartoolsworkflow through comparison with previously published toolsets and via the analysis of exemplar bulk, single-cell, and spatial transcriptomics cellular barcoding datasets.
CLUSTER ANALYSIS IDENTIFIES LONG COVID SUBTYPES IN BELGIAN PATIENTS
Authors: Kemajou Pamela Mfouth , Besse-Hammer Tatiana , Lebouc Claire , Coppieters Yves 
Published: November 2023

AbstractSARS CoV-2 infection presents complications known as long Covid, a multisystemic organ disease which allow multidimensional analysis.ObjectivesThis study aims to identify Long Covid clusters and to relate them to the clinical classification devised at the Clinical Research Unit of Brugmann University Hospital, Brussels.MethodA two-stage multidimensional exploratory analysis was performed on a cohort of 205 long Covid patients, involving a Factorial Analysis of Mixed Data (FAMD), and then Hierarchical Clustering Post Component Analysis (HCPC).ResultsThe study’s sample comprised 76% women, with an average age of 44.5 years. Three clinical forms were identified: long, persistent, and post-viral syndrome. Multidimensional analysis identified three clusters: cluster 1 (myalgia-like pain) associated with the persistent clinical form; cluster 2 (neurocognitive disorders) linked to the long clinical form; cluster 3 (neurocognitive disorders, anxio-depressive syndrome, joint pain and myalgia, peripheral nervous system disorders with dysautonomia, including Postural Orthostatic Tachycardia Syndrome, along with digestive system disorders). However, biological data did not provide sufficient differentiation between the clusters.ConclusionLong Covid phenotypes, as well as clinical forms, appear to be associated with distinct pathophysiological mechanisms or genetic predisposition, warranting further investigation.
Uncovering the Shared Genetic Components of Thyroid Disorders and Reproductive Health
Authors: Figuerêdo Jéssica , Krebs Kristi , Pujol-Gualdo Natàlia , Haller Toomas , Võsa Urmo , Volke Vallo ,   Estonian Biobank research team,   Health Informatics research team, Laisk Triin , Mägi Reedik 
Published: November 2023

ABSTRACTThyroid disorders are complex and polygenic, and thus result from the interaction of many genetic variants. Due to a central role of the thyroid hormones in the body, their dysfunction can have a significant impact on the reproductive health in men and women. Mapping the shared genetic component and relationships between thyroid and reproductive health traits will improve the understanding about the interplay between those domains. Here, a large-scale genetic analysis of thyroid traits (hyper- and hypothyroidism, and thyroid stimulating hormone levels) was conducted in up to 743,088 individuals of European ancestry from various cohorts. We evaluated genetic and phenotypic associations using genome-wide association study (GWAS) meta-analysis, gene prioritisation, genetic correlation analysis, and phenotype vs phenome-wide-association analysis. The results showed that 32% of thyroid-associated genes also had an impact on reproductive phenotypes, with the most affected functions being related to genitourinary tract issues. The study highlights the shared genetic determinants between thyroid function and reproductive health, providing evidence for the genetic pleiotropy between these traits in both men and women.
Comparison of the audiological knowledge of three chatbots – ChatGPT, Bing Chat, and Bard
Authors: Jedrzejczak W. Wiktor , Kochanek Krzysztof 
Published: November 2023

AbstractObjectiveThe purpose of this study was to evaluate three chatbots – OpenAI ChatGPT, Microsoft Bing Chat, and Google Bard – in terms of their responses to a defined set of audiological questions.DesignEach chatbot was presented with the same 10 questions. The authors rated the responses on a Likert scale ranging from 1 to 5. Additional features, such as the number of inaccuracies or errors and the provision of references, were also examined.ResultsMost responses given by all three chatbots were rated as satisfactory or better. However all chatbots generated at least a few errors or inaccuracies. ChatGPT achieved the highest overall score, while Bard was the worst. Bard was also the only chatbot unable to provide a response to one of the questions. ChatGPT was the only chatbot that did not provide information about its sources.ConclusionsChatbots are an intriguing tool that can be used to access basic information in a specialized area like audiology. Nevertheless, one needs to be careful, as correct information is not infrequently mixed in with errors that are hard to pick up unless the user is well versed in the field.
Modulation of Extracellular Matrix Composition and Chronic Inflammation by Pirfenidone Promotes Scar Reduction in Retinal Wound Repair
Authors: Jahnke Laura , Perrenoud Virginie , Zandi Souska , Li Yuebing , Conedera Federica Maria , Enzmann Volker 
Published: November 2023

AbstractWound repair in the retina is a complex mechanism and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent degenerative processes leading to photoreceptor loss. In this study, we harnessed a laser-induced retinal degeneration model, enabling a profound molecular elucidation and a comprehensive, prolonged observation of the wound healing sequence in a murine laser-induced degeneration model until day 49 post laser. Our observations included the expression of specific extracellular matrix proteins and myofibroblast activity, along with an analysis of gene expression related to extracellular matrix and adhesion molecules through RNA measurements. Furthermore, the administration of pirfenidone, an anti-inflammatory and anti-fibrotic compound, was used to modulate the scar formation after laser treatment. Our data revealed upregulated collagen expression in late regenerative phases and sustained inflammation in the damaged tissue. Notably, treatment with pirfenidone was found to mitigate scar tissue formation, effectively downregulating collagen production and diminishing the presence of inflammatory markers. However, it did not lead to the regeneration of the photoreceptor layer.
Hepatitis C virus cell culture adaptive mutations enhance cell culture propagation by multiple mechanisms but boost antiviral responses in primary human hepatocytes
Authors: Frericks Nicola , Brown Richard J.P. , Reinecke Birthe M. , Herrmann Maike , Brüggemann Yannick , Todt Daniel , Miskey Csaba , Vondran Florian W. R. , Steinmann Eike , Pietschmann Thomas , Sheldon Julie 
Published: November 2023

AbstractHepatitis C virus (HCV) infection progresses to chronicity in the majority of infected individuals. Its high intra-host genetic variability enables HCV to evade the continuous selection pressure exerted by the host, contributing to persistent infection. Utilizing a cell culture adapted HCV population (p100pop) which exhibits increased replicative capacity in various liver cell lines, this study investigated virus and host determinants which underlie enhanced viral fitness. Characterization of a panel of molecular p100 clones revealed that cell culture adaptive mutations optimize a range of virus-host interactions, resulting in expanded cell tropism, altered dependence on the cellular co-factor micro-RNA 122 and increased rates of virus spread. On the host side, comparative transcriptional profiling of hepatoma cells infected either with p100pop or its progenitor virus revealed that enhanced replicative fitness correlated with activation of endoplasmic reticulum stress signaling and the unfolded protein response. In contrast, infection of primary human hepatocytes with p100pop led to a mild attenuation of virion production which correlated with a greater induction of cell-intrinsic antiviral defense responses. In summary, long-term passage experiments in cells where selective pressure from innate immunity is lacking improves multiple virus-host interactions, enhancing HCV replicative fitness. However, this study further indicates that HCV has evolved to replicate at low levels in primary human hepatocytes to minimize innate immune activation, highlighting that an optimal balance between replicative fitness and innate immune induction is key to establishing persistence.Author SummaryHCV infection remains a global health burden with 58 million people currently chronically infected. However, the detailed molecular mechanisms which underly persistence are incompletely defined. We utilized a long-term cell culture adapted HCV, exhibiting enhanced replicative fitness in different human liver cell lines, in order to identify molecular principles by which HCV optimizes its replication fitness. Our experimental data revealed that cell culture adaptive mutations confer changes in the host response and usage of various host factors. The latter allows functional flexibility at different stages of the viral replication cycle. However, increased replicative fitness resulted in an increased activation of the innate immune system, which likely poses boundary for functional variation in authentic hepatocytes, explaining the observed attenuation of the adapted virus population in primary hepatocytes.
The impact of reference price effect on pricing decisions
Authors: Wang Chen-hao , Liu Yong , Pan Zi-yi 
Published: November 2023

PurposeThe paper attempts to discuss the impact of reference price effect on pricing decisions.Design/methodology/approachWith the growth of the Internet and e-commerce, more and more customers purchase products in through online channels and choose products by comparing different prices and services, and the reference price effect has an impact on pricing decisions. To investigate the impact of consumers' reference price effect on the dual-channel supply chain, the authors establish a basic model consisting of a single dominant manufacturer and a single downstream retailer, and analyze the optional decisions under different situations and discuss the influence of reference price effect. Finally, a number case verifies the validity and rationality of the proposed model.FindingsThe results show that (1) the reference price effect has varying effects on the price, channel demand and income of manufacturers and retailers in the channel depending on the role of customers' channel preferences. (2) The manufacturer's online channel demand and profits always increase with the reference pricing effect, whereas the retailer's offline demand and profits always decline. (3) When the proportion of consumers preferring offline is higher, the manufacturer's network price and wholesale price increase with the reference price effect, while the retailer's retail price decreases with the reference price effect; when the proportion of consumers preferring offline is lower, the opposite is true, and the centralized decision results are consistent with the decentralized decision results.Practical implicationsThis paper can clarify the impact of consumer reference price effects on the operation of dual-channel supply chains, and help inform pricing decisions of manufacturers and retailers in dual-channel supply chains.Originality/valueThe proposed approach can well analyze the impact of consumer reference price effect and give channel their optional decisions.
Curvilinear effects of corporate philanthropy on stakeholders and financial performance
Authors: Lee Jungwon , Kim Ohsung , Park Cheol 
Published: November 2023

PurposeThe purpose of this study is to analyze the nonlinear effects of corporate philanthropy on the responses of both internal and external stakeholders as well as its impact on corporate financial performance.Design/methodology/approachBased on the stakeholder theory, the authors developed a conceptual model to examine the nonlinear effects of corporate philanthropy on company performance. For the empirical analysis, data from 397 company-years was analyzed using a using a Heckman two-stage model. The robustness of the findings was also confirmed through panel regression analysis.FindingsThe study revealed a linear relationship between corporate reputation and corporate philanthropy, whereas job satisfaction exhibited a nonlinear relationship with corporate philanthropy.Originality/valueThis research bridges the gap in extant literature by scrutinizing the nonlinear associations between corporate philanthropy and financial performance. Additionally, it addresses an emerging scholarly demand to uncover the “dark side” of corporate philanthropy through an investigation into its adverse impacts on employee satisfaction. Moreover, the study augments existing understandings of stakeholder theory and corporate philanthropy, positing that the influence of corporate philanthropy, as conceptualized through stakeholder theory, hinges on perceived fairness in multilateral relationships.
Time-averaged flow field reconstruction based on a multifidelity model using physics-informed neural network (PINN) and nonlinear information fusion
Authors: Rui En-Ze , Zeng Guang-Zhi , Ni Yi-Qing , Chen Zheng-Wei , Hao Shuo 
Published: November 2023

Purpose
Current methods for flow field reconstruction mainly rely on data-driven algorithms which require an immense amount of experimental or field-measured data. Physics-informed neural network (PINN), which was proposed to encode physical laws into neural networks, is a less data-demanding approach for flow field reconstruction. However, when the fluid physics is complex, it is tricky to obtain accurate solutions under the PINN framework. This study aims to propose a physics-based data-driven approach for time-averaged flow field reconstruction which can overcome the hurdles of the above methods.

Design/methodology/approach
A multifidelity strategy leveraging PINN and a nonlinear information fusion (NIF) algorithm is proposed. Plentiful low-fidelity data are generated from the predictions of a PINN which is constructed purely using Reynold-averaged Navier–Stokes equations, while sparse high-fidelity data are obtained by field or experimental measurements. The NIF algorithm is performed to elicit a multifidelity model, which blends the nonlinear cross-correlation information between low- and high-fidelity data.

Findings
Two experimental cases are used to verify the capability and efficacy of the proposed strategy through comparison with other widely used strategies. It is revealed that the missing flow information within the whole computational domain can be favorably recovered by the proposed multifidelity strategy with use of sparse measurement/experimental data. The elicited multifidelity model inherits the underlying physics inherent in low-fidelity PINN predictions and rectifies the low-fidelity predictions over the whole computational domain. The proposed strategy is much superior to other contrastive strategies in terms of the accuracy of reconstruction.

Originality/value
In this study, a physics-informed data-driven strategy for time-averaged flow field reconstruction is proposed which extends the applicability of the PINN framework. In addition, embedding physical laws when training the multifidelity model leads to less data demand for model development compared to purely data-driven methods for flow field reconstruction.