bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Unfolded Protein Response Sensor PERK Mediates Mechanical Stress-induced Maturation of Focal Adhesion Complexes in Glioblastoma Cells
Authors: Khoonkari Mohammad , Liang Dong , Kamperman Marleen , van Rijn Patrick , Kruyt Frank A.E. 
Published: March 2024

AbstractStiffening of the brain extracellular matrix (ECM) in glioblastoma leads to mechanical stress, which is known to contribute to tumor formation and progression. Previously, we found that protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a component of the unfolded protein response (UPR), plays a role in the adaptation of glioblastoma stem cells (GSCs) to matrix stiffness through PERK/FLNA dependent F-Actin remodeling. Here, we found that increases in matrix stiffness induces differentiation of GSCs that was not seen in PERK deficient GSCs. Furthermore, we investigated whether PERK is involved in detecting changes in matrix stiffness through focal adhesion complex (FAC) formation and maturation, which are instrumental for transmitting ECM dependent signaling. In PERK deficient GSCs, Vinculin and Tensin expression was decreased, while Talin and Integrin-β1 expression was kept at the same level compared to PERK proficient cells. In addition, in the absence of PERK, Tubulin expression is sharply increased coupled with low Vimentin expression, which was observed as an opposite trend in the presence of PERK. In conclusion, our study reveals a novel role for PERK in regulating the formation of FACs during matrix stiffening, possibly associated with its regulatory capacity in F-Actin remodeling.
GRASPS: a simple-to-operate translatome technology reveals omics-hidden disease-associated pathways in TDP-43-related amyotrophic lateral sclerosis
Authors: Lin Ya-Hui , Dodd Jennifer E. , Cutillo Luisa , Castelli Lydia M. , Mihaylov Simeon R. , Norris Karl , Higginbottom Adrian , Walsh Matthew J. , Cooper-Knock Johnathan , Highley J. Robin , Granata Ilaria , Evans Caroline A. , Guarracino Mario R. , Campbell Susan G. , Dickman Mark J. , Shaw Pamela J. , Milo Marta , Hautbergue Guillaume M. 
Published: March 2024

AbstractTranscriptomes and translatomes measure genome-wide levels of total and ribosome-associated RNAs. A few hundred translatomes were reported over >250,000 transcriptomes highlighting the challenges of identifying translating RNAs. Here, we used a human isogenic inducible model of TDP-43-linked amyotrophic lateral sclerosis, which exhibits altered expression of thousands of transcripts, as a paradigm for the direct comparison of whole-cell, cytoplasmic and translating RNAs, showing broad uncoupling and poor correlation between disease-altered transcripts. Moreover, based on precipitation of endogenous ribosomes, we developed GRASPS (Genome-wide RNA Analysis of Stalled Protein Synthesis), a simple-to-operate translatome technology. Remarkably, GRASPS identified three times more differentially-expressed transcripts with higher fold changes and statistical significance, providing unprecedented opportunities for data modeling at stringent filtering and discovery of previously omics-missed disease-relevant pathways, which functionally map on dense gene regulatory networks of protein-protein interactions. Based on its simplicity and robustness, GRASPS is widely applicable across disciplines in the biotechnologies and biomedical sciences.
N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine
Authors: Wang Chuchu , Zhao Chunyu , Hu Xiao , Qiang Jiali , Liu Zhenying , Gu Jinge , Zhang Shengnan , Li Dan , Zhang Yaoyang , Burré Jacqueline , Diao Jiajie , Liu Cong 
Published: March 2024

AbstractPost-translational modifications (PTMs) of α-synuclein (α-syn) such as acetylation and phosphorylation play important yet distinct roles in regulating α-syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate α-syn function in presynaptic terminals remains unclear. Previously, we reported that α-syn clusters synaptic vesicles (SV)1, and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering2. Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of α-syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of α-syn’s N-terminus and increased intermolecular interactions on the LPC-containing membrane. Our work demonstrates that N-acetylation fine-tunes α-syn–LPC interaction for mediating α-syn’s function in SV clustering.
Computationally accelerated identification of P-glycoprotein inhibitors
Authors: McCormick Lauren A. , McCormick James W. , Park Chanyang , Follit Courtney A. , Wise John G. , Vogel Pia D. 
Published: March 2024

AbstractOverexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1,ABCB1), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump’s transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump’s cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.
A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity
Authors: Mosharov Eugene V. , Rosenberg Ayelet M , Monzel Anna S , Osto Corey A. , Stiles Linsey , Rosoklija Gorazd B. , Dwork Andrew J. , Bindra Snehal , Zhang Ya , Fujita Masashi , Mariani Madeline B , Bakalian Mihran , Sulzer David , De Jager Philip L. , Menon Vilas , Shirihai Orian S , Mann J. John , Underwood Mark , Boldrini Maura , Thiebaut de Schotten Michel , Picard Martin 
Published: March 2024

AbstractMitochondrial oxidative phosphorylation (OxPhos) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4, underscoring the need to define the brain’s molecular energetic landscape5–10. To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
Locus-specific stratification and prioritization unveil high risk genes underlying hyperuricemia
Authors: Zhang Jing , Guo Yue , Gong Luyu , Xia Limei , Liu Qiaoqiao , Wang Kangchun , Wang Qi , Liu Zhaojun , Qin Zhaohui , Shi Shaolin , Yang Jingping 
Published: March 2024

AbstractThe development of alternative medications for urate-lowering therapies is imperative for patients that are intolerant to current treatments. Despite GWAS have identified hundreds of loci associated with serum urate levels, the mechanistic understanding and discovery of drug targets remain difficult. This difficulty arises from the multiple-independent-associations challenge in the genomic studies of complex diseases as hyperuricemia. Here, we introduced a locus-specific stratification (LSS) and gene regulatory prioritization score (GRPS) approach to address the multiple-independent-associations challenge. By integrating with kidney single-cell chromatin accessibility and gene expression, LSS identified functional SNPs, regulatory elements, and genes for 118 loci. The interpretability was increased by 1.4 to 5.2 fold. GRPS prioritized genes and nominated under-explored drug target with high confidence, which was validated using CRISPR activation and phenotypic assays. Our findings not only identified top causal genes but also proposed the regulatory mechanisms for pathogenic genes, expanding our knowledge of the genetic contribution in complex diseases as hyperuricemia.One-sentence summaryA novel approach to comprehensively explore genetic contribution and nominate reliable causal genes for complex diseases as hyperuricemia.
Impacts of yeast Tma20/MCTS1, Tma22/DENR and Tma64/eIF2D on translation reinitiation and ribosome recycling
Authors: Jendruchová Kristína , Gaikwad Swati , Poncová Kristýna , Gunišová Stanislava , Valášek Leoš Shivaya , Hinnebusch Alan G. 
Published: March 2024

ABSTRACTRecycling of 40S ribosomal subunits following translation termination, entailing release of deacylated tRNA and dissociation of the empty 40S subunit from mRNA, involves yeast Tma20/Tma22 heterodimer and Tma64, counterparts of mammalian MCTS1/DENR and eIF2D. MCTS1/DENR enhance reinitiation at short upstream open reading frames (uORFs) harboring penultimate codons that confer dependence on these factors in bulk 40S recycling. Tma factors, by contrast, inhibited reinitiation at particular uORFs in extracts; however, their roles at regulatory uORFs in vivo were unknown. We examined effects of eliminating Tma proteins on reinitiation at regulatory uORFs mediating translational control ofGCN4optimized for either promoting (uORF1) or preventing (uORF4) reinitiation. We found that the Tma proteins generally impede reinitiation at native uORF4 and uORF4 variants equipped with various penultimate codons regardless of their Tma-dependence in bulk recycling. The Tma factors have no effect on reinitiation at native uORF1, and equipping uORF1 with Tma-dependent penultimate codons generally did not confer Tma-dependent reinitiation; nor did converting the uORFs to AUG-stop elements. Thus, effects of the Tma proteins vary depending on the reinitiation potential of the uORF and the penultimate codon, but unlike in mammals, are not principally dictated by the Tma-dependence of the codon in bulk 40S recycling.
A history of repeated antibiotic usage leads to microbiota-dependent mucus defects
Authors: Krigul Kertu Liis , Feeney Rachel H. , Wongkuna Supapit , Aasmets Oliver , Holmberg Sandra M. , Andreson Reidar , Puértolas-Balint Fabiola , Pantiukh Kateryna , Sootak Linda , Org Tõnis , Tenson Tanel , Org Elin , Schroeder Bjoern O. 
Published: March 2024

AbstractRecent evidence indicates that repeated antibiotic usage lowers microbial diversity and lastingly changes the gut microbiota community. However, the physiological effects of repeated – but not recent – antibiotic usage on microbiota-mediated mucosal barrier function are largely unknown. By selecting human individuals from the deeply-phenotyped Estonian Microbiome Cohort (EstMB) we here utilised human-to-mouse faecal microbiota transplantation to explore long-term impacts of repeated antibiotic use on intestinal mucus function. While a healthy mucus layer protects the intestinal epithelium against infection and inflammation, usingex-vivomucus function analyses of viable colonic tissue explants, we show that microbiota from humans with a history of repeated antibiotic use causes reduced mucus growth rate and increased mucus penetrability compared to healthy controls in the transplanted mice. Moreover, shotgun metagenomic sequencing identified a significantly altered microbiota composition in the antibiotic-shaped microbial community, with known mucus-utilising bacteria, includingAkkermansia muciniphilaandBacteroides fragilis, dominating in the gut. The altered microbiota composition was further characterised by a distinct metabolite profile, which may be caused by differential mucus degradation capacity. Consequently, our findings suggest that long-term antibiotic use in humans results in an altered microbial community that has reduced capacity to maintain proper mucus function in the gut.
DNA binding site II is required for RAD51 recombinogenic activity inArabidopsis thaliana
Authors: Petiot Valentine , White Charles , Ines Olivier Da 
Published: March 2024

AbstractHomologous recombination is a major pathway for the repair of DNA double strand breaks, essential both to maintain genomic integrity and to generate genetic diversity. Mechanistically, homologous recombination involves the use of a homologous DNA molecule as a template to repair the break. In eukaryotes, the search for and invasion of the homologous DNA molecule is carried out by two recombinases, RAD51 in somatic cells and RAD51 and DMC1 in meiotic cells. During recombination, the recombinases bind overhanging single-stranded DNA ends to form a nucleoprotein filament, which is the active species in promoting DNA invasion and strand exchange. RAD51 and DMC1 carry two major DNA binding sites - essential for nucleofilament formation and DNA strand exchange, respectively. Here, we show that the function of RAD51 DNA binding Site II is conserved in the plant, Arabidopsis. Mutation of three key amino acids in Site II does not affect RAD51 nucleofilament formation but inhibits its recombinogenic activity, analogous to results from studies of the yeast and human proteins. We further confirm that recombinogenic function of RAD51 DNA binding site II is not required for meiotic DSB repair when DMC1 is present. The Arabidopsis RAD51-II3A separation of function mutant shows a dominant negative phenotype, pointing to distinct biochemical properties of eukaryotic RAD51 proteins.Summary blurbThe activity promoted by RAD51 DNA binding site II is not required for nucleofilament formation, but is essential for subsequent invasion and strand exchange activity of RAD51 inArabidopsis thaliana.
Mapping the mutational landscape of a full viral proteome reveals distinct profiles of mutation tolerability
Authors: Álvarez-Rodríguez Beatriz , Velandia-Álvarez Sebastian , Toft Christina , Geller Ron 
Published: March 2024

SUMMARYRNA viruses have notoriously high mutation rates due to error-prone replication by their RNA polymerase. However, natural selection concentrates variability in a few key viral proteins. To test whether this stems from different mutation tolerance profiles among viral proteins, we measured the effect of >40,000 non-synonymous mutations across the full proteome of coxsackievirus B3 as well as >97% of all codon deletions in the non-structural proteins. We find significant variation in mutational tolerance within and between individual viral proteins, which correlated with both general and protein-specific structural and functional attributes. Further, mutational fitness effects remained largely constant across cell lines, highlighting conserved selection pressures. In addition to providing a rich dataset for understanding virus biology and evolution, our results illustrate that incorporation of mutational tolerance data into druggable pocket discovery can aid in selecting targets with high barriers to drug resistance.
Pinhole camera for electron beam size diagnostic at storage ring with an ultralow emittance
Authors: Trebushinin Andrei , Geloni Gianluca , Serkez Svitozar , Khubbutdinov Ruslan , Saldin Evgeny 
Published: March 2024

In this work, we propose to use a pinhole camera at high photon energies, specifically 200–300 keV, to measure ultra-small electron beam size by means of bending magnet radiation. We show that there is a sufficient photon flux at the detector position. Our theoretical analysis includes an examination of the applicability of the van Cittert-Zernike theorem for the bending magnet radiation generated by an ultralow emittance electron beam and a detailed analysis of the imaging properties of rectangular pinhole cameras. This led us to practical, universal formulas. We identify the optimal aperture size and resolution of the camera in the given geometry. The theoretical findings are further substantiated by wavefront propagation numerical simulations of partially coherent radiation. This study serves both as a practical guide for optical engineering and an educational resource for explaining the imaging properties of pinhole cameras.

Published by the American Physical Society
2024
A bibliometric review of IFRS adoption and compliance research in Africa
Authors: Effah Nana Adwoa Anokye 
Published: March 2024

PurposeThis article aims to identify and review existing studies on the adoption and compliance of International Financial Reporting Standards (IFRS) in Africa.Design/methodology/approachThe methodology involves a sole focus on studies conducted with an African sample, using a bibliometric method and data from the Web of Science (WoS) database. Visualizations from VOSViewer and Biblioshiny software are employed to identify the dominant authors, journals and countries contributing to research in the region.FindingsThe findings reveal existing collaborations among authors in the field. However, the study emphasizes the need for additional research to enhance the intellectual structure of the research domain, as the majority of related documents are concentrated within twenty articles with at least one citation.Practical implicationsThe practical implications underscore the importance of collaboration in practice, emphasizing the need for cooperation among corporations, experts and regulatory agencies involved in IFRS adoption and compliance in Africa. By fostering collaborative efforts and knowledge-sharing among corporations, experts and regulatory agencies, practitioners can enhance their understanding, streamline implementation processes and improve compliance methods.Originality/valueThis review is one of the few to explicitly conduct a bibliometric review of IFRS adoption and compliance studies in Africa, providing a foundation for future research to determine the current direction of IFRS studies in this region.
External pressure, internal managerial interpretation and green entrepreneurial orientation
Authors: Zhang Xiu-e , Yang Liu , Teng Xinyu , Li Yijing 
Published: March 2024

PurposeBased on the attention-based view (ABV), this study examines the mechanism of external pressure and internal managerial interpretation affecting the promotion of green entrepreneurial orientation (GEO) of agricultural enterprises.Design/methodology/approachBased on data collected from 208 agricultural enterprises in China, the conceptual model was tested by using hierarchical regression.FindingsThe results show that managerial interpretation can affect the promotion of GEO. Command and control regulation, market-based regulation and green market pressure are important external pressures that affect the promotion of GEO. In addition, managerial interpretation mediates the relationship between command and control regulation and GEO, market-based regulation and GEO, as well as green market pressure and GEO.Practical implicationsThis study proposes a key path for promoting the adoption and implementation of GEO by agricultural enterprises. The research results provide experience for emerging and developing countries to promote the GEO of agricultural enterprises, which is helpful to alleviate the environmental problems caused by the development of agricultural enterprises.Originality/valueFor the first time, this study introduced the ABV into the research of GEO. The research results enrich the theoretical perspective of GEO and expand the research field of the ABV. In addition, this study fills the research gap that existing research has not paid enough attention to the internal driving factors of GEO and opens the black box between the external pressure and GEO.
Comparative genomics reveals the adaptation of ammonia‐oxidising Thaumarchaeota to arid soils
Authors: Li Chaonan , Liao Haijun , Xu Lin , Wang Changting , Yao Minjie , Wang Junming , Li Xiangzhen 
Published: March 2024

AbstractThaumarchaeota are predominant in oligotrophic habitats such as deserts and arid soils, but their adaptations to these arid conditions are not well understood. In this study, we assembled 23 Thaumarchaeota genomes from arid and semi‐arid soils collected from the Inner Mongolia Steppe and the Qinghai‐Tibet Plateau. Using a comparative genomics approach, integrated with 614 Thaumarchaeota genomes from public databases, we identified the traits and evolutionary forces that contribute to their adaptations to aridity. Our results showed that the newly assembled genomes represent an early diverging group within the lineage of ammonia‐oxidising Thaumarchaeota. While the genomic functions previously identified in arid soil lineages were conserved across terrestrial, shallow‐ocean and deep‐ocean lineages, several traits likely contribute to Thaumarchaeota's adaptation to aridity. These include chlorite dismutase, arsenate reductase, V‐type ATPase and genes dealing with oxidative stresses. The acquisition and loss of traits at the last common ancestor of arid soil lineages may have facilitated the specialisation of Thaumarchaeota in arid soils. Additionally, the acquisition of unique adaptive traits, such as a urea transporter, Ca2+:H+ antiporter, mannosyl‐3‐phosphoglycerate synthase and phosphatase, DNA end‐binding protein Ku and phage shock protein A, further distinguishes arid soil Thaumarchaeota. This study provides evidence for the adaptations of Thaumarchaeota to arid soil, enhancing our understanding of the nitrogen and carbon cycling driven by Thaumarchaeota in drylands.