bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach
Authors: Shikder Mita , Ahmed Kazi Ahsan , Moin Abu Tayab , Patil Rajesh B. , Hasib Tasnin Al , Hossan Mohammad Imran , Mahasin Deera , Sakib Mohammad Najmul , Ahmed Iqrar , Patel Harun , Chowdhury Afrin Sultana 
Published: June 2023

AbstractThe coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory illness that has become a global health crisis with new variants, an unprecedented number of infections, and deaths and demands urgent manufacturing of potent therapeutics. Despite the success of vaccination campaigns around the globe, there is no particular therapeutics approved to date for efficiently treating infected individuals. Repositioning or repurposing previously effective antivirals against RNA viruses to treat COVID-19 patients is a feasible option. Remdesivir is a broad-spectrum antiviral drug that the Food and Drug Administration (FDA) licenses for treating COVID-19 patients who are critically ill patients. Remdesivir’s low efficacy, which has been shown in some clinical trials, possible adverse effects, and dose-related toxicities are issues with its use in clinical use. Our study aimed to design potent derivatives of remdesivir through the functional group modification of the parent drug targeting RNA-dependent RNA polymerase (RdRp) and main protease (MPro) of SARS-CoV-2. The efficacy and stability of the proposed derivatives were assessed by molecular docking and extended molecular dynamics simulation analyses. Furthermore, the pharmacokinetic activity was measured to ensure the safety and drug potential of the designed derivatives. The derivatives were non-carcinogenic, chemically reactive, highly interactive, and stable with the target proteins. D-CF3 is one of the designed derivatives that finally showed stronger interaction than the parent drug, according to the docking and dynamics simulation analyses, with both target proteins. However,in vitroandin vivoinvestigations are guaranteed to validate the findings in the future.
Fungal small RNAs ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis
Authors: He Baoye , Wang Huan , Liu Guosheng , Chen Angela , Calvo Alejandra , Cai Qiang , Jin Hailing 
Published: June 2023

AbstractSmall RNAs (sRNAs) of the fungal pathogenBotrytis cinereacan enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate thatB. cinereautilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). TheB. cinereatetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerousArabidopsisclathrin-coated vesicles (CCVs) aroundB. cinereainfection sites and the colocalization ofB. cinereaEV marker BcPLS1 andArabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and theB. cinerea-secreted sRNAs are detected in purified CCVs after infection.Arabidopsisknockout mutants and inducible dominant-negative mutants of key components of CME pathway exhibit increased resistance toB. cinereainfection. Furthermore, Bc-sRNA loading intoArabidopsisAGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.
SARS-CoV-2 Delta Variant Remains Viable in Environmental Biofilms found in Meat Packaging Plants
Authors: Featherstone Austin B. , Mathijssen Arnold J. T. M. , Brown Amanda , Chitlapilly Dass Sapna 
Published: June 2023

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a coronavirus that directly infects human airway epithelial cells and caused the COVID-19 pandemic. At the start of the pandemic in 2020, meat-packaging plants saw a surge in SARS-CoV-2 cases, which forced many to temporarily close. To determine why SARS-CoV-2 appears to thrive specifically well in meat packaging plants, we used SARS-CoV-2 Delta variant and meat packaging plant drain samples to develop mixed-species biofilms on materials commonly found within meat packaging plants (stainless steel (SS), PVC, and ceramic tile). Our data provides evidence that SARS-CoV-2 Delta variant remained viable on all the surfaces tested with and without an environmental biofilm. We observed that SARS-CoV-2 Delta variant was able to remain infectious with each of the environmental biofilms, however, we detected a significant reduction in viability post-exposure to Plant B biofilm on SS, PVC, and on ceramic tile chips, and to Plant C biofilm on SS and PVC chips. The numbers of viable SARS-CoV-2 Delta viral particles was 1.81 – 4.57-fold high than the viral inoculum incubated with the Plant B and Plant C environmental biofilm on SS, and PVC chips. We did not detect a significant difference in viability when SARS-CoV-2 Delta variant was incubated with the biofilm obtained from Plant A on any of the materials tested and SARS-CoV-2 Delta variant had higher plaque numbers when inoculated with Plant C biofilm on tile chips, with a 2.75-fold difference compared to SARS-CoV-2 Delta variant on tile chips by itself. In addition, we detected an increase in the biofilm biovolume in response to SARS-CoV-2 Delta variant which is also a concern for food safety due to the potential for foodborne pathogens to respond likewise when they come into contact with the virus. These results indicate a complex virus-environmental biofilm interaction which correlates to the different bacteria found in each biofilm. Our results also indicate that there is the potential for biofilms to protect SARS-CoV-2 from disinfecting agents and remaining prevalent in meat packaging plants. With the highly infectious nature of some SARS-CoV-2 variants such as Delta, and more so with the Omicron variant, even a minimal amount of virus could have serious health implications for the spread and reoccurrence of SARS-CoV-2 outbreaks in meat packaging plants.
Comparative genomics of Japanese encephalitis virus shows low rates of recombination and a suite of sites under episodic diversifying selection
Authors: Sistrom Mark , Andrews Hannah , Edwards Danielle 
Published: June 2023

AbstractJapanese encephalitis virus (JEV) is the dominant cause of viral encephalitis in the Asian region with 100,000 cases and 25,000 deaths reported annually. The genome is comprised of a single polyprotein that encodes three structural and seven non-structural proteins. We collated a dataset of 347 complete genomes from a number of public databases, and analysed the data for recombination, evolutionary selection and phylogenetic structure. There are low rates of recombination in JEV, subsequently recombination is not a major evolutionary force shaping JEV. We found a strong overall signal of purifying selection in the genome, which is the main force affecting the evolutionary dynamics in JEV. There are also a small number of genomic sites under episodic diversifying selection, especially in the envelope protein and non-structural proteins 3 and 5. Overall, these results support previous analyses of JEV evolutionary genomics and provide additional insight into the evolutionary processes shaping the distribution and adaptation of this important pathogenic arbovirus.Author SummaryThis comparative study of Japanese Encephalitis Virus is the largest genomic analysis of the virus to date. We undertake a suite of analyses to investigate phylogenetic relationships, rates of recombination and patterns of genomic selection. We show that recombination is not a significant driver of evolution in JEV, demonstrate support for previous phylogenetic reconstructions of the virus, and find a number of sites across the genome under episodic diversifying selection. These adaptive hotspots of evolution serve as key genomic points for the adaptive evolution of this important vector borne pathogen.
CC+: A Searchable Database of Validated Coiled coils in PDB Structures and AlphaFold2 Models
Authors: Kumar Prasun , Petrenas Rokas , Dawson William M. , Schweke Hugo , Levy Emmanuel D. , Woolfson Derek N. 
Published: June 2023

ABSTRACTα-Helical coiled coils are common tertiary and quaternary elements of protein structure. In coiled coils, two or more α helices wrapped around each other to form bundles. This apparently simple structural motif can generate many architectures and topologies. Understanding the variety of and limits on coiled-coil assemblies and their sequence-to-structure relationships impacts on protein structure, design, and engineering. Coiled coil-forming sequences can be predicted from heptad repeats of hydrophobic and polar residues,hpphppp, although this is not always reliable. Alternatively, coiled-coil structures can be identified using the program SOCKET, which finds knobs-into-holes (KIH) packing between side chains of neighboring helices. SOCKET also classifies coiled-coil architecture and topology, thus allowing sequence-to-structure relationships to be garnered. In 2009, we used SOCKET to create a relational database of coiled-coil structures, CC+, from the RCSB Protein Data Bank (PDB). Here we report an update of CC+following the recent explosion of structural data and the success of AlphaFold2 in predicting protein structures from genome sequences. With the most-stringent SOCKET parameters, CC+contains ≈12,000 coiled-coil assemblies from experimentally determined structures, and ≈120,000 potential coiled-coil structures within single-chain models predicted by AlphaFold2 across 48 proteomes. CC+allows these and other less-stringently defined coiled coils to be searched at various levels of structure, sequence, and side-chain interactions. The identified coiled coils can be viewed directly from CC+using the Socket2 application, and their associated data can be downloaded for further analyses. CC+is available freely athttp://coiledcoils.chm.bris.ac.uk/CCPlus/Home.html. It will be regularly updated automatically.FOR THE BROADER AUDIENCEProtein assemblies and protein-protein interactions are key to all biological processes. α-Helical coiled coils are one of the most common modes of directing and stabilising these interfaces. Here, we report an updated CC+database of structurally validated coiled coils from experimental protein structures and AlphaFold2 models. CC+contains many thousands of coiled-coil structures and models, associated parameters, and sequences. It enables the compilation of rich datasets for advancing protein structure, design, and engineering research.
FixNCut: Single-cell genomics through reversible tissue fixation and dissociation
Authors: Jiménez-Gracia Laura , Marchese Domenica , Nieto Juan C. , Caratù Ginevra , Melón-Ardanaz Elisa , Gudiño Victoria , Roth Sara , Wise Kellie , Ryan Natalie K , Jensen Kirk B. , Hernando-Momblona Xavier , Bernardes Joana P. , Tran Florian , Sievers Laura Katharina , Schreiber Stefan , van den Berge Maarten , Kole Tessa , van der Velde Petra L. , Nawijn Martijn C. , Rosenstiel Philip , Batlle Eduard , Butler Lisa M. , Parish Ian A. , Plummer Jasmine , Gut Ivo , Salas Azucena , Heyn Holger , Martelotto Luciano G. 
Published: June 2023

AbstractThe use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.
Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2
Authors: Goradia Nishit , Werner Stefan , Mullapudi Edukondalu , Greimeier Sarah , Merkens Lina , Lang Andras , Mertens Haydyn , Węglarz Aleksandra , Sander Simon , Chojnowski Grzegorz , Wikman Harriet , Ohlenschläger Oliver , von Amsberg Gunhild , Pantel Klaus , Wilmanns Matthias 
Published: June 2023

AbstractWhile the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities.
Bacterial tolerance to host-exuded specialized metabolites structures the maize root microbiome
Authors: Thoenen Lisa , Giroud Caitlin , Kreuzer Marco , Waelchli Jan , Gfeller Valentin , Deslandes-Hérold Gabriel , Mateo Pierre , Robert Christelle A.M. , Ahrens Christian H. , Rubio-Somoza Ignacio , Bruggmann Rémy , Erb Matthias , Schlaeppi Klaus 
Published: June 2023

AbstractPlants exude specialized metabolites from their roots and these compounds are known to structure the root microbiome. However, the underlying mechanisms are poorly understood. We established a representative collection of maize root bacteria and tested their tolerance against benzoxazinoids, the dominant specialized and bioactive metabolites in the root exudates of maize plants.In vitroexperiments revealed that benzoxazinoids inhibited bacterial growth in a strain- and compound-dependent manner. Tolerance against these selective antimicrobial compounds depended on bacterial cell wall structure. Further, we found that native root bacteria isolated from maize tolerated the benzoxazinoids better compared to non-host Arabidopsis bacteria. This finding suggests the adaptation of the root bacteria to the specialized metabolites of their host plant. Bacterial tolerance to 6-methoxy-benzoxazolin-2-one (MBOA), the most abundant and selective antimicrobial metabolite in the maize rhizosphere, correlated significantly with the abundance of these bacteria on benzoxazinoid-exuding maize roots. Thus, strain-dependent tolerance to benzoxazinoids largely explained the abundance pattern of bacteria on maize roots. Abundant bacteria generally tolerated MBOA, while low abundant root microbiome members were sensitive to this compound. Our findings reveal that tolerance to plant specialized metabolites is an important competence determinant for root colonization. We propose that bacterial tolerance to plant-secreted antimicrobial compounds is an underlying mechanism determining the structure of host-specific microbial communities.Significance StatementDiverse microbial communities colonize plant roots. They feed on carbon rich root exudates which contain a diverse mix of chemicals including primary and specialized metabolites. Here we show that specialized metabolites act as selective antibiotics to shape the root bacterial communities. By growing single isolates of maize root bacteria in the presence of benzoxazinoidsin vitro, we find that the strains differ greatly in their tolerance to benzoxazinoids. Their different levels of tolerance largely explained their abundance on benzoxazinoid-exuding roots. Our work shows how plant specialized metabolites act to shape the maize root microbial community and thus deepened our mechanistic understanding of how plants shape their microbiome.
Warming affects routine swimming activity and novel odour molecular response in larval zebrafish
Authors: Sourisse Jade M. , Bonzi Lucrezia C. , Semmelhack Julie , Schunter Celia 
Published: June 2023

AbstractTemperature is a primary factor affecting the survival, development, and physiology of aquatic ectothermic animals and global warming of water bodies may therefore impact several biological levels of aquatic life. Understanding the effects of near-future predicted temperature changes on the behaviour and the underlying molecular mechanisms of aquatic animals is of particular importance, since behaviour mediates key interactions and, in turn, population dynamics. In this study, we investigate the effects of elevated developmental temperature on locomotor behaviour and olfactory learning in the zebrafish,Danio rerio. We exposed zebrafish from cleavage embryonic stage to either current day control (28°C) or predicted future elevated temperature (30°C) for seven days. Overall, warming reduced the total routine swimming distance and caused the upregulation of a small number of genes involved in metabolism and neuron development, suggesting accelerated development at elevated temperature. When fish were exposed to two different olfactory cues, namely catfish cue, a non-alarming but novel odour, and injured conspecifics alarm cue expected to cause a fear reaction, warming differently affected larvae response to the two cues. In particular, a large transcriptional reprogramming was observed at elevated temperature in response to novel odour exposure, with upregulation of cell signalling, neuron development and neuron functioning genes. As this response was coupled with downregulation of genes involved in protein translation and ATP metabolism, it indicates that novel odour recognition in future-predicted thermal conditions will require energetic trade-offs between expensive baseline processes and responsive functions. To also evaluate their learning abilities at both temperatures, 7 days post fertilization (dpf) zebrafish were conditioned with a mixture of injured conspecifics alarm cue and non-alarming catfish cue. Regardless of temperature, no behavioural (freezing) nor gene expression changes were detected, reinforcing our previous findings that warming mainly affects zebrafish molecular response to novel odours. Overall, our results show that future thermal conditions will likely impact developing stages, causing energy trade-offs following olfactory detection of novel substances in the environment.
The role of GpsB in cell morphogenesis ofStaphylococcus aureus
Authors: Costa Sara F. , Saraiva Bruno M. , Veiga Helena , Marques Leonor B. , Schäper Simon , Sporniak Marta , Vega Daniel E. , Jorge Ana M. , Duarte Andreia M. , Brito António D. , Tavares Andreia C. , Reed Patricia , Pinho Mariana G. 
Published: June 2023

AbstractFor decades, cells of the gram-positive bacterial pathogenStaphylococcus aureuswere thought to lack a dedicated elongation machinery. However,S. aureuscells were recently shown to elongate before division, in a process that requires a SEDS (Shape Elongation Division and Sporulation) / PBP (Penicillin Binding Protein) pair for peptidoglycan synthesis, consisting of the glycosyltransferase RodA and the transpeptidase PBP3. In ovococci and rod-shaped bacteria the elongation machinery, known as elongasome, is composed of various proteins besides a dedicated SEDS/PBP pair. To identify proteins involved in the elongation ofS. aureus, we screened the Nebraska Transposon Mutant Library, which contains transposon mutants in virtually all non-essential staphylococcal genes, for mutants with modified cell shape. We confirmed the roles of RodA/PBP3 inS. aureuselongation and identified GpsB, SsaA, and RodZ as additional proteins involved in this process. ThegpsBmutant showed the strongest phenotype, mediated by the partial delocalization from the division septum of PBP2, the only bifunctional PBP inS. aureus, with both glycosyltransferase and transpeptidase activity, and of the PBP4 transpeptidase. Increased levels of these PBPs at the cell periphery result in higher levels of peptidoglycan insertion throughout the entire cell, overriding the RodA/PBP3-mediated peptidoglycan synthesis at the outer edge of the septum, which leads to cell elongation. As a consequence, in the absence of GpsB,S. aureuscells become more spherical.
Auditory cortex anatomy reflects multilingual phonological experience
Authors: Kepinska Olga , Dalboni da Rocha Josue , Tuerk Carola , Hervais-Adelman Alexis , Bouhali Florence , Green David W. , Price Cathy J. , Golestani Narly 
Published: June 2023

ABSTRACTThis study explores the relationship between the anatomy of the auditory cortex and multilingual experience, shedding light on the complex mechanisms of auditory processing in humans. Integrating previous research on auditory information processing and the impact of bi- and multilingualism on brain structure, we investigate how the morphology of auditory brain regions reflects individuals’ language experience and, more specifically, their phonological repertoire. Leveraging two distinct samples comprising over 200 participants, each exposed to between 1 and 7 languages encompassing 36 different languages, we explore whether the morphological variability of auditory brain regions reflects individual language experience, specifically focusing on the phonological repertoire. Additionally, we examine the potential influence of typological distances between languages spoken by multilingual individuals on the neural signatures of multilingualism within the auditory cortex. Our findings revealed a relationship between the average thickness of the left and right second transverse temporal gyrus (TTG) and participants’ language experience. Model comparisons demonstrated that the inclusion of phoneme-level information in the language experience index accounted for the greatest variance in average TTG thickness (bilaterally). The direction of this effect was negative, indicating that a more extensive and more phonologically diverse language experience was associated with thinner cortices in the second TTG. Across two independent datasets, we provide robust evidence linking the degree of language experience and typological distance between languages to cortical thickness in early auditory brain regions. We propose that this phenomenon may reflect experience-driven pruning and neural efficiency, warranting further investigation through longitudinal studies of language acquisition. Moreover, our findings support the notion that experiences with typologically similar languages differ from those with typologically distant languages, offering valuable insights into the intricate relationship between language diversity and brain structure. Our findings also indicate that early auditory regions seem to represent phoneme-level cross-linguistic information, contrary to the most established models of language processing in the brain, which suggest that phonological processing happens in more lateral posterior STG and STS.