Viral pores are everywhere.

Jones et al. (2021) and Zhang et al. (2021) reveal by cryo-EM the oligomeric crown-like structure formed by a membrane-associated Chikungunya virus replication protein that gates the export of newly synthesized viral RNA from viral replication organelles.

The European Nucleotide Archive in 2023.

The European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena) is maintained by the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI). The ENA is one of the three members of the International Nucleotide Sequence Database Collaboration (INSDC). It serves the bioinformatics community worldwide via the submission, processing, archiving and dissemination of sequence data. The ENA supports data types ranging from raw reads, through alignments and assemblies to functional annotation. The data is enriched with contextual information relating to samples and experimental configurations. In this article, we describe recent progress and improvements to ENA services. In particular, we focus upon three areas of work in 2023: FAIRness of ENA data, pandemic preparedness and foundational technology. For FAIRness, we have introduced minimal requirements for spatiotemporal annotation, created a metadata-based classification system, incorporated third party metadata curations with archived records, and developed a new rapid visualisation platform, the ENA Notebooks. For foundational enhancements, we have improved the INSDC data exchange and synchronisation pipelines, and invested in site reliability engineering for ENA infrastructure. In order to support genomic surveillance efforts, we have continued to provide ENA services in support of SARS-CoV-2 data mobilisation and have adapted these for broader pathogen surveillance efforts.

Lagrangian stretching reveals stress topology in viscoelastic flows.

Viscoelastic flows are pervasive in a host of natural and industrial processes, where the emergence of nonlinear and time-dependent dynamics regulates flow resistance, energy consumption, and particulate dispersal. Polymeric stress induced by the advection and stretching of suspended polymers feeds back on the underlying fluid flow, which ultimately dictates the dynamics, instability, and transport properties of viscoelastic fluids. However, direct experimental quantification of the stress field is challenging, and a fundamental understanding of how Lagrangian flow structure regulates the distribution of polymeric stress is lacking. In this work, we show that the topology of the polymeric stress field precisely mirrors the Lagrangian stretching field, where the latter depends solely on flow kinematics. We develop a general analytical expression that directly relates the polymeric stress and stretching in weakly viscoelastic fluids for both nonlinear and unsteady flows, which is also extended to special cases characterized by strong kinematics. Furthermore, numerical simulations reveal a clear correlation between the stress and stretching field topologies for unstable viscoelastic flows across a broad range of geometries. Ultimately, our results establish a connection between the Eulerian stress field and the Lagrangian structure of viscoelastic flows. This work provides a simple framework to determine the topology of polymeric stress directly from readily measurable flow field data and lays the foundation for directly linking the polymeric stress to flow transport properties.

A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.

ProsmORF-pred: a machine learning-based method for the identification of small ORFs in prokaryotic genomes.

Small open reading frames (smORFs) encoding proteins less than 100 amino acids (aa) are known to be important regulators of key cellular processes. However, their computational identification remains a challenge. Based on a comprehensive analysis of known prokaryotic small ORFs, we have developed the ProsmORF-pred resource which uses a machine learning (ML)-based method for prediction of smORFs in the prokaryotic genome sequences. ProsmORF-pred consists of two ML models, one for initiation site recognition in nucleic acid sequences upstream of putative start codons and the other uses translated amino acid sequences to decipher functional protein like sequences. The nucleotide sequence-based initiation site recognition model has been trained using longer ORFs (>100 aa) in the same genome while the ML model for identification of protein like sequences has been trained using annotated smORFs from Escherichia coli. Comprehensive benchmarking of ProsmORF-pred reveals that its performance is comparable to other state-of-the-art approaches on the annotated smORF set derived from 32 prokaryotic genomes. Its performance is distinctly superior to other tools like PRODIGAL and RANSEPS for prediction of newly identified smORFs which have a length range of 10-30 aa, where prediction of smORFs has been a major challenge. Apart from identification of smORFs in genomic sequences, ProsmORF-pred can also aid in functional annotation of the predicted smORFs based on sequence similarity and genomic neighbourhood similarity searches in ProsmORFDB, a well-curated database of known smORFs. ProsmORF-pred along with its backend database ProsmORFDB is available as a user-friendly web server (http://www.nii.ac.in/prosmorfpred.html).

Association of the C allele of rs479200 in the EGLN1 gene with COVID-19 severity in Indian population: a novel finding.

The present study investigated two single nucleotide polymorphisms (SNPs)-rs479200 and rs516651 in the host EGLN1/PHD2 gene for their association with COVID-19 severity. A retrospective cohort of 158 COVID-19 patients from the Indian population (March 2020 to June 2021) was enrolled. Notably, the frequency of C allele (0.664) was twofold higher than T allele (0.336) in severe COVID-19 patients. Here, we report a novel finding that the C allele of rs479200 in the EGLN1 gene imparts a high risk of severe COVID-19 (odds ratio-6.214 (1.84-20.99) p = 0.003; 9.421 (2.019-43.957) p = 0.004), in additive inheritance model (adjusted and unadjusted, respectively).

The European Nucleotide Archive in 2022.

The European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena), maintained by the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI), offers those producing data an open and supported platform for the management, archiving, publication, and dissemination of data; and to the scientific community as a whole, it offers a globally comprehensive data set through a host of data discovery and retrieval tools. Here, we describe recent updates to the ENA's submission and retrieval services as well as focused efforts to improve connectivity, reusability, and interoperability of ENA data and metadata.

A long noncoding RNA influences the choice of the X chromosome to be inactivated.

X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element (Xce). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA, one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist. This effect is counteracted by enhanced binding of Rex1 in DxPas34, another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34, and that Lppnx represents a decisive factor in explaining the action of the Xce.

Atomic Reconstruction of Au Thin Films through Interfacial Strains.

Interfaces play a critical thermodynamic role in the existence of multilayer systems. Due to their utility in bridging energetic and compositional differences between distinct species, the formation of interfaces inherently creates internal strain in the bulk due to the reorganization needed to accommodate such a change. We report the effect of scaling interfacial stress by deposition of different adlayers on a host thin metal film. Intrinsic property differences between host and deposited metal atoms result in varying degree of composition and energy gradient within the interface. Interfacial stress can increase defects in the host leading to (i) energy dissipation and reorganization to minimize surface energy, and (ii) increased material strength. We infer that dissipation of interfacial stress induces defect migration, hence bulk and surface atomic reconstruction as captured by the surface roughness and grain size reduction coupled with a concomitant increase in material strength.

Sarcopenia and Cardiovascular Diseases.

Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.

Transcriptome responses of Arabidopsis to necrotrophic fungus Alternaria brassicae reveal pathways and candidate genes associated with resistance.

Alternaria leaf blight (ALB), caused by a necrotrophic fungus Alternaria brassicae is a serious disease of oleiferous Brassicas resulting in significant yield losses worldwide. No robust resistance against A. brassicae has been identified in the Brassicas. Natural accessions of Arabidopsis show a spectrum of responses to A. brassicae ranging from high susceptibility to complete resistance. To understand the molecular mechanisms of resistance/ susceptibility, we analysed the comparative changes in the transcriptome profile of Arabidopsis accessions with contrasting responses- at different time points post-infection. Differential gene expression, GO enrichment, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) revealed reprogramming of phenylpropanoid biosynthetic pathway involving lignin, hydroxycinnamic acids, scopoletin, anthocyanin genes to be highly associated with resistance against A. brassicae. T-DNA insertion mutants deficient in the biosynthesis of coumarin scopoletin exhibited enhanced susceptibility to A. brassicae. The supplementation of scopoletin to medium or exogenous application resulted in a significant reduction in the A. brassicae growth. Our study provides new insights into the transcriptome dynamics in A. brassicae-challenged Arabidopsis and demonstrates the involvement of coumarins in plant immunity against the Brassica pathogen A. brassicae.

On-Surface Synthesis of a Radical 2D Supramolecular Organic Framework.

The design of supramolecular organic radical cages and frameworks is one of the main challenges in supramolecular chemistry. Their interesting material properties and wide applications make them very promising for (photo)redox catalysis, sensors, or host-guest spin-spin interactions. However, the high reactivity of radical organic systems makes the design of such supramolecular radical assemblies challenging. Here, we report the on-surface synthesis of a purely organic supramolecular radical framework on Au(111), by combining supramolecular and on-surface chemistry. We employ a tripodal precursor, functionalized with 7-azaindole groups that, catalyzed by a single gold atom on the surface, forms a radical molecular product constituted by a π-extended fluoradene-based radical core. The radical products self-assemble through hydrogen bonding, leading to extended 2D domains ordered in a Kagome-honeycomb lattice. This approach demonstrates the potential of on-surface synthesis for developing 2D supramolecular radical organic chemistry.

GABAergic implications in anxiety and related disorders.

Evidence indicates that anxiety disorders arise from an imbalance in the functioning of brain circuits that govern the modulation of emotional responses to possibly threatening stimuli. The circuits under consideration in this context include the amygdala's bottom-up activity, which signifies the existence of stimuli that may be seen as dangerous. Moreover, these circuits encompass top-down regulatory processes that originate in the prefrontal cortex, facilitating the communication of the emotional significance associated with the inputs. Diverse databases (e.g., Pubmed, ScienceDirect, Web of Science, Google Scholar) were searched for literature using a combination of different terms e.g., "anxiety", "stress", "neuroanatomy", and "neural circuits", etc. A decrease in GABAergic activity is present in both anxiety disorders and severe depression. Research on cerebral functional imaging in depressive individuals has shown reduced levels of GABA within the cortical regions. Additionally, animal studies demonstrated that a reduction in the expression of GABAA/B receptors results in a behavioral pattern resembling anxiety. The amygdala consists of inhibitory networks composed of GABAergic interneurons, responsible for modulating anxiety responses in both normal and pathological conditions. The GABAA receptor has allosteric sites (e.g., α/γ, γ/ß, and α/ß) which enable regulation of neuronal inhibition in the amygdala. These sites serve as molecular targets for anxiolytic medications such as benzodiazepine and barbiturates. Alterations in the levels of naturally occurring regulators of these allosteric sites, along with alterations to the composition of the GABAA receptor subunits, could potentially act as mechanisms via which the extent of neuronal inhibition is diminished in pathological anxiety disorders.

Aminic Organoselenium Compounds as Glutathione Peroxidase Mimics and Inhibitors of Ferroptosis.

The synthesis of diarylamine-based organoselenium compounds via the nucleophilic substitution reactions has been described. Symmetrical monoselenides and diselenides were conveniently synthesized by the reduction of their corresponding selenocyanates using sodium borohydride. Selenocyanates were obtained from 2-chloro acetamides by the nucleophilic displacement with potassium selenocyanate. Selenides were synthesized by treating the 2-chloro acetamides with in situ generated sodium butyl selenolate as nucleophile. Further, the newly synthesized organoselenium compounds were evaluated for their glutathione peroxidase (GPx)-like activity in thiophenol assay. This study revealed that the methoxy-substituted organoselenium compounds showed significant effect on the GPx-like activity. The catalytic parameters for the most efficient catalysts were also determined. The anti-ferroptotic activity for all GPx-mimics evaluated in a 4-OH-tamoxifen (TAM) inducible GPx4 knockout cell line using liproxstatin as standard.

AFRbase: a database of protein mutations responsible for antifungal resistance.

MOTIVATION: Fungal pathogens are known to cause life threatening invasive infections with rising global mortality rates. Besides, the indiscriminate use of antifungals in both clinics and agriculture has promoted antifungal drug resistance in the last decade. Fungi can show drug resistance by a variety of mechanisms. But primary driver in all these hitherto documented mechanisms is stable and heritable point mutations in the key proteins. Therefore, cataloguing mutations that can confer resistance is the first step toward understanding the mechanisms leading to the emergence of antifungal resistance. RESULTS: In the present, work we have described a database of all the mutations responsible for antifungal resistance. Named as antifungal resistance database (AFRbase), it is better than the existing databases of antifungal resistance namely, FunResDB and MARDy which have a limited scope and inadequate information. Data of AFRbase was collected using both text mining and manual curation. AFRbase provides a separate window for visualization of mutations in the 2D and 3D formats making it easy for researchers to analyze the mutation data and ensures interoperability with other standard molecular biology databases like NCBI and UniProtKB. We hope AFRbase can be useful to both clinicians and basic biomedical scientists as we envision it as an important resource for genotypic susceptibility testing of fungi and to study/predict the course of evolution of antifungal resistance. The current version of AFRbase contains manually curated 3691 unique mutations present in 29 proteins of 32 fungal species along with the information of drugs against which resistance is caused. AVAILABILITY AND IMPLEMENTATION: AFRbase is an open access database available at http://proteininformatics.org/mkumar/afrbase/.

RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.

BACKGROUND: Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. METHODS: Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. RESULTS: Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. CONCLUSION: Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.

Instabilities and self-organization in spatiotemporal epidemic dynamics driven by nonlinearity and noise.

Theoretical analysis of epidemic dynamics has attracted significant attention in the aftermath of the COVID-19 pandemic. In this article, we study dynamic instabilities in a spatiotemporal compartmental epidemic model represented by a stochastic system of coupled partial differential equations (SPDE). Saturation effects in infection spread-anchored in physical considerations-lead to strong nonlinearities in the SPDE. Our goal is to study the onset of dynamic, Turing-type instabilities, and the concomitant emergence of steady-state patterns under the interplay between three critical model parameters-the saturation parameter, the noise intensity, and the transmission rate. Employing a second-order perturbation analysis to investigate stability, we uncover both diffusion-driven and noise-induced instabilities and corresponding self-organized distinct patterns of infection spread in the steady state. We also analyze the effects of the saturation parameter and the transmission rate on the instabilities and the pattern formation. In summary, our results indicate that the nuanced interplay between the three parameters considered has a profound effect on the emergence of dynamical instabilities and therefore on pattern formation in the steady state. Moreover, due to the central role played by the Turing phenomenon in pattern formation in a variety of biological dynamic systems, the results are expected to have broader significance beyond epidemic dynamics.

Cholesterol Lowering in Older Adults: Should We Wait for Further Evidence?

PURPOSE OF REVIEW: Current guidelines for primary and secondary prevention of cardiovascular events in adults up to age 75 years are well-established. However, recommendations for lipid-lowering therapies (LLT), particularly for primary prevention, are inconclusive after age 75. In this review, we focus on adults ≥ 75 years to assess low-density lipoprotein-cholesterol (LDL-C) as a marker for predicting atherosclerotic cardiovascular disease (ASCVD) risk, review risk assessment tools, highlight guidelines for LLT, and discuss benefits, risks, and deprescribing strategies. RECENT FINDINGS: The relationship between LDL-C and all-cause mortality and cardiovascular outcomes in older adults is complex and confounded. Current ASCVD risk estimators heavily depend on age and lack geriatric-specific variables. Emerging tools may reclassify individuals based on biologic rather than chronologic age, with coronary artery calcium scores gaining popularity. After initiating LLT for primary or secondary prevention, target LDL-C levels for older adults are lacking, and non-statin therapy thresholds remain unknown, relying on evidence from younger populations. Shared decision-making is crucial, considering therapy's time to benefit, life expectancy, adverse events, and geriatric syndromes. Deprescribing is recommended in end-of-life care but remains unclear in fit or frail older adults. After an ASCVD event, LLT is appropriate for most older adults, and deprescribing can be considered for those approaching the last months of life. Ongoing trials will guide statin prescription and deprescribing among older adults free of ASCVD. In the interim, for adults ≥ 75 years without a limited life expectancy who are free of ASCVD, an LLT approach that includes both lifestyle and medications, specifically statins, may be considered after shared decision-making.

The F-box protein encoding genes of the leaf-rust fungi Puccinia triticina: genome-wide identification, characterization and expression dynamics during pathogenesis.

The F-box proteins in fungi perform diverse functions including regulation of cell cycle, circadian clock, development, signal transduction and nutrient sensing. Genome-wide analysis revealed 10 F-box genes in Puccinia triticina, the causal organism for the leaf rust disease in wheat and were characterized using in silico approaches for revealing phylogenetic relationships, gene structures, gene ontology, protein properties, sequence analysis and gene expression studies. Domain analysis predicted functional domains like WD40 and LRR at C-terminus along with the obvious presence of F-box motif in N-terminus. MSA showed amino acid replacements, which might be due to nucleotide substitution during replication. Phylogenetic analysis revealed the F-box proteins with similar domains to be clustered together while some sequences were spread out in different clades, which might be due to functional diversity. The clustering of Puccinia triticina GG705409 with Triticum aestivum TaAFB4/TaAFB5 in a single clade suggested the possibilities of horizontal gene transfer during the coevolution of P. triticina and wheat. Gene ontological annotation categorized them into three classes and were functionally involved in protein degradation through the protein ubiquitination pathway. Protein-protein interaction network revealed F-box proteins to interact with other components of the SCF complex involved in protein ubiquitination. Relative expression analysis of five F-box genes in a time course experiment denoted their involvement in leaf rust susceptible wheat plants. This study provides information on structure elucidation of F-box proteins of a basidiomycetes plant pathogenic fungi and their role during pathogenesis.

Photostimulated Extended Nitric Oxide (NO) Release from Water-Soluble Block Copolymer to Enhance Antibacterial Activity.

N-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic N-nitrosamine-based block copolymers (BCPx-NO) are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm2). The water-soluble BCPx-NO forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92-160 µM within 11.5 h, which is 36.8-64.0% of the calculated value. To understand the NO release mechanism, a small molecular NO donor (NOD) resembling the NO releasing functional motif of BCPx-NO is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar BCPx-NO enhances antibacterial activity over NOD and exhibits a superior bactericidal effect on Gram-positive Staphylococcus aureus. In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity.