Mutational robustness

The brown dog tick or Rhipicephalus sanguineus sensu lato is an ixodid tick, responsible for the dissemination of pathogens that cause canine infectious diseases besides inflicting the direct effects of tick bite. The hot humid climate of Kerala, a south Indian state, is favorable for propagation of tick vectors and acaricides are the main stay of tick control. Though the resistance against synthetic pyrethroids is reported among these species, the status of amitraz resistance in R. sanguineus s. l. in the country is uncertain due to the lack of molecular characterization data and scarce literature reports...

UNLABELLED: Multi-resistant bacteria are a rapidly emerging threat to modern medicine. It is thus essential to identify and validate novel antibacterial targets that promise high robustness against resistance-mediating mutations. This can be achieved by simultaneously targeting several conserved function-determining protein-protein interactions in enzyme complexes from prokaryotic primary metabolism. Here, we selected two evolutionary related glutamine amidotransferase complexes, aminodeoxychorismate synthase and anthranilate synthase, that are required for the biosynthesis of folate and tryptophan in most prokaryotic organisms...

BACKGROUND: Tumor genetic anomalies and immune dysregulation are pivotal in the progression of multiple myeloma (MM). Accurate patient stratification is essential for effective MM management, yet current models fail to comprehensively incorporate both molecular and immune profiles. METHODS: We examined 776 samples from the MMRF CoMMpass database, employing univariate regression with LASSO and CIBERSORT algorithms to identify 15 p53-related genes and six immune cells with prognostic significance in MM...

In December 2023, we observed a notable shift in the COVID-19 landscape, when the JN.1 emerged as a predominant SARS-CoV-2 variant with a 95% incidence. We characterized the clinical profile, and genetic changes in JN.1, an emerging SARS-CoV-2 variant of interest. Whole genome sequencing was performed on SARS-CoV-2 positive samples, followed by sequence analysis. Mutations within the spike protein sequences were analyzed and compared with the previous lineages and sublineages of SARS-CoV-2, to identify the potential impact of these unique mutations on protein structure and possible functionality...

BACKGROUND: Influenza vaccine viruses grown in eggs may acquire egg-adaptive mutations that may reduce antigenic similarity between vaccine and circulating influenza viruses and decrease vaccine effectiveness. We compared cell- and egg-based quadrivalent influenza vaccines (QIVc and QIVe, respectively) for preventing test-confirmed influenza over 3 US influenza seasons (2017-2020). METHODS: Using a retrospective test-negative design, we estimated the relative vaccine effectiveness (rVE) of QIVc vs QIVe among individuals aged 4 to 64 years who had an acute respiratory or febrile illness and were tested for influenza in routine outpatient care...

We consider a single genetic locus with two alleles A1 and A2 in a large haploid population. The locus is subject to selection and two-way, or recurrent, mutation. Assuming the allele frequencies follow a Wright-Fisher diffusion and have reached stationarity, we describe the asymptotic behaviors of the conditional gene genealogy and the latent mutations of a sample with known allele counts, when the count n1 of allele A1 is fixed, and when either or both the sample size n and the selection strength |α| tend to infinity...

BACKGROUND: The cell endocrine pathway is a critical physiological process composed of the endoplasmic reticulum, Golgi apparatus and associated vesicles. Loss of enzymes or proteins can cause dysfunction of endoplasmic reticulum and Golgi apparatus and affect secretion pathways leading to a variety of human diseases, including cancer. METHODS: The single-cell RNA sequencing and single nucleotide variant principal component analysis data of ovarian cancer were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets...

OBJECTIVE: This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor potential in thyroid cancer. MATERIALS AND METHODS: Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days...

BACKGROUND: Recent studies have unveiled disulfidptosis as a phenomenon intimately associated with cellular damage, heralding new avenues for exploring tumor cell dynamics. We aimed to explore the impact of disulfide cell death on the tumor immune microenvironment and immunotherapy in lung adenocarcinoma (LUAD). METHODS: We initially utilized pan-cancer transcriptomics to explore the expression, prognosis, and mutation status of genes related to disulfidptosis. Using the LUAD multi- -omics cohorts in the TCGA database, we explore the molecular characteristics of subtypes related to disulfidptosis...

BACKGROUND: Nicotinamide phosphoribosyltransferase (Nampt) is required for recycling NAD+ in numerous cellular contexts. Morpholino-based knockdown of zebrafish nampt-a has been shown to cause abnormal development and defective hematopoiesis concomitant with decreased NAD+ levels. However, surprisingly, nampt-a mutant zebrafish were recently found to be viable, suggesting a discrepancy between the phenotypes in knockdown and knockout conditions. Here, we address this discrepancy by directly comparing loss-of-function approaches that result in identical defective transcripts in morphants and mutants...

Colistin- and carbapenem-resistant Acinetobacter baumannii is a serious multidrug resistant (MDR) bacterium in clinical settings. Discovery of new antibacterial drugs against MDR is facing multiple challenges in drug development. Combination of known antibiotics with a robust adjuvant might be an alternative effective strategy for MDR treatment. In the study herein, we report an antibiotic adjuvant activity of a natural compound panduratin A from fingerroot (Boesenbergia rotunda) as a potent adjuvant to colistin...

Next-generation sequencing offers highly multiplexed and accurate detection of nucleic acid sequences but at the expense of complex workflows and high input requirements. The ease of use of CRISPR-Cas12 assays is attractive and may enable highly accurate detection of sequences implicated in, for example, cancer pathogenic variants. CRISPR assays often employ end-point measurements of Cas12 trans-cleavage activity after Cas12 activation by the target; however, end point-based methods can be limited in accuracy and robustness by arbitrary experimental choices...

Urgent research into innovative severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus-vectored vaccine named Ad5-Beta/Delta. This vaccine was created by incorporating the receptor-binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5-Beta/Deta vaccine induced robust broad-spectrum neutralization against Omicron BA...

In the Alzheimer's disease (AD) brain, the microtubule-associated protein tau aggregates into paired helical filaments (PHFs) in which each protofilament has a C-shaped conformation. In vitro assembly of tau fibrils adopting this fold is highly valuable for both fundamental and applied studies of AD without requiring patient-brain extracted fibrils. To date, reported methods for forming AD-fold tau fibrils have been irreproducible and sensitive to subtle variations in fibrillization conditions. Here we describe a route to reproducibly assemble tau fibrils adopting the AD fold on the multi-milligram scale...

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018)...

ETHNOPHARMACOLOGICAL RELEVANCE: Leeches exhibit robust anticoagulant activity, making them useful for treating cardiovascular diseases in traditional Chinese medicine. Whitmania pigra, the primary source species of leech-derived medicinal compounds in China, has been demonstrated to possess formidable anticoagulant properties. Hirudin-like peptides, recognized as potent thrombin inhibitors, are prevalent in hematophagous leeches. Considering that W. pigra is a nonhematophagic leech, the following question arises: does a hirudin variant exist in this species? AIM OF THE STUDY: In this study we identified the hirudin-encoding gene (WP_HV1) in the W...

De novo protein folding into a native three-dimensional structure is indispensable for biological function, is instructed by its amino acid sequence, and occurs along a vectorial trajectory. The human proteome contains thousands of membrane-spanning proteins, whose biosynthesis begins on endoplasmic reticulum-associated ribosomes. Nearly half of all membrane proteins traverse the membrane more than once, including therapeutically important protein families such as solute carriers, G-protein-coupled receptors, and ABC transporters...

The Microtubule-binding repeat region (MTBR) of Tau has been studied extensively due to its pathological implications in neurodegenerative diseases like Alzheimer's disease. The pathological property of MTBR is mainly due to the R3 repeat's high propensity for self-aggregation, highlighting the critical molecular grammar of the repeat. Utilizing the R1R3 construct (WT) and its G326E mutant (EE), we determine the distinct characteristics of various peptide segments that modulate the aggregation propensity of the R3 repeat using NMR spectroscopy...

The western flower thrips, Frankliniella occidentalis, poses a significant challenge in global agriculture as a notorious pest and a vector of economically significant orthotospoviruses. However, the limited availability of genetic tools for F. occidentalis hampers the advancement of functional genomics and the development of innovative pest control strategies. In this study, we present a robust methodology for generating heritable mutations in F. occidentalis using the CRISPR/Cas9 genome editing system. Two eye-colour genes, white (Fo-w) and cinnabar (Fo-cn), frequently used to assess Cas9 function in insects were identified in the F...

SARS-CoV-2 variants have evolved over time in recent years, demonstrating immune evasion of vaccine-induced neutralizing antibodies directed against the original S protein. Updated S-targeted vaccines provide a high level of protection against circulating variants of SARS-CoV-2, but this protection declines over time due to ongoing virus evolution. To achieve a broader protection, novel vaccine candidates involving additional antigens with low mutation rates are currently needed. Based on our recently studied mRNA lipid nanoparticle (mRNA-LNP) platform, we have generated mRNA-LNP encoding SARS-CoV-2 structural proteins M, N, S from different virus variants and studied their immunogenicity separately or in combination in vivo...