Novel characterization discoveries of ferroptosis-associated molecules in COAD microenvironment based TCGA data

Background and Objective: One of the most recent forms of programmed cell death, ferroptosis, is crucial in tumorigenesis. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system’s failure. However, it is unknown whether ferroptosis-related genes (FRGs) are associated with colon adenocarcinoma (COAD) metastasis, immune cell infiltration, and oxidative stress in COAD. The current study concentrated on FRGs expression in colon cancer metastasis, their relationship to immune cell infiltration (ICI), and potential pathological pathways in COAD.Methods and Results: Clinical information and mRNA expression patterns for patients with COAD metastasis were obtained from the public TCGA database. Patients with low mRNA levels showed good overall survival than patients with high mRNA levels. The genomic-clinicopathologic nomogram was subsequently created by combining risk score and clinicopathological features. Absolute Shrinkage and Selection Operator have shown a 4 gene signature that can stratify cancer patients into high-risk versus low-risk. These four FRGs were found to be significantly linked to the overall survival of COAD patients and predicted high risk score. Next, age, stage, and PTNM were combined in univariate and multivariate cox regression models to perform a filtering procedure. The receiver operating characteristic (ROC) and calibration curves indicated that constructed signature model exhibited high prediction accuracy and clinical relevance in COAD. ARID3A showed a strong negative correlation with a wide range of immune tumour-infiltrating cells in COAD microenvironment. According to the single sample gene set enrichment analysis (ssGSEA) results, FRGs are involved in variety of pathological pathways including PI3K-AKT-mTOR pathway, reactive oxygen species (ROS) pathway, response to hypoxia pathway, and other inflammation related pathways. Moreover, dysregulation of FRGs in COAD patients showed a significance correlation with wide range of miRNAs and transcription factors (TFs).Conclusion: We identified new diagnostic biomarkers and established prognostic models for ferroptosis related programmed cell death in COAD metastasis. FRGs may improve tumor cell survival by activating the TGFB pathway, which can stimulate ROS production, accelerates ECM breakdown, and promote tumor progression and invasion. Genes implicated in ferroptosis, as revealed by the Kaplan Meier and a genomic-clinicopathologic nomogram, are potential therapeutic targets and prognosis indications for metastasis COAD patients

Public Perception Toward COVID-19 Disease Nature, Susceptibility to Complication, and Relationship to Influenza: A Cross-Sectional Study from Yemen

Background: Following the coronavirus disease (COVID-19) declaration as a pandemic, Yemen has started applying preventive measures to prevent its spread. This study aims to identify the perception regarding the nature of the COVID-19 disease, susceptibility to severe forms of the disease, and its relationship to seasonal influenza among the population of Yemen. Methods: This was a cross-sectional study of the public in Yemen. The relationship between participants’ sociodemographic factors and their responses was assessed by the chi-square test. Results: A total of 748 participants agreed to participate in the study. Regarding the nature of the diseases, nearly half of the participants (48.8%, n=352) believed that COVID-19 is a naturally occurring human virus that is a serious and fatal disease (61.2%, n=448). The majority (74.9%; n=518) did not agree that bacteria cause COVID-19. More than half of the participants (57.5%, n=423) believed this disease is transmitted to humans through a host animal. Regarding the vulnerable groups to develop severe COVID-19 infection, most of the participants pointed out that the elderly (94.3%, n=705), people with chronic diseases (89.9%, n=669), and pregnant women (53%, n=365) were more susceptible to severe diseases. Regarding symptoms, the majority (61.9%, n=458) of the participants agreed that the symptoms of COVID-19 are similar to those of seasonal influenza. Additionally, the majority (81.9%, n=579) agreed that some individuals develop more severe symptoms than seasonal influenza, particularly those with chronic illness. Gender, age, and education were found to be associated with participants’ perceptions regarding the nature of the virus and susceptibility to severe disease. Conclusion: Participants demonstrate a good understanding of the nature and susceptibility to complications associated with COVID-19 disease and its relationship to influenza. However, the respondents with a lower level of education might require additional educational campaigns to improve their awareness of the disease

Data_Sheet_1_Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii.pdf

IntroductionAcinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses.MethodsX-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains.ResultsThe receiver domain of PmrA follows the canonical α5β5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.</p