Explore the vast range of titles available.

Viral-host protein-protein interaction plays a vital role in pathogenesis, since it defines viral infection of the host and regulation of the host proteins. Identification of key viral-host protein-protein interactions (PPIs) has great implication for therapeutics. In this study, a systematic attempt has been made to predict viral-host PPIs by integrating different features, including domain-domain association, network topology and sequence information using viral-host PPIs from VirusMINT. The three well-known supervised machine learning methods, such as SVM, Naïve Bayes and Random Forest, which are commonly used in the prediction of PPIs, were employed to evaluate the performance measure based on five-fold cross validation techniques. Out of 44 descriptors, best features were found to be domain-domain association and methionine, serine and valine amino acid composition of viral proteins. In this study, SVM-based method achieved better sensitivity of 67% over Naïve Bayes (37.49%) and Random Forest (55.66%). However the specificity of Naïve Bayes was the highest (99.52%) as compared with SVM (74%) and Random Forest (89.08%). Overall, the SVM and Random Forest achieved accuracy of 71% and 72.41%, respectively. The proposed SVM-based method was evaluated on blind dataset and attained a sensitivity of 64%, specificity of 83%, and accuracy of 74%. In addition, unknown potential targets of hepatitis B virus-human and hepatitis E virus-human PPIs have been predicted through proposed SVM model and validated by gene ontology enrichment analysis. Our proposed model shows that, hepatitis B virus \"C protein\" binds to membrane docking protein, while \"X protein\" and \"P protein\" interacts with cell-killing and metabolic process proteins, respectively. The proposed method can predict large scale interspecies viral-human PPIs. The nature and function of unknown viral proteins (HBV and HEV), interacting partners of host protein were identified using optimised SVM model.

Background With the global spread of multidrug resistance in pathogenic microbes, infectious diseases emerge as a key public health concern of the recent time. Identification of host genes associated with infectious diseases will improve our understanding about the mechanisms behind their development and help to identify novel therapeutic targets. Results We developed a machine learning techniques-based classification approach to identify infectious disease-associated host genes by integrating sequence and protein interaction network features. Among different methods, Deep Neural Networks (DNN) model with 16 selected features for pseudo-amino acid composition (PAAC) and network properties achieved the highest accuracy of 86.33% with sensitivity of 85.61% and specificity of 86.57%. The DNN classifier also attained an accuracy of 83.33% on a blind dataset and a sensitivity of 83.1% on an independent dataset. Furthermore, to predict unknown infectious disease-associated host genes, we applied the proposed DNN model to all reviewed proteins from the database. Seventy-six out of 100 highly-predicted infectious disease-associated genes from our study were also found in experimentally-verified human-pathogen protein-protein interactions (PPIs). Finally, we validated the highly-predicted infectious disease-associated genes by disease and gene ontology enrichment analysis and found that many of them are shared by one or more of the other diseases, such as cancer, metabolic and immune related diseases. Conclusions To the best of our knowledge, this is the first computational method to identify infectious disease-associated host genes. The proposed method will help large-scale prediction of host genes associated with infectious-diseases. However, our results indicated that for small datasets, advanced DNN-based method does not offer significant advantage over the simpler supervised machine learning techniques, such as Support Vector Machine (SVM) or Random Forest (RF) for the prediction of infectious disease-associated host genes. Significant overlap of infectious disease with cancer and metabolic disease on disease and gene ontology enrichment analysis suggests that these diseases perturb the functions of the same cellular signaling pathways and may be treated by drugs that tend to reverse these perturbations. Moreover, identification of novel candidate genes associated with infectious diseases would help us to explain disease pathogenesis further and develop novel therapeutics.

Background Shigella and Salmonella are major foodborne and waterborne pathogens responsible for acute gastrointestinal infections and significant global morbidity and mortality. Both species are capable of forming bacterial biofilms in the food processing industry, a key survival mechanism that significantly reduces the effectiveness of antibacterial drugs. The global rise in antimicrobial resistance (AMR) necessitates the urgent development of new strategies. Bacteriophages, particularly phage cocktails, provide a potential alternative because of their host specificity and ability to degrade biofilms. Results In this study, a new bacteriophage, Sspk23, infecting Shigella sonnei , was isolated from lake water and biologically characterized to assess its lytic activity and stability under varying conditions. Furthermore, this study investigates the effectiveness of a phage cocktail, including a newly isolated Sspk23 and two previously identified phages, Sfk20 and STWB21, against Shigella and Salmonella infections with a focus on its ability to combat single and polymicrobial infections. The biofilm removal potential of the phage cocktail was observed using Scanning Electron Microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM), and also quantitatively assessed in a microtiter plate. Cytotoxicity tests were conducted on human adherent epithelial cell line and macrophage cell line to confirm the safety of the phage and phage cocktail for therapeutic use. Conclusions The findings demonstrate the possibility of a phage cocktail as a substitute for conventional antibiotics in controlling Shigella and Salmonella infections. Additionally, their capacity to destroy biofilms indicates potential applications in clinical therapies, environmental remediation, and food safety. Future studies will be focused on phage-antibiotic synergy optimization and in vivo validation to combat multidrug-resistant (MDR) bacteria.

Intracellular pathogens of Salmonella spp. survive and replicate within the phagosomes, called Salmonella-containing vacuoles (SCVs) inside macrophages by manipulating phagosomal maturation and phagolysosome formation. While controversies exist about the phagosomal traffic of Salmonella Typhimurium, little studies were carried out with the intracellular survival mechanisms of Salmonella Typhi ( S. Typhi). We had previously reported that a eukaryote-like serine/threonine kinase of S. Typhi (T4519) contributes to survival within macrophages and activates host pro-inflammatory signaling pathways regulated by NF-κB. However, neither the mechanisms underlying NF-κB activation nor how it contributes to intracellular survival of S. Typhi were studied. Here we show, by using antibody-mediated blocking and gene knockdown studies that T4519 activates Toll-like receptor 2 (TLR2) signals in the human monocyte-derived macrophages. We computationally predicted the NH2-terminal glycine rich repeat domain of T4519 as the TLR2-binding moiety and confirmed the interaction by co-immunoprecipitation experiment. TLR2-T4519 interaction transcriptionally repressed cystatin B, a cathepsin B inhibitor, leading to the activation of cytosolic cathepsin B, leaked from the lysosomes of the infected cells. Through a series of RT-qPCR, western blotting, gene knockdown, flow cytometry and confocal microscopy experiments, we have shown that active cytosolic cathepsin B cleaves IKB-α, resulting in nuclear translocation of NF-κB and transactivation of its target genes, including reactive oxygen species (ROS), which in turn induces lysosomal membrane permeabilization (LMP). TLR2-dependent targeting of the cystatin B-cathepsin B-NF-κB-ROS pathways by T4519, leading to LMP promotes phagosomal survival of S. Typhi. This study describes a unique mechanism of the exploitation of host NF-κB signaling pathways by bacterial pathogens to promote its own persistence within macrophage cells.

Human Salmonella infections pose significant public health challenges globally, primarily due to low diagnostic yield of systemic infections, emerging and expanding antibiotic resistance of both the typhoidal and non-typhoidal Salmonella strains and the development of asymptomatic carrier state that functions as a reservoir of infection in the community. The limited long-term efficacy of the currently licensed typhoid vaccines, especially in smaller children and non-availability of vaccines against other Salmonella serovars necessitate active research towards developing a multivalent vaccine with wider coverage of protection against pathogenic Salmonella serovars. We had earlier reported immunogenicity and protective efficacy of a subunit vaccine containing a recombinant outer membrane protein (T2544) of Salmonella Typhi in a mouse model. This was achieved through the robust induction of serum IgG, mucosal secretory IgA and Salmonella -specific cytotoxic T cells as well as memory B and T cell response. Here, we report the development of a glycoconjugate vaccine, containing high molecular weight complexes of Salmonella Typhimurium O-specific polysaccharide (OSP) and recombinant T2544 that conferred simultaneous protection against S. Typhi, S. Paratyphi, S. Typhimurium and cross-protection against S. enteritidis in mice. Our findings corroborate with the published studies that suggested the potential of Salmonella OSP as a vaccine antigen. The role of serum antibodies in vaccine-mediated protection is suggested by rapid seroconversion with high titers of serum IgG and IgA, persistently elevated titers after primary immunization along with a strong antibody recall response with higher avidity serum IgG against both OSP and T2544 and significantly raised SBA titers of both primary and secondary antibodies against different Salmonella serovars. Elevated intestinal secretory IgA and bacterial motility inhibition by the secretory antibodies supported their role as well in vaccine-induced protection. Finally, robust induction of T effector memory response indicates long term efficacy of the candidate vaccine. The above findings coupled with protection of vaccinated animals against multiple clinical isolates confirm the suitability of OSP-rT2544 as a broad-spectrum candidate subunit vaccine against human infection due to typhoidal and non-typhoidal Salmonella serovars.

Cardioprotective potential of anthocyanin rich red cabbage extract (ARCE) was assessed in H2O2 treated rat neonatal cardiomyoblasts (H9c2 cells) and isoproterenol (ISO) induced rodent model of myocardial infarction. H2O2 treated H9c2 cells recorded cytotoxicity (48-50%) and apoptosis (57.3%), the same were reduced in presence of ARCE (7-10% & 12.3% respectively). Rats pretreated with ARCE for 30 days followed by ISO treatment recorded favourable heart: body weight ratio as compared to ISO treated group. Also, the mRNA levels of enzymatic antioxidants (sod and catalase) and apoptotic genes (bax and bcl-2) in ARCE+ISO treated group were similar to the control group suggesting that ARCE pretreatment prevents ISO induced depletion of enzymatic antioxidants and apoptosis. Histoarchitecture of ventricular tissue of ISO treated group was marked by infracted areas (10%) and derangement of myocardium whereas, ARCE+ISO treated group (4.5%) recorded results comparable to control (0%). ARCE+ISO treated group accounted for upregulation of caveolin-3 and SERCA2a expression as compared to the ISO treated group implying towards ARCE mediated reduction in membrane damage and calcium imbalance. Molecular docking scores and LigPlot analysis of cyanidin-3-glucoside (-8.7 Kcal/mol) and delphinidin-3-glucoside (-8.5 Kcal/mol) showed stable hydrophobic and electrostatic interactions with β1 adrenergic receptor. Overall this study elucidates the mechanism of ARCE mediated prevention of experimentally induced myocardial damage.

Background Measurement of glucose-6-phosphate dehydrogenase (G6PD) activity guides hypnozoitocidal treatment of P vivax malaria. The G6PD Standard (SDBiosensor, Republic of Korea) here referred to as “Biosensor” is a quantitative point-of-care diagnostic that measures G6PD activity in U/gHb. The manufacturer recommends cutoffs to define G6PD deficient (≤ 4.0U/gHb), intermediate (4.1- ≤ 6.0U/gHb) and normal (> 6.0U/gHb) individuals. The aim of this individual patient data (IPD) meta-analysis was to evaluate these cutoffs (CRD42023406595). Methods A systematic review identified studies reporting population-level G6PD activity measured by Biosensor, published between January 2017 and May 2023. IPD were collated and standardised. The adjusted male median (AMM) was defined as 100% activity and calculated across all studies (universal AMM) and separately for each setting. The proportion of participants classified as deficient or intermediate were compared using the manufacturer-recommended cutoffs and 30% and 70% of the universal AMM and setting-specific AMM. Associations between G6PD activity and blood sampling method, malaria status, and age were assessed. Results Eleven studies with 9724 participants from eight countries were included in this analysis. The universal AMM was 7.7U/gHb and the setting-specific AMMs ranged from 6.2U/gHb to 9.9U/gHb. When using the universal AMM, 4.2% of participants were classified as deficient and 11.9% as intermediate or deficient. The corresponding values were 3.9% and 10.8% for setting-specific cutoffs, and 7.2% and 18.3% for manufacturer-recommended definitions for deficients and intermediates respectively. The manufacturer-recommended cutoff for deficient individuals fitted the distribution of G6PD activities better than definitions based on the percentage of AMM. There was no significant association between malaria status or blood sampling method and G6PD activity. Measured G6PD activity decreased in children 1–5 years and plateaued thereafter. Conclusion The manufacturer’s recommended cutoff is conservative but more reliable at categorising G6PD deficient individuals than those based on calculations of 30% activity using the AMM. The observed decrease in G6PD activity in children between 1 and 5 years of age warrants further investigation.

Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency. Data from similar clinical studies evaluating the performance of the STANDARD G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement. The sensitivity of the STANDARD G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%-100%) for G6PD deficient cases with <30% activity and 77% (95% CI 66.8%-85.4%) for females with intermediate activity between 30%-70%. Specificity was 98.1% (95% CI 97.6%-98.5%) and 92.8% (95% CI 91.6%-93.9%) for G6PD deficient individuals and intermediate females, respectively. Out of 20 G6PD intermediate females with false normal results, 12 had activity levels >60% on the reference assay. The negative predictive value for females with G6PD activity >60% was 99.6% (95% CI 99.1%-99.8%) on capillary specimens. Sensitivity among 396 P. vivax malaria cases was 100% (69.2%-100.0%) for both deficient and intermediate cases. Across the full dataset, 37% of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, over 95% of cases would receive correct treatment with primaquine, over 87% of cases would receive correct treatment with tafenoquine, and no true G6PD deficient cases would be treated inappropriately based on the result of the STANDARD G6PD Test. The STANDARD G6PD Test enables safe access to drugs which are contraindicated for individuals with G6PD deficiency. Operational considerations will inform test uptake in specific settings.

Background Point-of-care glucose-6-phosphate dehydrogenase (G6PD) testing has the potential to make the use of radical treatment for vivax malaria safer and more effective. Widespread use of G6PD tests as part of malaria case management has been limited, in part due to due concerns regarding product usability, user training, and supervision. This study seeks to assess how well end users can understand the Standard™ G6PD Test (SD Biosensor, Suwon, South Korea) workflow, result output, and label after training. This will ultimately help inform test registration and introduction. Methods Potential G6PD test users who provide malaria case management at three sites in Brazil, Ethiopia, and India were trained on the use of the SD Biosensor Standard G6PD Test and assessed based on their ability to understand the test workflow and interpret results. The assessment was done through a questionnaire, designed to assess product usability against key technical product specifications and fulfill regulatory evidence requirements. Any participant who obtained 85% or above correct responses to the questionnaire was considered to adequately comprehend how to use and interpret the test. Results Forty-five participants, including malaria microscopists, laboratory staff, nurses, and community health workers took part in the study. Seventy-eight percent of all participants in the study (35/45) obtained passing scores on the assessment with minimal training. Responses to the multiple-choice questions indicate that most participants understood well the test intended use, safety claims, and warnings. The greatest source of error regarding the test was around the correct operating temperature. Most test results were also read and interpreted correctly, with the haemoglobin measurement being a more problematic output to interpret than the G6PD measurement. Conclusions These data results show how a standardized tool can be used to assess a user’s ability to run a point-of-care diagnostic and interpret results. When applied to the SD Biosensor Standard G6PD Test, this tool demonstrates that a range of users across multiple contexts can use the test and suggests improvements to the test instructions and training that can improve product usability, increase user comprehension, and ultimately contribute to more widespread effective use of point-of-care G6PD tests. Trial registration : NCT04033640

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the main risk factor for severe haemolysis following treatment with 8-aminoquinolines (8AQ). The World Health Organization recommends G6PD testing prior to 8AQ-based hypnozoitocidal treatment. We undertook an individual level meta-analysis of the performance of commercially available quantitative point-of-care diagnostics (PoCs) compared with reference spectrophotometry. A systematic literature search (PROSPERO: CRD42022330733) identified 595 articles of which 16 (2.7%) fulfilled pre-defined inclusion criteria and were included in the analysis, plus an additional 4 datasets. In total there were 12,678 paired measurements analyzed, 10,446 (82.4%) by STANDARD G6PD Test (SD Biosensor, RoK, [SDB]), 2,042 (16.1%) by CareStart G6PD Biosensor (AccessBio, USA, [CSA]), 150 (1.2%) by CareStart Biosensor (WellsBio, RoK [CSW]), and 40 (0.3%) by FINDER (Baebies, USA, [FBA]). The pooled sensitivities of the SDB when measuring G6PD activity <30% of normal were 0.82 (95% confidence interval [CI]: 0.72-0.89) for capillary and 0.93 (95% CI: 0.75-0.99) for venous blood samples. The corresponding values for measuring <70% G6PD activity were 0.93 (95% CI: 0.67-0.99) and 0.89 (95% CI: 0.73-0.96), respectively. The pooled specificity of the SDB was high (>96%) for all blood samples and G6PD activity thresholds. Irrespective of the blood samples and thresholds applied, sensitivity of the CSA did not exceed 62%, although specificity remained high at both 30% and 70% thresholds (>88%). Only one study each for CSW and FBA was included. Sensitivities of the CSW were 0.04 (95% CI: 0.01-0.14) and 0.81 (95% CI: 0.71-0.89) at the 30% and 70% thresholds, respectively (venous blood samples). Sensitivities of the FBA were 1.00 (95% CI: 0.29-1.00) and 0.75 (95% CI: 0.19-0.99) at the 30% and 70% thresholds (venous blood samples). Specificities of the CSW and FBA were consistently high (>90%) at both thresholds. Accuracy of the SDB was higher in females at the 30% cut-off (OR: 3.49, p=0.002) and lower in malaria patients at the 70% cut-off (OR: 0.59, p = 0.005). The SDB performed better than other PoCs. More evidence was available for the performance of the SDB compared to other PoCs, giving higher confidence in its utility in diagnosing G6PD deficiency.