Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis.

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1ß signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1ß overproduction can completely rescue hemochromatotic mice from the lethal infection.

Assessment of ambient air quality in relation to the burning of firecrackers during the festival of Diwali: A case study of Jodhpur City (India).

The study attempts to examine the impact of firework activities during Diwali Festival on ambient air quality of Jodhpur city. Air quality parameters particulate matter of diameter 10 µm (PM10), particulate matter of diameter 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2) and heavy metals in PM2.5 like Pb, Ni, Ba, Al, As and Sr are monitored at two locations, for 15 days, starting from 7 days before the festival of Diwali, on the day of the festival (Diwali) and 7 days after Diwali. On the occasion of Diwali, it was discovered that the 24-h average levels of various pollutants were significantly elevated compared to regular days preceding the festival. Specifically, at the HBO site, the concentrations were notably increased, with sulfur dioxide (SO2) reaching 5.62 times higher, nitrogen dioxide (NO2) at 3 times higher, particulate matter of diameter 10 µm (PM10) at 2.35 times higher, and particulate matter of diameter 2.5 µm (PM2.5) at 1.01 times higher than the usual levels before Diwali. Similarly, at the PTMM site, there were substantial elevations in pollutant concentrations during Diwali compared to pre-festival days, with SO2 registering 2.53 times higher, NO2 at 2.37 times higher, PM2.5 at 1.9 times higher, and PM10 at 1.57 times higher levels than normal. Concentration of Al, Ba, Sr and Pb at HBO site and Al at PTMM site was highest on Diwali day. Air quality index which was in good category on normal days before Diwali, fell into poor category starting from the day before Diwali and remain in poor category on normal days after Diwali. The result indicates the worsening of ambient air quality during Diwali which can adversely impact the human health in terms of various respiratory complications.

Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.

Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal ß-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11ß, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.

Forecasting COVID-19 outbreak progression using hybrid polynomial-Bayesian ridge regression model.

In 2020, Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2) Coronavirus, unforeseen pandemic put humanity at big risk and health professionals are facing several kinds of problem due to rapid growth of confirmed cases. That is why some prediction methods are required to estimate the magnitude of infected cases and masses of studies on distinct methods of forecasting are represented so far. In this study, we proposed a hybrid machine learning model that is not only predicted with good accuracy but also takes care of uncertainty of predictions. The model is formulated using Bayesian Ridge Regression hybridized with an n-degree Polynomial and uses probabilistic distribution to estimate the value of the dependent variable instead of using traditional methods. This is a completely mathematical model in which we have successfully incorporated with prior knowledge and posterior distribution enables us to incorporate more upcoming data without storing previous data. Also, L2 (Ridge) Regularization is used to overcome the problem of overfitting. To justify our results, we have presented case studies of three countries, -the United States, Italy, and Spain. In each of the cases, we fitted the model and estimate the number of possible causes for the upcoming weeks. Our forecast in this study is based on the public datasets provided by John Hopkins University available until 11th May 2020. We are concluding with further evolution and scope of the proposed model.

Principal component based support vector machine (PC-SVM): a hybrid technique for software defect detection.

Defects are the major problems in the current situation and predicting them is also a difficult task. Researchers and scientists have developed many software defects prediction techniques to overcome this very helpful issue. But to some extend there is a need for an algorithm/method to predict defects with more accuracy, reduce time and space complexities. All the previous research conducted on the data without feature reduction lead to the curse of dimensionality. We brought up a machine learning hybrid approach by combining Principal component Analysis (PCA) and Support vector machines (SVM) to overcome the ongoing problem. We have employed PROMISE (CM1: 344 observations, KC1: 2109 observations) data from the directory of NASA to conduct our research. We split the dataset into training (CM1: 240 observations, KC1: 1476 observations) dataset and testing (CM1: 104 observations, KC1: 633 observations) datasets. Using PCA, we find the principal components for feature optimization which reduce the time complexity. Then, we applied SVM for classification due to very native qualities over traditional and conventional methods. We also employed the GridSearchCV method for hyperparameter tuning. In the proposed hybrid model we have found better accuracy (CM1: 95.2%, KC1: 86.6%) than other methods. The proposed model also presents higher evaluation in the terms of other criteria. As a limitation, the only problem with SVM is there is no probabilistic explanation for classification which may very rigid towards classifications. In the future, some other method may also introduce which can overcome this limitation and keep a soft probabilistic based margin for classification on the optimal hyperplane.

Mycobacterium indicus pranii protein MIP_05962 induces Th1 cell mediated immune response in mice.

Utility of Mycobacterium indicus pranii (MIP) as a multistage vaccine against mycobacterial infections demands identification of its protective antigens. We explored antigenicity and immunogenicity of a candidate protein MIP_05962 that depicts homology to HSP18 of M. leprae and antigen1 of Mycobacterium tuberculosis. This protein elicited substantial antibody response in immunized mice along with modulation of cellular immune response towards protective Th1 type. Both CD4+ and CD8+ subsets from immunized mice produced hallmark protective cytokines, IFN-γ, TNF-α and IL-2. This protein also enhanced the CD4+ effector memory that could act as first line of defence during infections. These results point to MIP_05962 as a protective antigen that contributes, in conjunction with others, to the protective immunity of this live vaccine candidate.

Differential requirement of Formyl Peptide Receptor 1 in macrophages and neutrophils in the host defense against Mycobacterium tuberculosis Infection.

Formyl peptide receptors (FPR), part of the G-protein coupled receptor superfamily, are pivotal in directing phagocyte migration towards chemotactic signals from bacteria and host tissues. Although their roles in acute bacterial infections are well-documented, their involvement in immunity against tuberculosis (TB) remains unexplored. This study investigates the functions of Fpr1 and Fpr2 in defense against Mycobacterium tuberculosis (Mtb), the causative agent of TB. Elevated levels of Fpr1 and Fpr2 were found in the lungs of mice, rabbits and peripheral blood of humans infected with Mtb, suggesting a crucial role in the immune response. The effects of Fpr1 and Fpr2 deletion on bacterial load, lung damage, and cellular inflammation were assessed using a TB model of hypervirulent strain of Mtb from the W-Beijing lineage. While Fpr2 deletion showed no impact on disease outcome, Fpr1-deficient mice demonstrated improved bacterial control, especially by macrophages. Bone marrow-derived macrophages from these Fpr1 -/- mice exhibited an enhanced ability to contain bacterial growth over time. Contrarily, treating genetically susceptible mice with Fpr1-specific inhibitors caused impaired early bacterial control, corresponding with increased bacterial persistence in necrotic neutrophils. Furthermore, ex vivo assays revealed that Fpr1 -/- neutrophils were unable to restrain Mtb growth, indicating a differential function of Fpr1 among myeloid cells. These findings highlight the distinct and complex roles of Fpr1 in myeloid cell-mediated immunity against Mtb infection, underscoring the need for further research into these mechanisms for a better understanding of TB immunity.

Neuroprotective effect of ropinirole against Aß1-42 -induced neurochemical perturbations and cognitive impairments in a rodent model.

The primary objective of this study was to investigate the protective effects of ropinirole (ROP) medication given for an extended period following the induction of cognitive decline, oxidative stress, and deterioration of mitochondria in a Wistar rat model by Aß1-42 . This study aimed to examine the neuroprotective efficacy of ROP in a stereotaxis model of AD. The Wistar rats were randomly assigned into four groups. Group I was considered as a sham, group II served as Aß-infusion alone, Group III was Aß1-42 + ROP (5 mg/kg/i.p.), and Group IV was Aß1-42 + ROP (10 mg/kg/i.p.). Our research revealed that ROP (10 mg/kg, b.wt.) attenuates the cognitive deficits caused by Aß1-42 -infused, which also correlates with the barnes maze, where (10 mg/kg, b.w.t.) shows significant improvement in spatial learning and memory. At the same time, ROP was rescued from oxidative damage, decreased lipid peroxidation rates, and inhibited acetylcholinesterase activity caused, demonstrating antioxidant benefits. In addition, a higher dose of ROP restored mitochondrial membrane potential in Aß1-42 rats. Furthermore, histopathological examination showed that ROP treatment reduced neuronal loss, especially in the hippocampus. We conclude that ROP's protective effects in reducing oxidative stress and modulating mitochondrial function might have a propensity in AD pathogenesis.

Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques.

In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However, total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.