The ΔfbpAΔsapM candidate vaccine derived from Mycobacterium tuberculosis H37Rv is markedly immunogenic in macrophages and induces robust immunity to tuberculosis in mice.

Tuberculosis (TB) remains a significant global health challenge, with approximately 1.5 million deaths per year. The Bacillus Calmette-Guérin (BCG) vaccine against TB is used in infants but shows variable protection. Here, we introduce a novel approach using a double gene knockout mutant (DKO) from wild-type Mycobacterium tuberculosis (Mtb) targeting fbpA and sapM genes. DKO exhibited enhanced anti-TB gene expression in mouse antigen-presenting cells, activating autophagy and inflammasomes. This heightened immune response improved ex vivo antigen presentation to T cells. Subcutaneous vaccination with DKO led to increased protection against TB in wild-type C57Bl/6 mice, surpassing the protection observed in caspase 1/11-deficient C57Bl/6 mice and highlighting the critical role of inflammasomes in TB protection. The DKO vaccine also generated stronger and longer-lasting protection than the BCG vaccine in C57Bl/6 mice, expanding both CD62L-CCR7-CD44+/-CD127+ effector T cells and CD62L+CCR7+/-CD44+CD127+ central memory T cells. These immune responses correlated with a substantial ≥ 1.7-log10 reduction in Mtb lung burden. The DKO vaccine represents a promising new approach for TB immunization that mediates protection through autophagy and inflammasome pathways.

Examining the Time Varying Spillover Dynamics of Indian Financial Indictors from Global and Local Economic Uncertainty.

The research aims to excavate the role of global (Fed Rate, Crude, Real Dollar Index) and endogenous economic variables (GDP and Consumer Price Index) in shaping the spillover amongst the major Indian Financial indicators, viz. Nifty Index, MCX Gold, USDINR, Govt. Bond 10Y maturity and agricultural index N-Krishi. To facilitate cross-comparison decomposition of time-varying spillover output generated from Time-Varying Vector Autoregression (TVP-VAR) with aggregation at three layers is performed. The research finds that Indian Financial Indicators are vulnerable to spillover shocks from global variables predominantly driven by Fed Rate and Real Dollar Index. USDINR turns out to be most sensitive to global shocks and transgresses the shock to other financial indicators. Importantly, persistently high inflation has brought volatility spikes in the directional spillover to financial indicators. Though spillover subsidence is observed post-2014, with an all-time high during GFC, a sudden spurt in all financial indicators has been observed post-Covid-19, with Govt. bonds showing a sporadic rise. An important observation relates to staunch spillover from GDP during GFC with reoccurrence post-Covid. Additionally, a closely knit spillover tie is observed among USDINR, N-Krishi, and Crude. The study is beneficial to RBI to proactively monitor the weakening rupee along with Fed tapering to manage the rising spillover post-Covid-19. The effort of RBI has to be reciprocated by the government in inflation targeting to reinforce the curbing efforts of rising shock spillover.

Deep learning empowered COVID-19 diagnosis using chest CT scan images for collaborative edge-cloud computing platform.

The novel coronavirus outbreak has spread worldwide, causing respiratory infections in humans, leading to a huge global pandemic COVID-19. According to World Health Organization, the only way to curb this spread is by increasing the testing and isolating the infected. Meanwhile, the clinical testing currently being followed is not easily accessible and requires much time to give the results. In this scenario, remote diagnostic systems could become a handy solution. Some existing studies leverage the deep learning approach to provide an effective alternative to clinical diagnostic techniques. However, it is difficult to use such complex networks in resource constraint environments. To address this problem, we developed a fine-tuned deep learning model inspired by the architecture of the MobileNet V2 model. Moreover, the developed model is further optimized in terms of its size and complexity to make it compatible with mobile and edge devices. The results of extensive experimentation performed on a real-world dataset consisting of 2482 chest Computerized Tomography scan images strongly suggest the superiority of the developed fine-tuned deep learning model in terms of high accuracy and faster diagnosis time. The proposed model achieved a classification accuracy of 96.40%, with approximately ten times shorter response time than prevailing deep learning models. Further, McNemar's statistical test results also prove the efficacy of the proposed model.

B Cells Are Required to Generate Optimal Anti-Melanoma Immunity in Response to Checkpoint Blockade.

Immunotherapies such as checkpoint blockade therapies are known to enhance anti-melanoma CD8+ T cell immunity, but only a fraction of patients treated with these therapies achieve durable immune response and disease control. It may be that CD8+ T cells need help from other immune cells to generate effective and long-lasting anti-tumor immunity or that CD8+ T cells alone are insufficient for complete tumor regression and cure. Melanoma contains significant numbers of B cells; however, the role of B cells in anti-melanoma immunity is controversial. In this study, B16 melanoma mouse models were used to determine the role of B cells in anti-melanoma immunity. C57BL/6 mice, B cell knockout (KO) C57BL/6 mice, anti-CD19, and anti-CXCL13 antibody-treated C57BL/6 mice were used to determine treatment efficacy and generation of tumor-specific CD8+ T cells in response to PD-L1 blockade alone or combination with TLR-7/8 activation. Whole transcriptome analysis was performed on the tumors from B cell depleted and WT mice, untreated or treated with anti-PD-L1. Both CD40-positive and CD40-negative B cells were isolated from tumors of TLR-7/8 agonist-treated wild-type mice and adoptively transferred into tumor-bearing B cell KO mice, which were treated with anti-PD-L1 and TLR-7/8 agonist. Therapeutic efficacy was determined in the presence of activated or inactivated B cells. Microarray analysis was performed on TLR-7/8-treated tumors to look for the B cell signatures. We found B cells were required to enhance the therapeutic efficacy of monotherapy with anti-PD-L1 antibody and combination therapy with anti-PD-L1 antibody plus TLR-7/8 agonist. However, B cells were not essential for anti-CTLA-4 antibody activity. Interestingly, CD40-positive but not CD40-negative B cells contributed to anti-melanoma immunity. In addition, melanoma patients' TCGA data showed that the presence of B cell chemokine CXCL13 and B cells together with CD8+ T cells in tumors were strongly associated with improved overall survival. Our transcriptome data suggest that the absence of B cells enhances immune checkpoints expression in the tumors microenvironment. These results revealed the importance of B cells in the generation of effective anti-melanoma immunity in response to PD-1-PD-L1 blockade immunotherapy. Our findings may facilitate the design of more effective anti-melanoma immunotherapy.

Studies on oxidative stress induced nerve conduction deficits in cigarette smokers.

An important role of oxidative stress for the development of vascular and neurological complications has encouraged us to undertake a study to assess the oxidative stress induced nerve conduction deficits among cigarette smokers. Eighteen regular male cigarette smokers and twenty nine male non-smokers were diagnosed for clinical neuro-physiological tests viz., motor and sensory nerve conduction velocity (MNCV and SNCV) and redox status. Significant depletion of reduced glutathione (GSH) level (p < 0.05) and significant increase in malondialdehyde (MDA) level (p < 0.01) was found in smokers compared to non-smokers. Motor and sensory nerve conduction velocity showed no significant difference among smokers compared to non-smokers. The present study shows that smoking can induce oxidative stress among smokers but could not exacerbate to nerve conduction deficits.

GM-CSF Dependent Differential Control of Mycobacterium tuberculosis Infection in Human and Mouse Macrophages: Is Macrophage Source of GM-CSF Critical to Tuberculosis Immunity?

Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is being increasingly recognized for its potential role in innate resistance against tuberculosis (TB). While the GM-CSF is produced by a variety of host cells, including conventional and non-conventional T cells, macrophages, alveolar epithelial cells, the cell population that promotes GM-CSF mediated innate protection against Mycobacterium tuberculosis infection remains unclear. This is because studies related to the role of GM-CSF so far have been carried out in murine models of experimental TB, which is inherently susceptible to TB as compared to humans, who exhibit a resolution of infection in majority of cases. We found a significantly higher amount of GM-CSF production by human macrophages, compared to mouse macrophages, after infection with M. tuberculosis in vitro. The higher levels of GM-CSF produced by human macrophages were also directly correlated with their increased life span and ability to control M. tuberculosis infection. Other evidence from recent studies also support that M. tuberculosis infected human macrophages display heterogeneity in their antibacterial capacity, and cells with increased expression of genes involved in GM-CSF signaling pathway can control intracellular M. tuberculosis growth more efficiently. Collectively, these emerging evidence indicate that GM-CSF produced by lung resident macrophages could be vital for the host resistance against M. tuberculosis infection in humans. Identification of GM-CSF dependent key cellular pathways/processes that mediate intracellular host defense can lay the groundwork for the development of novel host directed therapies against TB as well as other intracellular infections.

Macrophage heterogeneity and plasticity in tuberculosis.

Macrophages are the primary host cells for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), during its intracellular survival in humans. The pathogen has a remarkable capacity to survive within the hostile environment of macrophages. However, primary infection does not result in active TB disease in most individuals. The majority of individuals remain latently infected, wherein the bacteria are held in check by the host immune response. Nevertheless, such individuals can develop active TB later upon the decline in their immune status. In contrast, in a small fraction of infected individuals, the host immune response fails to control the growth of M. tuberculosis bacilli, and granulomatous TB develops progressively. Elucidating the molecular and phenotypic events that govern the outcome of the infection within macrophages is fundamental to understanding the key features of these cells that could be equally critical in infection control. The molecular details of the M. tuberculosis-macrophage interaction continue to be discerned, and emerging evidence suggests that macrophage population that participate in infection is heterogeneous. While the local environment and developmental origin could influence the phenotypic heterogeneity and functional plasticity of macrophages, M. tuberculosis has also been demonstrated to modulate the polarization of macrophages. In this review, we draw on work investigating specialized macrophage populations and their interactions with M. tuberculosis with respect to pathogenesis and specific immune responses. Understanding the mechanisms that control the repertoire of macrophage phenotypes and behaviors during infection may provide prospects for novel TB control strategies through modulation of immunobiological functions of macrophages.

Comparison of polycyclic aromatic hydrocarbon levels in placental tissues of Indian women with full- and preterm deliveries.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants formed from combustion products of fossil fuels, cigarette smoking and in grilled/smoked foods. They are reported to alter trophoblast proliferation in placenta, in addition to disturbing its endocrine functions, which may be able to increase the risk of preterm delivery in pregnant women. The present study was planned to assess possible involvement of PAHs exposure of pregnant women (measured as placental PAHs concentrations) with preterm delivery cases among women of Lucknow city (India). We performed a case-control study and a total of 60 mothers (n=31 full term and n=29 preterm deliveries) were recruited at a local nursing home of Lucknow, for the period of August 2005-February 2006. Subsequent to parturition, placental tissues from each participant were immediately collected and kept at -20 degrees C until PAHs analyses. Placental tissue PAHs concentrations were determined by HPLC, using a fluorescence detector. Mean+/-SD placental level (61.91+/-12.43ppb) of benzo(b)fluoranthene, a carcinogenic PAH, was found significantly elevated (p<0.05) among women with preterm delivery when compared with the level (23.84+/-7.01) in women having full-term deliveries. In the same way, non-carcinogenic fluoranthene level (325.91+/-45.14ppb) was also detected to be higher in the preterm delivery group compared to 208.6+/-21.93ppb level from the full-term delivery group of women. Additionally naphthalene, acenaphthylene, phenanthrene, anthracene, benzo(a)pyrene and dibenzo(a,h)anthracene levels in placental tissue were also found to be higher in the preterm delivery group of women but the difference did not reach statistically significant levels. This foremost study from India with modest samples size and limited statistical power does not show a substantial involvement of PAHs with preterm delivery, but higher concentrations of placental PAHs detected among preterm delivery group of women could show some possible association with these environmental toxicants. Further study with large sample size, controlled for confounders and great statistical power, is reasonable to elucidate the association of PAHs exposure with preterm delivery of women in India.