Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence.

The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse. Administration of these drugs led to a reduction in innate immune activation and also the cytokines required to trigger protective T cell responses. Moreover, these drugs led to activation-induced cell death in the mycobacterial-specific T cell leading to a reduced killing capacity. Furthermore, these drugs stalled the T cell differentiation into memory subsets by modulating the activation of STAT3, STAT4, FOXO1, and NFκB transcription factors and hampering the Th1 and Th17-mediated long-term host protective memory responses. These findings suggest the urgent need to augment directly observed treatment, short-course (DOTS) therapy with immunomodulatory agents to mitigate the adverse effects linked to the treatment.IMPORTANCEAs a central component of TB eradication initiatives, directly observed treatment, short-course (DOTS) therapy imparts immune-dampening effects during the course of treatment. This approach undermines the host immune system by delaying the activation process and lowering the immune response. In our investigation, we have unveiled the impact of DOTS on specific immune cell populations. Notably, the signaling pathways involving STAT3 and STAT4 critical for memory responses and NFκß associated with pro-inflammation were substantially declined due to the therapy. Consequently, these drugs exhibit limited effectiveness in preventing recurrence of the disease. These observations highlight the imperative integration of immunomodulators to manage TB infection.

Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia's Protein-Protein Interaction Network.

Dementia-a syndrome affecting human cognition-is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer's disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a whole is required. In this study, we try to find the high-impact core regulating processes and factors involved in dementia's protein-protein interaction network. We also explore various aspects related to its stability and signal propagation. Using gene interaction databases such as STRING and GeneMANIA, a principal dementia network (PDN) consisting of 881 genes and 59,085 interactions was achieved. It was assortative in nature with hierarchical, scale-free topology enriched in various gene ontology (GO) categories and KEGG pathways, such as negative and positive regulation of apoptotic processes, macroautophagy, aging, response to drug, protein binding, etc. Using a clustering algorithm (Louvain method of modularity maximization) iteratively, we found a number of communities at different levels of hierarchy in PDN consisting of 95 "motif-localized hubs", out of which, 7 were present at deepest level and hence were key regulators (KRs) of PDN (HSP90AA1, HSP90AB1, EGFR, FYN, JUN, CELF2 and CTNNA3). In order to explore aspects of network's resilience, a knockout (of motif-localized hubs) experiment was carried out. It changed the network's topology from a hierarchal scale-free topology to scale-free, where independent clusters exhibited greater control. Additionally, network experiments on interaction of druggable genome and motif-localized hubs were carried out where UBC, EGFR, APP, CTNNB1, NTRK1, FN1, HSP90AA1, MDM2, VCP, CTNNA1 and GRB2 were identified as hubs in the resultant network (RN). We finally concluded that stability and resilience of PDN highly relies on motif-localized hubs (especially those present at deeper levels), making them important therapeutic intervention candidates. HSP90AA1, involved in heat shock response (and its master regulator, i.e., HSF1), and EGFR are most important genes in pathology of dementia apart from KRs, given their presence as KRs as well as hubs in RN.

Comparative In Vitro Cytotoxicity Study of Carbon Dot-Based Organometallic Nanoconjugates: Exploration of Their Cell Proliferation, Uptake, and Localization in Cancerous and Normal Cells.

Organometallic nanoconjugates have raised great interest due to their bimodal properties and high stability. In the present study, we analyzed the cytotoxicity property of carbon dots (CDs) and a series of organometallic nanoconjugates including gold@carbon dots (Au@CDs) and silver@carbon dots (Ag@CDs) synthesized via an aqueous mode. We aimed to divulge a comparative analysis of cell proliferation, uptake, and localization of the particles in HeLa and HEK293 cell lines. Our results showed dose-dependent cytotoxicity of Au@CDs, Ag@CDs, and CDs. However, Ag@CDs showed the highest inhibition through HeLa cells with an IC50 value of around 50 ± 1.0 µg/mL. Confocal imaging signified the uptake of the particles suggested by blue fluorescence in the interior region of HeLa cells. Furthermore, the TEM micrographs depicted that the particles are entrapped by endocytosis assisted through the cell microvilli. The CDs and Au@CDs were thus observed to be relatively safe up to a concentration of 100 µg/mL and did not induce any morphological changes in the cells. Moreover, the cell proliferation assay of these nanoconjugates against HEK 293 cells signified the nontoxic nature of the nanoconjugates. The results thus revealed two major facts: firstly, the Ag@CDs had potent therapeutic potential, signifying their potential as a promising anticancer drug, and secondly, the CDs and Au@CDs at a defined dose could be used as probes for detection and also bioimaging agents.

Correction: Luteolin-mediated Kv1.3 K+ channel inhibition augments BCG vaccine efficacy against tuberculosis by promoting central memory T cell responses in mice.

[This corrects the article DOI: 10.1371/journal.ppat.1008887.].

Luteolin-mediated Kv1.3 K+ channel inhibition augments BCG vaccine efficacy against tuberculosis by promoting central memory T cell responses in mice.

Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.

Enhanced functional properties of soft polymer-ceramic composites by swift heavy ion irradiation.

The physical and chemical properties of soft polymer-ceramic composites with 50 MeV swift heavy, Li3+ ion irradiation were studied. A solution-casting technique was employed to synthesize free standing, flexible composite films of ferroelectric polymer PVDF and ferroelectric ceramic BNBT mixtures with 0-3 connectivity. However, only 35 wt% ceramic was chosen for the study as it showed the highest dielectric constant and enhanced ferroelectric properties without irradiation. The effects of ion irradiation on the structural, microstructural, morphological, dielectric and ferroelectric properties of this particular composition were systematically investigated and conclusions were drawn. The mechanism for the enhancement of the electroactive ß-phase due to the swift heavy ion irradiation was discussed and the enhancement was well correlated with its ferroelectric and dielectric properties.

Organization in complex brain networks: Energy distributions and phase shift.

The Hamiltonian function of a network, derived from the intrinsic distributions of nodes and edges, magnified by resolution parameter has information on the distribution of energy in the network. In brain networks, the Hamiltonian function follows hierarchical features reflecting a power-law behavior which can be a signature of self-organization. Further, the transition of three distinct phases driven by resolution parameter is observed which could correspond to various important brain states. This resolution parameter could thus reflect a key parameter that controls and balances the energy distribution in the brain network.