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The persistence of Mycobacterium tuberculosis despite prolonged chemotherapy represents a major obstacle for the control of tuberculosis. The mechanisms used by Mtb to persist in a quiescent state are largely unknown. Chemical genetic and genetic approaches were used here to study the physiology of hypoxic nonreplicating mycobacteria. We found that the intracellular concentration of ATP is five to six times lower in hypoxic nonreplicating Mtb cells compared with aerobic replicating bacteria, making them exquisitely sensitive to any further depletion. We show that de novo ATP synthesis is essential for the viability of hypoxic nonreplicating mycobacteria, requiring the cytoplasmic membrane to be fully energized. In addition, the anaerobic electron transport chain was demonstrated to be necessary for the generation of the protonmotive force. Surprisingly, the alternate ndh-2, but not -1, was shown to be the electron donor to the electron transport chain and to be essential to replenish the [NAD⁺] pool in hypoxic nonreplicating Mtb. Finally, we describe here the high bactericidal activity of the F₀F₁ ATP synthase inhibitor R207910 on hypoxic nonreplicating bacteria, supporting the potential of this drug candidate for shortening the time of tuberculosis therapy.

This paper highlights the review of work done in the area of 3D printed tools for the spark machining process. In recent times, additive manufacturing has gained wide popularity in different sectors. The additive manufacturing process or 3D printing, is a method for creating three-dimensional objects by layering material. Using the additive manufacturing technique of atomic diffusion, a tool for electrical discharge machining was developed. In this method, a mixture of metal and polymer that are formed into wire was employed and kept in a cartridge. The material mix is deposited in similar to extrusion process. A computer software does all the calculation, costing, weight analysis and printing time assessment. The procedure of the same is discussed. The scanning electron microscopic analysis of the same is done along with porosity measurement using ImageJ software. The surface characteristics of the printed tool was measured with Gwyddion software. Discussion on applicability of printed tool for electrical discharge machining process is done. words.

We have developed a software program that weights and integrates specific properties on the genes in a pathogen so that they may be ranked as drug targets. We applied this software to produce three prioritized drug target lists for Mycobacterium tuberculosis, the causative agent of tuberculosis, a disease for which a new drug is desperately needed. Each list is based on an individual criterion. The first list prioritizes metabolic drug targets by the uniqueness of their roles in the M. tuberculosis metabolome (\"metabolic chokepoints\") and their similarity to known \"druggable\" protein classes (i.e., classes whose activity has previously been shown to be modulated by binding a small molecule). The second list prioritizes targets that would specifically impair M. tuberculosis, by weighting heavily those that are closely conserved within the Actinobacteria class but lack close homology to the host and gut flora. M. tuberculosis can survive asymptomatically in its host for many years by adapting to a dormant state referred to as \"persistence.\" The final list aims to prioritize potential targets involved in maintaining persistence in M. tuberculosis. The rankings of current, candidate, and proposed drug targets are highlighted with respect to these lists. Some features were found to be more accurate than others in prioritizing studied targets. It can also be shown that targets can be prioritized by using evolutionary programming to optimize the weights of each desired property. We demonstrate this approach in prioritizing persistence targets.

Resilience of engineered systems is measured by the ability to anticipate, prepare for, recover, learn, and improve from an external disturbance regime that comprises of a series of chronic low-intensity and infrequent acute shocks, which disrupt functionality. Here, we present a new systems-level model for coupled technological systems, which provide functionality, and social systems in charge of management. Each system is characterized by a single, aggregated, dynamic state variable, namely (1) critical service deficit, representing services/functionality not provided by the technological system to match demands, and (2) adaptive capacity, representing total resources available to the managing/social institutions to maintain and repair critical services. These coupled systems are subjected to an external stochastic disturbance regime (Poisson shocks), and temporal perturbations in the two state variables are simulated. We use this “toy” model to simulate four hypothetical scenarios to illustrate likely coupled system temporal trajectories and shifts between a desirable (full service) and an undesirable (limited service) regime or complete system collapse (no service, no adaptive capacity). We also present several quantitative approaches to assess time series data and examine coupled systems dynamics. Resilience of the coupled systems for coping with and recovering from service losses is a dynamic property, contingent on system parameters that define the initial conditions before the shocks and recovery, and the frequency and magnitude of shocks.

A selective inhibitor of the kinetoplastid proteasome (GNF6702) is identified that is highly efficacious in vivo , clearing the parasites that cause leishmaniasis, Chagas disease and sleeping sickness from mice, highlighting the possibility of developing a single class of drugs for these neglected diseases. Three tropical diseases targeted by new drug Chagas disease, leishmaniasis, and sleeping sickness are caused by the kinetoplastid parasites Trypanosoma cruzi , Leishmania spp. and Trypanosoma brucei spp., respectively, and affect 20 million people worldwide. This study reports the results of a screen to find new conserved molecular targets and broad spectrum drugs that could be used to treat all three diseases. A selective inhibitor of the kinetoplastid proteasome (GNF6702) was identified as the most effective. It is highly efficacious in vivo , clearing parasites from mice in all three models of infection. GNF6702 is a non-competitive inhibitor, specific for kinetoplastid proteasome, and is well-tolerated in mice. These results highlight the possibility of developing a single class of drugs for these neglected diseases. Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually 1 . The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi , Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target 2 . However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

•13% of all cases of rotavirus gastroenteritis in a Delhi hospital were between 0 and 2 months of age.•18% of all cases of rotavirus gastroenteritis were between 3 and 5 months.•Severe dehydration, acidosis and acidemia were more common in the 0–5 age group than in older children. This study investigated the severity of rotavirus gastroenteritis (RVGE) in hospitalized children less than 60 months of age and compared severity in the first five months of life to severity in children 6 to 23 months of age. Results from a 3 year surveillance study show an early peak of rotavirus disease, with 117 (31%) RVGE hospitalizations in children <6 months old. Higher incidence of severe dehydration, acidemia and acidosis at admission and prolonged hospitalization >7 days were seen in infants 0–5 months of age. The findings support the need for consideration of timely immunization or an accelerated immunization schedule with a birth dose to protect this vulnerable age.

This paper presents the theoretical study and analyzes the comparison of porous structures on the performance of a couple stress fluid based on rough slider bearing. The globular sphere model of Kozeny-Carman and Irmay’s capillary fissures model have been subjected to investigations. A more general form of surface roughness is mathematically modeled by a stochastic random variable with non-zero mean, variance and skewness. The stochastically averaged Reynolds type equation has been solved under suitable boundary conditions to obtain the pressure distribution in turn which gives the expression for the load carrying capacity, frictional force and coefficient of friction. The results are illustrated by graphical representations which show that the introduction of combined porous structure with couple stress fluid results in an enhanced load carrying capacity more in the case of Kozeny-Carman model as compared to Irmay’s model.

Tuberculosis kills more than a million people annually, and new treatments are necessary to counter the spread of drug-resistant forms of Mycobacterium tuberculosis . In this issue, Kevin Pethe and his colleagues report their identification of a new antibercular drug, called Q203, that targets the mycobacterial cytochrome bc 1 complex and that showed efficacy in vitro and in vivo . New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide 1 , 2 . The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis 3 , 4 , 5 , several of which are currently in clinical trials 6 , 7 , 8 . However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc 1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

Tissue-repair regulatory T cells (trTregs) comprise a specialized cell subset essential for tissue homeostasis and repair. While well-studied in sterile injury models, their role in infection-induced tissue damage and antimicrobial immunity is less understood. We investigated trTreg dynamics during acute Trypanosoma cruzi infection, marked by extensive tissue damage and strong CD8+ immunity. Unlike sterile injury models, trTregs significantly declined in secondary lymphoid organs and non-lymphoid target tissues during infection, correlating with systemic and local tissue damage, and downregulation of function-associated genes in skeletal muscle. This decline was linked to decreased systemic IL-33 levels, a key trTreg growth factor, and promoted by the Th1 cytokine IFN-γ. Early recombinant IL-33 treatment increased trTregs, type 2 innate lymphoid cells, and parasite-specific CD8+ cells at specific time points after infection, leading to reduced tissue damage, lower parasite burden, and improved disease outcome. Our findings not only provide novel insights into trTregs during infection but also highlight the potential of optimizing immune balance by modulating trTreg responses to promote tissue repair while maintaining effective pathogen control during infection-induced injury.