Cystatin F Depletion in -Infected Macrophages Improves Cathepsin C/Granzyme B-Driven Cytotoxic Effects on HIV-Infected Cells during Coinfection.

Cystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in activating the perforin/granzyme cytotoxic pathways. It is targeted at the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CstF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loads.

Investigating the potent TOPO IIα inhibitors in breast cancer through the study of computational drug discovery research approaches.

Breast cancer (BC) is the second-leading cause of cancer after lung cancer. The disease has affected millions of people and resulted in many deaths. In the metastasis of breast cancer cells, Topoisomerase IIα plays a vital role.

Modulation of Cystatin F in Human Macrophages Impacts Cathepsin-Driven Killing of Multidrug-Resistant .

Tuberculosis (TB) treatment relies primarily on 70-year-old drugs, and prophylaxis suffers from the lack of an effective vaccine. Among the 10 million people exhibiting disease symptoms yearly, 450,000 have multidrug or extensively drug-resistant (MDR or XDR) TB. A greater understanding of host and pathogen interactions will lead to new therapeutic interventions for TB eradication.

ESAT-6 a Major Virulence Factor of .

(Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission arises.

HIV/Mtb Co-Infection: From the Amplification of Disease Pathogenesis to an "Emerging Syndemic".

Human immunodeficiency virus (HIV) and (Mtb) are pathogens responsible for millions of new infections each year; together, they cause high morbidity and mortality worldwide. In addition, late-stage HIV infection increases the risk of developing tuberculosis (TB) by a factor of 20 in latently infected people, and even patients with controlled HIV infection on antiretroviral therapy (ART) have a fourfold increased risk of developing TB. Conversely, Mtb infection exacerbates HIV pathogenesis and increases the rate of AIDS progression.

Development of Chitosan Particles Loaded with siRNA for Cystatin C to Control Intracellular Drug-Resistant .

The golden age of antibiotics for tuberculosis (TB) is marked by its success in the 1950s of the last century. However, TB is not under control, and the rise in antibiotic resistance worldwide is a major threat to global health care. Understanding the complex interactions between TB bacilli and their host can inform the rational design of better TB therapeutics, including vaccines, new antibiotics, and host-directed therapies.

Release of a Proton and Formation of a Low-Barrier Hydrogen Bond between Tyrosine D and D2-His189 in Photosystem II.

In photosystem II (PSII), the second-lowest oxidation state (S) of the oxygen-evolving MnCaO cluster is the most stable, as the radical form of the redox-active D2-Tyr160 is considered to be a candidate that accepts an electron from the lowest oxidation state (S) in the dark. Using quantum mechanical/molecular mechanical calculations, we investigated the redox potential ( ) of TyrD and its H-bond partner, D2-His189. The potential energy profile indicates that the release of a proton from the TyrD.

Substitution of Ca and changes in the H-bond network near the oxygen-evolving complex of photosystem II.

Ca, which provides binding sites for ligand water molecules W3 and W4 in the MnCaO cluster, is a prerequisite for O evolution in photosystem II (PSII). We report structural changes in the H-bond network and the catalytic cluster itself upon the replacement of Ca with other alkaline earth metals, using a quantum mechanical/molecular mechanical approach. The small radius of Mg makes W3 donate an H-bond to D1-Glu189 in Mg-PSII.

Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by and Helps Control the Phagosomal Replicative Niches.

is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the switch for the active infection called tuberculosis to occur. Our group found that the pathogen is able to manipulate the activity of endolysosomal enzymes, cathepsins, directly at the level of gene expression or indirectly by regulating their natural inhibitors, cystatins.

Spatial localization of cathepsins: Implications in immune activation and resolution during infections.

Cathepsins were first described, as endolysosomal proteolytic enzymes in reference to the organelles where they degrade the bulk of endogenous and exogenous substrates in a slightly acidic environment. These substrates include pathogens internalized endocytosis and/or marked for destruction by autophagy. However, the role of cathepsins during infection far exceeds that of direct digestion of the pathogen.

Impact of air pollutants on COVID-19 transmission: a study over different metropolitan cities in India.

India is affected strongly by the Coronavirus and within a short period, it becomes the second-highest country based on the infected case. Earlier, there was an indication of the impact of pollution on COVID-19 transmission from a few studies with early COVID-19 data. The study of the effect of pollution on COVID-19 in Indian metropolitan cities is ideal due to the high level of pollution and COVID-19 transmission in these cities.

Impact of climate on COVID-19 transmission: A study over Indian states.

Coronavirus Disease-2019 (COVID-19) started in Wuhan province of China in November 2019 and within a short time, it was declared as a worldwide pandemic by World Health Organisation due to the very fast worldwide spread of the virus. There are a few studies that look for the correlation with infected individuals and different environmental parameters using early data of COVID-19 but there is no study so far that deals with the variation of effective reproduction number and environmental factors. Effective reproduction number is the driving parameter of the spread of a pandemic and it is important to study the effect of various environmental factors on effective reproduction number to understand the effect of those factors on the spread of the virus.

Natural Product-Based Potential Therapeutic Interventions of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a disease-refractive lung condition with an increased rate of mortality. The potential factors causing PF include viral infections, radiation exposure, and toxic airborne chemicals. Idiopathic PF (IPF) is related to pneumonia affecting the elderly and is characterized by recurring scar formation in the lungs.

Structure-based discovery of small molecules improving stability of human broadly-neutralizing anti-HIV antibody 2F5 in plant suspension cells.

The production of biopharmaceuticals in engineered plant-based systems is a promising technology that has proven its suitability for the production of various recombinant glyco-proteins that are currently undergoing clinical trials. However, compared to mammalian cell lines, the productivity of plant-based systems still requires further improvement. A major obstacle is the proteolytic degradation of recombinant target proteins by endogenous plant proteases mainly from the subtilisin family of serine proteases.

Requirement of Chloride for the Downhill Electron Transfer Pathway from the Water-Splitting Center in Natural Photosynthesis.

In photosystem II (PSII), Cl is a prerequisite for the second flash-induced oxidation of the MnCaO cluster (the S to S transition). We report proton transfer from the substrate water molecule via D1-Asp61 and electron transfer via redox-active D1-Tyr161 (TyrZ) to the chlorophyll pair in Cl-depleted PSII using a quantum mechanical/molecular mechanical approach. The low-barrier H-bond formation between the substrate water molecule and D1-Asp61 remained unaffected upon the depletion of Cl.

Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Infection and Coinfection With HIV.

Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches.

Effect of 2021 assembly election in India on COVID-19 transmission.

India is one of the countries in the world which is badly affected by the COVID-19 second wave. Assembly election in four states and a union territory of India was taken place during March-May 2021 when the COVID-19 second wave was close to its peak and affected a huge number of people. We studied the impact of assembly election on the effective contact rate and the effective reproduction number of COVID-19 using different epidemiological models like SIR, SIRD, and SEIR.

Role of redox-inactive metals in controlling the redox potential of heterometallic manganese-oxido clusters.

Photosystem II (PSII) contains Ca, which is essential to the oxygen-evolving activity of the catalytic MnCaO complex. Replacement of Ca with other redox-inactive metals results in a loss/decrease of oxygen-evolving activity. To investigate the role of Ca in this catalytic reaction, we investigate artificial Mn[M]O clusters redox-inactive metals  [M] ([M]  = Mg, Ca, Zn, Sr, and Y), which were synthesized by Tsui et al.

Proton exit pathways surrounding the oxygen evolving complex of photosystem II.

Photosystem II allows water to be the primary electron source for the photosynthetic electron transfer chain. Water is oxidized to dioxygen at the Oxygen Evolving Complex (OEC), a MnCaO inorganic core embedded on the lumenal side of PSII. Water-filled channels surrounding the OEC must bring in substrate water molecules, remove the product protons to the lumen, and may transport the product oxygen.

Two Distinct Oxygen-Radical Conformations in the X-ray Free Electron Laser Structures of Photosystem II.

We report the existence of two distinct oxygen-radical-containing MnCaO conformations with short O···O bonds in the crystal structures of the oxygen-evolving enzyme photosystem II (PSII), obtained using an X-ray free electron laser (XFEL). A short O···O distance of <2.3 Å between the O4 site of the MnCaO complex and the adjacent water molecule (W539) in the proton-conducting O4-water chain was observed in the second flash-induced (2F) XFEL structure (2F-XFEL), which may correspond to S.

Repurposing Saquinavir for Host-Directed Therapy to Control Mycobacterium Tuberculosis Infection.

Despite the available antibiotics, tuberculosis (TB) has made its return since the 90's of the last century as a global threat mostly due to co-infection with HIV, to the emergence of drug resistant strains and the lack of an effective vaccine. Host-directed strategies could be exploited to improve treatment efficacy, contain drug-resistant strains, improve immune responses and reduce disease severity. Macrophages in the lungs are often found infected with (Mtb) and/or with HIV.

The Nature of the Short Oxygen-Oxygen Distance in the MnCaO Complex of Photosystem II Crystals.

The O···O distance for a typical H-bond is ∼2.8 Å, whereas the radiation-damage-free structures of photosystem II (PSII), obtained using the X-ray free electron laser (XFEL), shows remarkably short O···O distances of ∼2 Å in the oxygen-evolving MnCaO complex. Herein, we report the protonation/oxidation states of the short O···O atoms in the XFEL structures using a quantum mechanical/molecular mechanical approach.

Redox potentials along the redox-active low-barrier H-bonds in electron transfer pathways.

Low-barrier H-bonds form when the pKa values of the H-bond donor and acceptor moieties are nearly equal. Here, we report redox potential (Em) values along two redox-active low-barrier H-bonds in the water-oxidizing enzyme photosystem II (PSII), using a quantum mechanical/molecular mechanical approach. The low-barrier H-bond between D1-Tyr161 (TyrZ) and D1-His190 is located in the middle of the electron transfer pathway.

Characterization of the J2315 Surface-Exposed Immunoproteome.

Infections by the complex (Bcc) remain seriously life threatening to cystic fibrosis (CF) patients, and no effective eradication is available. A vaccine to protect patients against Bcc infections is a highly attractive therapeutic option, but none is available. A strategy combining the bioinformatics identification of putative surface-exposed proteins with an experimental approach encompassing the "shaving" of surface-exposed proteins with trypsin followed by peptide identification by liquid chromatography and mass spectrometry is here reported.

Energetics of Ionized Water Molecules in the H-Bond Network near the Ca and Cl Binding Sites in Photosystem II.

In photosystem II, water oxidation occurs at the oxygen-evolving complex (OEC). The presence of a hydronium ion (HO) was proposed at the Cl binding site and Ca-depleted OEC. Using a quantum mechanical/molecular mechanical approach, we report the stability of HO in the PSII protein environment.