Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

BACKGROUND: HIV-1 escapes antiretroviral drugs by integrating into the host DNA and forming a latent transcriptionally silent HIV-1 provirus. This provirus presents the major hurdle in HIV-1 eradication and cure. Transcriptional activation, which is prerequisite for reactivation and the eradication of latent proviruses, is impaired in latently infected T cells due to the lack of host transcription factors, primarily NF-κB and P-TEFb (CDK9/cyclin T1). We and others previously showed that protein phosphatase-1 (PP1) regulates HIV-1 transcription by modulating CDK9 phosphorylation. Recently we have developed a panel of small molecular compounds targeting a non-catalytic site of PP1. RESULTS: Here we generated a new class of sulfonamide-containing compounds that activated HIV-1 in acute and latently infected cells. Among the tested molecules, a small molecule activator of PP1 (SMAPP1) induced both HIV-1 replication and reactivation of latent HIV-1 in chronically infected cultured and primary cells. In vitro, SMAPP1 interacted with PP1 and increased PP1 activity toward a recombinant substrate. Treatment with SMAPP1 increased phosphorylation of CDK9\u27s Ser90 and Thr186 residues, but not Ser175. Proteomic analysis showed upregulation of P-TEFb and PP1 related proteins, including PP1 regulatory subunit Sds22 in SMAPP1-treated T cells. Docking analysis identified a PP1 binding site for SMAPP1 located within the C-terminal binding pocket of PP1. CONCLUSION: We identified a novel class of PP1-targeting compounds that reactivate latent HIV-1 provirus by targeting PP1, increasing CDK9 phosphorylation and enhancing HIV transcription. This compound represents a novel candidate for anti-HIV-1 therapeutics aiming at eradication of latent HIV-1 reservoirs

ASSESSMENT OF CYP2D6*10 POLYMORPHISM WITH POST HERPETIC NEURALGIA PATIENTS UNDERGOING TRAMADOL TREATMENT

objective: To evaluate association of CYP2D6*10 polymorphism with respect to demographic characteristics (age at onset, genders and weight), numerical rating scale (NRS) for measuring pain intensity in relation with resting and movement associated pain and adverse drug effects of PHN patients receiving tramadol therapy. Methods: Total 246 patients of PHN (148 males and 98 females) were selected who fulfilled the inclusion/exclusion criteria. Clinicians were recorded numerical rating scores (at rest and with movement), and note down adverse drug side effects during the time of study. All samples were analyzed for CYP2D6*10 polymorphism using PCR-RFLP method. results: We observed genotype distribution of CYP2D6* 10 did not vary significantly with age at onset [non-responders (p=0.317) and responders (p=0.260)], genders[ non-responders (p=0.317) and responders (p=0.949)], and weight [non-responders (p=0.298) and responders (p=0.279)] and also did not find significant role with respect to resting (p=0.428) and movement associated type of pain (p=0.178). In addition, CYP2D6*10 was not associated with adverse effects such as somnolence (p=0.135), dizziness (p=0.178), local site reactions (p=0.535), headache (p=0.502), hypotension (p=0.567) and nausea and vomiting (p=0.268) of analgesic therapy. Therefore we conclude that, CYP2D6*10 may not be a predictor of treatment outcomes of patients with PHN receiving tramadol

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

The Role of NGOs in Promoting Women Entrepreneurship in India

Entrepreneurship is emerging as an important avenue in gaining economic independence for women. In last two decades (in post-liberalisation era), the economic reforms coupled with loosening of social restrictions has further provided an impetus to women to become entrepreneurs. According to the current trends most of the emerging women entrepreneurs are in small and micro enterprises. A cursory look at their situation highlights a number of major challenges faced by them. These challenges can be broadly classified as: lack of awareness, lack of information, difficulty in accessibility of finance, lack of easy access of entrepreneurial training and post training support, lack of market and network support, lack of self-confidence and managerial skills etc. In recent times, the government has realised the importance of entrepreneurship as a prominent alternative to traditional wage employment in the new economy, and its role in increasing the pace of economic growth. Therefore, Indian government has come up with various special policy measures to help women entrepreneurs. However, there are major limitations among women entrepreneurs in accessing those facilities. These limitations arise due to various factors, such as: bureaucratic hassles, far reaching location of the government training centres, lack of transportation mainly in remote areas, restriction of government officials in terms of timing when women also have to perform household activities etc. At this point, the NGOs emerge as a viable and important medium to support and promote women entrepreneurs. A number of NGOs in India are trying to help women entrepreneurs at various levels. To name a few, the AWAKE, the ICECD and the FIWE, three prominent NGOs in this field providing services to women entrepreneurs for more than 15 years. An attempt has been made in the present study to explore the approach and activities of the NGOs (considering the AWAKE, the ICECD and the FIWE as case study for the present research) in order to meet the above mentioned challenges. This also provides the answer to the central research questions of the present research. It is important to highlight that a very limited number of substantial literatures are available on the NGOs and its contribution to the promotion of women entrepreneurship in India. The present study contributes significantly to the knowledge about the appropriate and effective approach of the NGOs to support women entrepreneurship in India. The study also highlights the various limitations of the NGOs while performing these activities. It is hoped that the finding will be helpful to the planners and policy makers in the field of women entrepreneurship. The study would also be great use to the researchers, professionals, corporate consultants and other NGOs interested in the field of entrepreneurship development in general and women entrepreneurship in particular

Metallomicelles as potent catalysts for the ester hydrolysis reactions in water

Synthetic amphiphiles have been employed for the investigation of diverse topics, e.g. membrane mimetics, drug delivery, ion sensing and even in certain separation processes. Metal-complexing amphiphiles comprise an interesting class of compounds possessing multiple utilities. Upon solubilization in water they form metallomicelles. For achieving specific catalysis of a variety of reactions, metallomicelles were utilized by applying the principles of coordination chemistry and self-organizing systems. Because of their certain similarities with the natural enzymes, metallomicelles were synthesized as catalysts for many reactions. In particular the metallomicelles play a catalytic role in reactions involving the hydrolysis of activated carboxylate esters, phosphate esters and amides at ambient conditions near neutral pH. Apart from the hydrolysis reactions, these were exploited to play pertinent role as Lewis acid catalysts in cycloaddition reactions, and in other reactions such as phenolic oxidation in presence of hydrogen peroxide. In this review we emphasize with the help of assorted examples, the design, synthesis of metal-complexing amphiphiles and their aggregation behavior leading to catalytic hydrolysis reactions in aqueous media

Detecting biologically relevant phosphates with locked salicylaldehyde probes in water

This communication describes a disassembly based approach for the detection of biologically relevant di- and triphosphates in water using locked fluorescent salicylaldehyde probes

Metallomicelles as potent catalysts for the ester hydrolysis reactions in water

Synthetic amphiphiles have been employed for the investigation of diverse topics, e.g. membrane mimetics, drug delivery, ion sensing and even in certain separation processes. Metal-complexing amphiphiles comprise an interesting class of compounds possessing multiple utilities. Upon solubilization in water they form metallomicelles. For achieving specific catalysis of a variety of reactions, metallomicelles were utilized by applying the principles of coordination chemistry and self-organizing systems. Because of their certain similarities with the natural enzymes, metallomicelles were synthesized as catalysts for many reactions. In particular the metallomicelles play a catalytic role in reactions involving the hydrolysis of activated carboxylate esters, phosphate esters and amides at ambient conditions near neutral pH. Apart from the hydrolysis reactions, these were exploited to play pertinent role as Lewis acid catalysts in cycloaddition reactions, and in other reactions such as phenolic oxidation in presence of hydrogen peroxide. In this review we emphasize with the help of assorted examples, the design, synthesis of metal-complexing amphiphiles and their aggregation behavior leading to catalytic hydrolysis reactions in aqueous media

Role of cellular iron and oxygen in the regulation of HIV-1 infection

Despite efficient antiretroviral therapy, eradication of HIV-1 infection is challenging and requires novel biological insights and therapeutic strategies. Among other physiological and environmental factors, intracellular iron greatly affects HIV-1 replication. Higher iron stores were shown to be associated with faster progression of HIV-1 infection and to inversely correlate with the survival of HIV-1 infected patients. Iron is required for several steps in the HIV-1 life cycle, including reverse transcription, HIV-1 gene expression and capsid assembly. Here, the authors present a comprehensive review of the molecular mechanisms involved in iron-and oxygen-mediated regulation of HIV-1 replication. We also propose key intracellular pathways that may be involved in regulating HIV-1 replication via protein kinase complexes, CDK9/cyclin T1 and CDK2/cyclin E, protein phosphatase-1 and other host factors. © 2013 Future Medicine Ltd

Influence of antibiotic on the growth of M.canis and H.capsulatum

ABSTRACT- Antibiotics are organic substance which check the the growth of fungus. During the study for the influence of antibiotic on the growth of fungi-10 gms of each antibiotics were added to 50 ml of Sabourd dextrose (SD) liquid media. Later on they inoculated with fungus and incubated at 25±1°c for 15 days.After 15 days grown fungal were measured. The growth performance of M. canis and Histoplasma capsulatum on different antibiotics are as in order – 1. Actidione< chloromycetin<penicillin< streptomycin< tetracycline< control (M. canis) 2. Actodione< streptomycin<tetracycline< chloromycetin <control (H. capsulatum). During my study finally It was concluded that actidione was antibiotic the best drug which check the growth of fungal growth population. tetracycline and penicillin was found to be best growth promoter of mycelial fungus in both genera Key words-Antibiotic,control, mycelia,fungus Antibiotics are organic substances which are responsible for influencing of mycelia fungus. Sometime they showed their worst growth and sometime they are responsible for the best growth of mycelia fungus. The present papers deals with influence o