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Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

Summary Background Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. Methods We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. Findings We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0–75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8–90·9), for 3 years was 97·3% (95·2–98·6), and for 5 years was 98·6% (97·6–100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3–95·9), for 3 years was 97·8% (96·6–99·3), and for 5 years was 96·6% (94·0–98·9). Interpretation These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. Funding European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d’HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.

Among the global coordinated patterns in soil temperature and methane emission from wetlands, a declining trend of optimal soil temperature for methane emissions from low to high latitudes has been witnessed, while the corresponding trend along the altitudinal gradient has not yet been investigated. We therefore selected two natural wetlands located at contrasting climatic zones from foothill and mountainside of Nepal Himalayas, to test: (1) whether the optimal temperature for methane emissions decreases from low to high altitude, and (2) whether there is a difference in temperature sensitivity of methane emissions from those wetlands. We found significant spatial and temporal variation of methane emissions between the two wetlands and seasons. Soil temperature was the dominant driver for seasonal variation in methane emissions from both wetlands, though its effect was perplexed by the level of standing water, aquatic plants, and dissolved organic carbon, particularly in the deep water area. When integrative comparison was conducted by adding the existing data from wetlands of diverse altitudes, and the latitude-for-altitude effect was taken into account, we found the baseline soil temperatures decrease whilst the altitude rises with respect to a rapid increase in methane emission from all wetlands, however, remarkably higher sensitivity of methane emissions to soil temperature (apparent Q10 ) was found in mid-altitude wetland. We provide the first evidence of an apparent decline in optimal temperature for methane emissions with increasing elevation. These findings suggest a convergent pattern of methane emissions with respect to seasonal temperature shifts from wetlands along altitudinal gradient, while a divergent pattern in temperature sensitivities exhibits a single peak in mid-altitude.

Development and progression of metastasis comprises synchronized erroneous expressions of several composite pathways, which are difficult to manage simultaneously with the representative anticancer molecules. The emergence of the drug resistance and the complex interplay between these pathways further potentiates cancer related complexities. Barbiturates and their derivatives present a commendable anticancer profile by attenuating the cancer manifesting metabolic and enzymatic pathways including, but not limited to matrix metalloproteinases, xanthine oxidase, amino peptidases, histone deacetylases, and Ras/mitogen-activated protein kinase. The derivatization and conjugation of barbiturates with pharmacophores delivers a suitable hybrid profile in containing the anomalous expression of these pathways. The present report presents a succinct collation of the barbiturates and their derivatives in managing the various cancer causing pathways.

Soil respiration (SR), a natural phenomenon, emits ten times more CO2 from land than anthropogenic sources. It is predicted that climate warming would increase SR in most ecosystems and give rise to positive feedback. However, there are uncertainties associated with this prediction primarily due to variability in the relationship of SR with its two significant drivers, soil temperature and moisture. Accounting for the variabilities, we use a climosequence in Himalaya with a temperature gradient of ~ 2.1 °C to understand the variations in the response of SR and its temperature sensitivity to climate change. Results indicate an equilibrium in SR ranging from 1.92 to 2.42 µmol m−2 s−1 across an elevation gradient (3300–3900 m) despite its increased sensitivity to temperature (Q10) from 0.47 to 4.97. Additionally, moisture reduction towards lower elevation weakens the temperature-SR relationship. Finally, soil organic carbon shows similarities at all the elevations, indicating a net-zero CO2 flux across the climosequence. The findings suggest that as the climate warms in this region, the temperature sensitivity of SR reduces drastically due to moisture reduction, limiting any change in SR and soil organic carbon to rising temperature. We introduce an equilibrium mechanism in this study which indicates the resilient nature of SR to climate change and will aid in enhancing the accuracy of climate change impact projections.

Though HIV interventions have been implemented in India since over a decade, HIV prevalence among men who have sex with men (MSM) and transgender women (TGW) in India (2.7% and 3.1%, respectively) continues to be 10–15 times higher than that observed among heterosexual communities (0.34%). While evidence for nationwide prevalence of STIs is lacking, independent studies have estimated STI rates at 12–38%. Further, clinic data from The Humsafar Trust--an LGBTQ+ organization in Mumbai providing HIV outreach services to over 7500 MSM and TGW annually--has estimated syphilis rates to be 10% in 2018 and 12% in 2019. A key challenge in addressing these STI trends is the limited availability of prevalence-focused programmatic implementation and bio-behavioral research on STI awareness/health seeking behavior among vulnerable communities. Though syphilis testing has been integrated in national HIV interventions, management of other STIs is syndromic resulting in under-diagnoses and under-reporting. Further, lack of dedicated resources toward building knowledge and awareness of STIs among vulnerable communities leads to low risk-perception and compromised uptake of testing and treatment. While evidence building and documentation can be strengthened by informed and uniform integration of STI testing within HIV programs, uptake of knowledge, awareness and health services much rely on engagement and involvement of vulnerable communities. Thus, enabling and building community response is critical in addressing issues pertaining to STI management. Community involvement can guide implementation and design for STI-focused interventions; strengthen on-ground outreach; identify barriers; and promote awareness of testing and treatment. As quality evidence is vital for informing strategies, it is critical to strengthen capacities and have communities’ involvement in STI research. While community engagement and -stake may not address all challenges, it will be a solid step toward mitigating critical issues of low risk-perception and low uptake of STI testing and treatment among vulnerable communities.

Diabetic ketoacidosis (DKA) is a life threatening metabolic disorder and a known complication of Diabetes mellitus, caused by insulin deficiency or insulin resistance, which allows the catabolism of free fatty acids into ketone bodies, with high blood sugar levels. A rare variant of it is, euglycemic diabetic ketoacidosis (EKDA). We report a case of 60 year old female who was posted for Posterior lumbar interbody fusion (PLIF) and had this complication postoperatively. We believe that this case would serve as a reminder to all practitioners and intensivist to consider ketosis in a diabetic patient despite their serum glucose levels being within the normal range and all anaesthetist to consider the use of insulin during the intra op period even the blood sugar level is normal in peri operative period. This case report summarizes, in brief, the etiology, pathophysiology and treatment of EDKA.

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four-drug treatment regimen was introduced 40 years ago but the emergence of multidrug-resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti-TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.

Curcumin has been known to possess diverse pharmacological effects at relatively nontoxic doses; however, its therapeutic potential is severely restricted because of its low aqueous solubility and poor stability under physiological conditions. To overcome its limitations, we had previously designed several monocarbonyl curcuminoids by modifying the central β-diketone moiety of curcumin. In this study, the antibacterial activity of 33 curcuminoids from this designed library has been screened, six of which displayed potent antibacterial activity against clinically relevant Staphylococcus aureus. These curcuminoids were found to be very stable at physiological conditions and did not cause any toxicity toward mammalian cells. Mechanistically, out of these six curcuminoids, five caused instant membrane depolarization and were able to permeabilize the bacterial membrane, which could be the reason for their potent bactericidal activity and the sixth one killed staphylococcal cells without damaging the bacterial ...

A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC50 values in the range 0.0189–0.945 μM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction.

The Himalayan region is one of the global biodiversity hotspots. However, its biodiversity and ecosystems are threatened due to abiotic and biotic drivers. One of the major biotic threats to biodiversity in this region is the rapid spread of Invasive Alien Species (IAS). Natural forests and grasslands are increasingly getting infested by IAS affecting regeneration of native species and decline in availability of bio-resources. Assessing the current status of IAS and prediction of their future spread would be vital for evolving specific species management interventions. Keeping this in view, we conducted an in-depth study on two IASs, viz.,Ageratina adenophoraandLantana camarain the Indian part of Kailash Sacred Landscape (KSL), Western Himalaya. Intensive field surveys were conducted to collect the presence ofA.adenophora(n= 567) andL.camara(n= 120) along an altitudinal gradient between 300 and 3000 m a.s.l. We performed Principal Component Analysis to nullify the multi-colinearity effects of the environmental predictors followingMaxEntspecies distribution model in the current and future climatic scenarios for both the species. All current and future model precision (i.e., Area Under the Curve; AUC) for both species was higher than 0.81. It is predicted that under the current rate of climate change and higher emission (i.e., RCP 8.5 pathway),A.adenophorawill spread 45.3% more than its current distribution and is likely to reach up to 3029 m a.s.l., whereas,L.camarawill spread 29.8% more than its current distribution range and likely to reach up to 3018 m a.s.l. Our results will help in future conservation planning and participatory management of forests and grasslands in the Kailash Sacred Landscape–India.

Serotonin is a neurotransmitter that plays a crucial role in the regulation of several behavioral and cognitive functions by binding to a number of different serotonin receptors present on the cell surface. We report here the synthesis and characterization of several novel fluorescent analogs of serotonin in which the fluorescent NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) group is covalently attached to serotonin. The fluorescent ligands compete with the serotonin1A receptor specific radiolabeled agonist for binding to the receptor. Interestingly, these fluorescent ligands display a high environmental sensitivity of their fluorescence. Importantly, the human serotonin1A receptor stably expressed in CHO-K1 cells could be specifically labeled with one of the fluorescent ligands with minimal nonspecific labeling. Interestingly, we show by spectral imaging that the NBD-labeled ligand exhibits a red edge excitation shift (REES) of 29 nm when bound to the receptor, implying that it is localized in a restricted microenvironment. Taken together, our results show that NBD-labeled serotonin analogs offer an attractive fluorescent approach for elucidating the molecular environment of the serotonin binding site in serotonin receptors. In view of the multiple roles played by the serotonergic systems in the central and peripheral nervous systems, these fluorescent ligands would be useful in future studies involving serotonin receptors.

Alpine ecosystems in the Himalaya, despite low primary productivity, store considerable amount of organic carbon. However, these ecosystems are highly vulnerable to climate warming which may stimulate ecosystem carbon efflux leading to carbon-loss and positive feedback. We used open-top chambers to understand warming responses of ecosystem respiration (ER) and soil respiration (SR) in two types of alpine meadows viz., herbaceous meadow (HM) and sedge meadow (SM), in the Western Himalaya. Experimental warming increased ER by 33% and 28% at HM and SM, respectively. No significant effect on SR was observed under warming, suggesting that the increase in ER was primarily due to an increase in above-ground respiration. This was supported by the warming-induced increase in above-ground biomass and decrease in SR/ER ratio. Soil temperature was the dominant controlling factor of respiration rates and temperature sensitivity of both ER and SR increased under warming, indicating an increase in contribution from plant respiration. The findings of the study suggest that climate warming by 1.5–2 °C would promote ER via increase in above-ground respiration during the growing season. Moreover, net C uptake in the alpine meadows may increase due to enhanced plant growth and relatively resistant SR under warming.

Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrug-resistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability. To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC99 in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC99 in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg.

A persistent infection prolongs treatment duration and also enhances the chance of resistance development against antibiotics. Recently, a class of amphiphilic indole derivatives was discovered exhibiting bactericidal activity against both growing and nongrowing Mycobacterium bovis BCG (M. bovis BCG). These antibacterials are suggested to disturb the integrity and functioning of the cell membrane, a property that can help eradicate persistent organisms. This study article describes field-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of 79 amphiphilic indole derivatives. The aim of this QSAR study is to optimize this class of compounds for the development of more potent antimycobacterial agents. The results obtained indicate that steric interactions are crucial for antimycobacterial activity, while hydrogen bond donor groups participate negligibly in activity. The derived 3D-QSAR models showed acceptable r2 (0.91) and q2 (0.91) with a root mean squared error (RMSE) of 0.08. The models were cross-validated using the leave-one-out method. Applying the same QSAR model to another congeneric series of amphiphilic indoles externally validated the QSAR model. The model could appreciably predict the activity (pMIC50 ) of this congeneric series of amphiphilic indoles, with an RMSE of 0.49, indicating the robustness of the model and its efficiency in predicting the potentially active compounds.

The increasing incident rates of drug-resistant tuberculosis (DR-TB) is a global health concern and has been further complicated by the emergence of extensive and total drug-resistant strains. Identification of new chemical entities which are compatible with first-line TB drugs, possess activity against DR-, and metabolically less active bacteria is required to tackle this epidemic. Here, we have performed phenotypic screening of a small molecule library against Mycobacterium bovis BCG and identified 24 scaffolds that exhibited MIC99 values of at least 2.5 μM. The most potent small molecule identified in our study was a nitroso containing pyrazole derivative, NSC 18725. We observed a significant reduction in viable bacilli load of starved Mycobacterium tuberculosis upon exposure to NSC 18725. The action of NSC 18725 was “synergistic” with isoniazid (INH) and “additive” with other drugs in our checkerboard assays. Structure-activity relationship (SAR) studies of the parent compound revealed that pyrazole derivatives without a functional group at fourth position lacked anti-mycobacterial activity in vitro. The derivative with para-chlorophenyl substitution at the first position of the pyrazole ring was the most active scaffold. We also demonstrate that NSC 18725 is able to induce autophagy in differentiated THP-1 macrophages. The induction of autophagy by NSC 18725 is the major mechanism for the killing of intracellular slow and fast-growing mycobacteria. Taken together, these observations support the identification of NSC 18725 as an antimycobacterial compound, which synergizes with INH, is active against non-replicative mycobacteria and induces autophagy in macrophages.

Poor oxidation stability of methyl esters is the major problem associated with its worldwide acceptance. As per the standards EN 14214 and prEN16091; and ASTM-D 7545-09 the oxidation stability limit should be 20 h for the blends and 8 h for neat methyl ester. One approach for increasing resistance of fatty acid methyl ester derivatives against autoxidation is to treat them with oxidation inhibitors known as antioxidants. This study examines the effectiveness of five such commercial antioxidants [viz. tert-butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PrG) and pyrogallol (PY)] on the storage stability of Jatropha methyl ester (JOME), Karanja methyl ester (KOME), and their 5%, 10%, 20% and 40% blends with low sulphur EURO-IV High speed Diesel (HSD) using Petrotest PetrOxymeter. The impact of the antioxidants strongly depends on the feed-stock used for biodiesel production. PY was found to be the most effective antioxidant for JOME and its EURO-IV blends; however, PrG has shown maximum effectiveness with KOME and its EURO-IV HSD blends. 500 ppm was found to be the most optimum concentration for both the antioxidants.

Background: The quality of herbal medicine is determined by its secondary metabolites, which may vary according to growth, season and altitude etc. Objective: We studied the variation in phytochemistry and biological activities of Thalictrum foliolosum (TF) roots collected from four sites at different altitudes. Material and methods: The berberine content in different extracts of T. foliolosum roots collected from various altitudes was estimated using HPTLC. Total phenolic and flavonoid contents were determined using Folin-Ciocalteau reagent and aluminum chloride method respectively. The sensitivity of microbes for the extracts was studied using disc diffusion and the MIC was estimated using broth dilution method. Antioxidant capacity of the plant was studied using β-carotene bleaching assay, lipid peroxidation assay using goat liver, reducing power assay and DPPH free radical scavenging activity. Results: Berberine content varied inversely with altitude; while phenol and flavonoid content of TF increased at higher altitudes. All the TF extracts showed moderate to high activity against Candida albicans, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Extracts with high berberine content were most effective against C. albicans and S. aureus and also showed relatively significant anti-lipid peroxidation, β-carotene bleaching and reducing power. TF extracts with higher phenol and flavonoid content showed better scavenging of DPPH free radicals. Berberine was used as a standard in all the antioxidant and antimicrobial experiments performed. Conclusion: Thalictrum from lower elevations can be explored as an alternate source of berberine and the plant has high antioxidant and antimicrobial properties owing to its berberine content. Keywords: Altitudinal variation, Antimicrobial, Antioxidant, Berberine, Flavonoid, HPTLC, Phenolics, Thalictrum foliolosum

Introduction: This study examined the decorporation potential of lansoprazole (LNP) as radioactivity decorporation agent for radiothallium (201Tl) in internally contaminated BALB/c mice and New Zealand White rabbits using radiometry and gamma scintigraphy. Methods: Animals were divided into three groups, that is, control, pretreatment-1 (1X LNP), and pretreatment-2 (2X LNP). Mice received LNP intraperitoneally, while in rabbits LNP was given through oral route 0.5 and 1.5 h before radiothallium administration, respectively. Mice and rabbits used in the experiment were administered 1.48 and 11.1 MBq radiothallium (201TlCl) through intravenous and oral route, respectively. Once started as prophylactic, LNP was continued as therapeutic twice a day till the end of study period. Radiometry and gamma scintigraphy were used to monitor radiothallium retention and uptake patterns in animals. Gamma scintigraphic images of rabbits were taken at different time intervals up to 72 h and were analyzed for comparative uptake pattern of 201TlCl in all the groups. Results: LNP treatment significantly increased the 201Tl elimination over untreated control and considerably reduced the retention of 201Tl in various tissues and organs. Decrease in radiothallium uptake up to 40% was observed in LNP-treated mice as compared to untreated control. While in rabbits, whole-body radioactivity burden at 72 h was found to be 31.24%, 26%, and 18.54% in untreated control, 9 and 18 mg/kg LNP-treated groups, respectively. Conclusion: LNP exhibited dose-dependent decorporation potential to effectively enhance the elimination of 201Tl in mice and rabbits experimentally contaminated with 201TlCl.

A series of antimalarial 4-aminoquinoline-pyrimidine hybrids incorporating modified anilines at the pyrimidine end was designed and synthesized through a facile synthetic route. The present hybrids displayed excellent equipotent in vitro antiplasmodial activities against both chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of P. falciparum with up to 11-fold (IC50=0.033 μM) better activity than the reference drug, (chloroquine, IC50=0.370 μM) against the resistant strain. The compounds were found to be non-cytotoxic towards the mammalian cells up to the highest tested concentration. The present hybrids displayed good binding interactions with both monomeric and dimeric heme, suggesting heme-detoxification as their mechanism of action. Furthermore, the most active hybrids were found to display good in silico docking interactions within the active site of plasmodial dihydrofolate reductase (DHFR) enzyme (wild and mutant type). Computational studies predicted favorable pharmacokinetic parameters and oral drugability for the synthesized molecules.

Ethnopharmacological relevance Terminalia bellerica Roxb. fruits are rich in a variety of biologically active ingredients. Tharu and Buksa tribes of Udham Singh Nagar, Uttarakhand, India use grilled fruits of Terminalia bellerica as an effective cure for diarrhea Aim of the study We validated the ethnobotanical claim by comparing the antidiarrheal effect of grilled fruits (GF) with dried fruits (DF). Materials and methods The 50% ethanolic extracts of GF and DF were successively fractionated; the antioxidant and bacterial inhibition activity were studied using DPPH free radical scavenging, anti-lipid peroxidation and broth dilution method respectively. Difference in metabolites of ethyl acetate fractions of GF and DF was analyzed using GC-MS, gallic acid content was determined through HPTLC. Further the in-vivo antidiarrheal effect of ethyl acetate fractions of DF and GF was studied on castor oil induced diarrhea model. Results The ethyl acetate fractions showed potential DPPH free radical scavenging (IC 50 11.13 µg/ml in DF and 8.56 µg/ml in GF), anti-lipid peroxidation and antibacterial activity. The non-targeted metabolic profiling showed higher content of tartaric acid, valeric acid, gallic acid, succinic acid, oxalic acid, malonic acid, malic acid, 1,2,3 trisbenzene, uridine and 11-eicosenoic acid in GF. The HPTLC results indicated that gallic acid content was 2.8 (±0.14) and 4.92 (±0.28) mg/g while ellagic acid content was 4.7 (±0.32) and 4.45 (±0.45) mg/g dry powder in DF and GF respectively. According to i n vivo antidiarrheal activity DF and GF (100 mg/kg oral) inhibited diarrhea by 41.87% and 71.72% respectively. Conclusion Grilling significantly altered the levels of metabolites in T. bellerica fruits which could be responsible for its increased therapeutic potential.

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.

A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 μM) compared to the reference drug CQ (IC50: 0.5 μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.

C1-Alkynylation of tetrahydroisoquinoline (THIQ) was achieved via the A3 coupling strategy from the reaction of THIQ as a secondary amine, aldehydes and alkynes using the CuO@Fe2O3 nanocatalyst under green reaction conditions. The wide scope of the present method was studied using various aliphatic/aromatic aldehydes and alkynes to afford the corresponding C1-alkynylated products in quantitative yields. Moreover, the present catalytic system was found to be versatile for the decarboxylative A3 coupling strategy with improved progress of reactions by replacing the alkynes with phenylpropiolic acid under optimized conditions. The present catalytic system was found to be robust, magnetically recoverable and recyclable 5 times without significant loss in its activity, offering a low E-factor and high atom economy (AE).

A research experiment was conducted during kharif season of 2017 at College of Agriculture, farm Gwalior (M.P.) under AICRP on Arid Legumes. On the basis of results obtained the variety X-10 gave significantly highest seed yield (2731 kg/ha), net monetary return (‘ 1,25,083/ha), BCR (7.74) and harvest index (27.83%) as compared to other varieties but at par with HG-563, RGC-1033 and HG 2-20 varieties. But the variety RGC-1066 gave significantly lowest seed yield (1736 kg/ha).

It is of utmost importance to research on the spatial patterns of human-wildlife conflicts to understand the underlying mechanism of such interactions, i.e. major land use changes and prominent ecological drivers. In the north eastern part of India there has been a disparity between nature, economic development and fragmentation of wildlife habitats leading to intense conflicts between humans and Asian elephants (Elephas maximus) in recent times. Both the elephant and human population have increased in the past few decades with large tracts of forests converted to commercial tea plantations, army camps and human settlements. We analyzed data maintained by the wildlife department on human deaths and injuries caused by elephant attacks between 2006–2016 to understand spatial and temporal patterns of human-elephant conflict, frequency and distribution. The average annual number of human deaths and injuries to elephant attacks between 2006 to 2016 was estimated to be 212 (SE 103) with the highest number of such incidents recorded in 2010–2011. Based on a grid based design of 5 km2 and 25 km2 resolution, the main spatial predictors of human-elephant conflicts identified through Maxent presence only models are annual mean precipitation, altitude, distance from protected area, area under forests, tea plantations and agriculture. Major land use changes were assessed for this region from 2008 to 2018 using satellite imageries in Arc GIS and a predicted imagery of 2028 was prepared using Idrisi Selva. Based on the 2018 imagery it was found that forest area had increased by 446 km2 within 10 years (2008–2018) and the annual rate of change was 12%. Area under agriculture had reduced by 128 km2 with an annual (-) rate of change of 2.5%. Area under tea plantation declined by 307 km2 with an annual (-) rate of change of 12% whereas area under human settlements increased by 61 km2 with an annual (-) rate of change of 44%. Hotspots of human-elephant conflicts were identified in an east west direction primarily around protected areas, tea plantations and along major riverine corridors. During informal interactions with farmers, tea estate labors it was revealed that local community members chased and harassed elephants from agriculture fields, human settlements under the influence of alcohol and thus were primary victims of fatal interactions. Our analytical approach can be replicated for other species in sites with similar issues of human-wildlife conflicts. The hotspot maps of conflict risk will help in developing appropriate mitigation strategies such as setting up early warning systems, restoration of wildlife corridors especially along dry river beds, using deterrents and barriers for vulnerable. Awareness about alcohol related incidents and basic biology of elephants should be organized regularly involving non-governmental organizations targeting the marginalized farmers and tea estate workers.

Computational fluid dynamics (CFD) is a powerful method to investigate aneurysms. The primary focus of most investigations has been to compute various hemodynamic parameters to assess the risk posed by an aneurysm. Despite the occurrence of transitional flow in aneurysms, turbulence has not received much attention. In this article, we investigate turbulence in the context of abdominal aortic aneurysms (AAA). Since the clinical practice is to diagnose an AAA on the basis of its size, hypothetical axisymmetric geometries of various sizes are constructed. In general, just after the peak systole, a vortex ring is shed from the expansion region of an AAA. As the ring advects downstream, an azimuthal instability sets in and grows in amplitude thereby destabilizing the ring. The eventual breakdown of the vortex ring into smaller vortices leads to turbulent fluctuations. A residence time study is also done to identify blood recirculation zones, as a recirculation region can lead to degradation of the arterial wall. In some of the geometries simulated, the enhanced local mixing due to turbulence does not allow a recirculation zone to form, whereas in other geometries, turbulence had no effect on them. The location and consequence of a recirculation zone suggest that it could develop into an intraluminal thrombus (ILT). Finally, the possible impact of turbulence on the oscillatory shear index (OSI), a hemodynamic parameter, is explored. To conclude, this study highlights how a small change in the geometric aspects of an AAA can lead to a vastly different flow field.

Herbaceous layer remains an underappreciated aspect of forest ecosystem, which serves a special role in maintaining the structure and functioning of forests. It provides important information regarding the site characteristics of forests. Present study examined the effects of site on herbaceous vegetation in an oak-mixed cypress forest in Central Himalaya, India. The study sites are located near Nainital town between 29o36’56”-29o36’79” N latitude and 79o46’03”-79o46’19” E longitude between 1600- 1850 m above mean sea level in the Central Himalaya. Both lowly and highly disturbed sites were further subdivided into three sub-sites (hill base, hill slope and hill top). A total of 35 species represented by twenty families were recorded from the studied sites. Maximum herb species belongs to the Asteraceae family. The lowly disturbed site was more diverse than the highly disturbed one. Total herb density was 344.4 ind.m-2 at highly disturbed site, whereas 481.2 ind.m-2 at lowly disturbed site.

MRSA causes 60-70% of Staphylococcus aureus infection in hospitals and it has developed resistance against the currently available drugs. Interestingly, a series of 35 metronidazole-triazole hybrids on screening against MRSA were found to be active. Compound 22 was found to be effective at 4 μg/mL concentration against nine strains of MRSA. The inhibitory activity was further enhanced upto 1 μg/mL when this compound was used in combination with oxacillin in 1:1 ratio. All the compounds were found to be non-toxic in THP-1 cell line upto a concentration of 50 μM. The time-kill kinetics studies suggested bacteriostatic nature of the compounds. In silico studies show that these compounds interact with Thr600, Ser598, Asn464, His583 and Tyr446 in the active site of PBP2a crystal structure from MRSA.

Background: Non-communicable diseases (NCDs) and psychological hazards are increasingly observed in industries, necessitating the need to strengthen industrial health systems to control the same. District level data on level of functioning of industrial health systems and services with special focus on systems available for mental health care is lacking in India. This information is vital to plan need-based interventions for system strengthening. Objective: To assess the status of functioning of industrial health systems and services in Kolar district, India, with special focus on systems and services available for mental health care. Methods: This cross-sectional study was undertaken between October and December 2014 on a stratified random sample of 69 industries located in Kolar, which were stratified proportionately by their hazardous nature. Interview and observation checklist were used to assess and classify functioning of industrial health systems and services including those available for mental health care. Results: Occupational safety and health (OSH) policy was present in 56% and health insurance in 39% of the 69 industries assessed. Pre-placement and periodical medical examination were conducted in 23% of industries. Health systems and services in hazardous industries were functioning at less than 50% level of functioning. Health systems and services for mental health care were non-existent. Conclusion: There is a need in Kolar district, India, to integrate the mental health components within existing industrial health systems, as per policy directives to implement setting based approaches in mental health programs.

The objective of this study is to develop a folic acid (FA) functionalized co-delivery system for oral delivery of curcumin (CUR) with bioenhancers (B) (“trikatu”) to attenuate hormone refractory prostate cancer. The nano-cur–bioenhancer exhibited significantly elevated cytotoxicity in a prostate cancer cell line (PC3) compared to CUR. Further, mechanistic studies in PC3 cells revealed that nano-cur–bioenhancers induce apoptosis by mitochondrial membrane disruption and a ROS mediated pathway. Collaborative efforts of bioenhancers, mucoadhesive chitosan (CH) and active uptake through FA governed the success of the nanoparticles (NPs) as evidenced through the cell uptake experiments and Hoechst assay for P-glycoprotein functioning. Pharmacokinetic results confirmed nearly 7.7 fold increases in Cmax of the nano-cur–bioenhancer CUR–B–CH-NPs as compared to a CUR solution and the AUC increased nearly 6 fold in CUR–B–CH-NPs than CUR. Thus, escalating drug uptake in prostate cancer PC3 and Caco-2 cell monolayers along with enhanced bioavailability substantiated effective oral delivery of nano-cur–bioenhancers. Thus, nano-cur–bioenhancers have remarkable potential as a multifunctional oral delivery system for management of hormone refractory prostate cancer.

The development of one-pot, multi-component and transition-metal-catalyst free synthetic protocol for N-heterocycles is a green and sustainable approach. The solvent plays a critical role in such catalyst free reactions as it constitutes the major portion of reaction mass and facilitates the stabilization of intermediates for the efficient product formation. We herein report a one-pot and catalyst-free tandem coupling among indole, aldehyde and tetrahydroisoquinoline (THIQ) to afford C1-indolyl-N-alkyl THIQ in biodegradable PEG600 solvent. The present method is found to be highly efficient (42–92%) with broad substrate scope. Further, the E-factor (0.3) of the present catalyst-free system is much better (5–593 times) than the previously reported catalyzed methodologies on virtue of recoverable PEG600 solvent. Overall, these results demonstrate a facile and environmentally benign approach for direct C1-functionalization of THIQ in biodegradable and recoverable solvent making it an industrially relevant methodology in near future.

In continuation of our effort to improve the physiological stability and the antibacterial activity of curcuminoids against drug-resistant bacteria, a series of novel monocarbonyl curcuminoids were synthesized and screened for antibacterial activity against S. aureus and E. coli strains. These curcuminoids showed potent antibacterial activity against both methicillin-sensitive and methicillin-resistant strains of S. aureus with MIC values 2–8 and 4–16 μg/mL, respectively. They also exhibited moderate potency against E. coli strains. The four most active curcuminoids (7d, 7i, 7m, and 7p) were on further investigation found to be very stable under physiological conditions, non-hemolytic, and non-toxic toward mammalian cells up to 150 μg/mL concentration. Mechanistic studies revealed that these curcuminoids displayed potent bactericidal activity by targeting cell membranes. Further, in an ex vivo mammalian co-culture infection model study, remarkably, the curcuminoids 7i and 7p were able to clear the internalized bacteria in mammalian cells and the activity was found to be superior to conventional antibiotics such as vancomycin and linezolid. Therefore, the present study affords us water-soluble, stable, non-toxic curcuminoids that may serve as lead molecules for development as antibacterial agents against MRSA infections.

Considering the prevalence of prostate cancer all over the world, it is desired to have tools, technologies, and biomarkers which help in early detection of the disease and discriminate different races and ethnic groups. Genetic information from the single gene analysis and genome-wide association studies have identified few biomarkers, however, the drivers of prostate cancer remain unknown in the majority of prostate cancer patients. In those cases where genetic association has been identified, the genes confer only a modest risk of this cancer, hence, making them less relevant for risk counseling and disease management. There is a need for additional biomarkers for diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146a (miR-146a) which may serve as a diagnostic and prognostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. Reduced expression of miR-146a was observed in African American tumor tissues compared to those from European Whites This report provides a novel insight into understanding the prostate carcinogenesis.

Objective In India, cervical cancer accounts for almost 14% of all female cancer cases. Although poverty continues to cast a wide net over the Indian subcontinent, the preceding three decades have borne witness to improvements in nutrition and sanitation for many citizens. However, due to an absence of a national immunization program to cover human papillomavirus (HPV) vaccination and lack of accessible cervical cancer screening, the disease is characterized by late detection, lack of access to affordable and quality health care, and high mortality rates. Treatment of cervical cancer is stage-specific and depends on the patient’s age, desire to preserve fertility, overall health, the clinician’s expertise, and accessibility to resources. There is a paucity of uniform treatment protocols for various stages of cervical cancer in India. Considering all these parameters, a need to optimize treatment paradigms for the Indian population emerged. Methods/materials Three expert panel meetings were held in different regions of India from 2016 to 2017. They were comprised of 15 experts from across the country, and included surgical oncologists, radiation oncologists, and medical oncologists. The panel members reviewed the literature from both national and global sources, discussed their clinical experience and local practices and evaluated current therapeutic options and management gaps for women diagnosed with cervical cancer. Results This article summarizes the expert opinion from these meetings. It discusses the available resources and highlights the current therapeutic options available for different cervical cancer stages: early stage disease, locally advanced tumors, recurrent/persistent/metastatic cancer. An Indian consensus governing treatment options emerged, including guidelines for use of the only approved targeted therapy in this disease, the anti-angiogenesis drug, bevacizumab. Conclusions The panel concluded that given the availability of state-of-the-art imaging modalities, surgical devices, radiotherapeutics, and novel agents in several population-dense urban centers, a uniform, multi-disciplinary treatment approach across patient care centers is ideal but not realistic due to cost and a paucity of third party payors for most Indian citizens. Preventative strategies including visual inspection with acetic acid to screen for precursor lesions (i.e., cervical intraepithelial neoplasia) with immediate referral for cervical cryotherapy and possible large-scale roll-out of the HPV vaccine in the near future can be expected to reduce mortality rates significantly in this country.

Oxidation has been measured a major problem for biodiesel commercialization. Auto-oxidation takes place when exposed to air, heat, light and metallic contaminants which affects adversely the fuel characteristics of biodiesel. Addition of synthetic antioxidants generally improves the oxidation stability of biodiesel; however the use of large concentration of additives makes the process uneconomical. This study investigates the effectiveness of individual as well as binary antioxidants to improve the oxidation stability of Jatropha and Karanja biodiesels. Antioxidant synergy was investigated using 500, 600 and 700 ppm of antioxidant combinations namly Pyrogallol:Propyl gallate (PY:PrG), Pyrogallol:tert-butyl hydroquinone (PY:TBHQ) and Pyrogallol:Butylated hydroxyanisole (PY:BHA) at weight ratios of 9:1, 3:1, 2:1, 1:1, 1:2, 1:3 and 1:9, respectively. It was observed that higher blends of binary mixture produced negative synergy, however the best antioxidant synergy showed by the binary systems of PY:PrG, and PY:TBHQ, when the additives are mixed at 1:3 weight ratios; whereas binary mixture of PY:BHA resulted in complete antagonism. However, the effectiveness of the binary system on oxidation stability was found in order of 1:3/3:1 > 1:2/2:1 > 1:1 > 1:9/9:1. The efficacy of antioxidant combinations was evaluated by using pressurized PetroOXY method. Further the dependency of oxidation stability and antioxidant synergy on the fatty acid composition of biodiesel was also observed.

This study aims to investigate calf mortality pattern in Gir breed. Research data were collected from the records of Gir herd, maintained at Kasturba Gandhi National Memorial Trust, Dairy Farm Kasturbagram Khandwa Road, Indore M.P., covering a period of 16 years (from 1994 to 2009). The period-wise distribution of calf mortality showed that highest mortality rate (18.9%) was recorded in period P4 (2006 to 2009) and the lowest (9.8%) in period P2 (1998 to 2001). Age-wise distribution of calf mortality showed that it was highest (5.4%) in 0 to 1 month age group in both sex. The lowest mortality was observed in 3 to 6 months of age group, which might be due to better management practices given to this age group. The mortality rate from 1 to 3 months and 6 to 12 months age group was also calculated and the values of mortality rate as 3.6 and 4.4% respectively. Sex-wise distribution of calf mortality indicates that out of total 208 male calves, 34 calves (15.9%) died, whereas, out of 196 female calves, a total of 27 calves (14.3%) were reported to be dead. Season-wise distribution showed that the highest calf mortality (5.7%) was determined in those calves born in the winter season. The overall mortality rates due to parity of the dam were 7.2, 4.5, 1.4 and 2.8% respectively for first, second, third and fourth calving. The highest mortality in Gir calves was recorded due to gastroenteritis (6.2%) followed by pneumonia (3.2%), insufficient or delayed colostrums feeding, handling causes and worm infestation (3.6%). Gastroenteritis as the prime cause of mortality could be synchronized with the results of high mortality rate in Gir calves during winter season in this investigation. Key words: Mortality rate, calf mortality, gastroenteritis, pneumonia.

Salvadora persica L. commonly known as Miswak and have immense medicinal value as anti-microbial and in prevention of tooth decay. Present study deals with phytochemical and antioxidant evaluation of S. persica twig and stem. Chloroform and ethanolic extracts from S. persica twig and stem are screened for antioxidant activity using, DPPH free radical scavenging activity. Methanolic extract has been studied through HPTLC. In S. persica twig, IC 50 of chloroform extract and ethanolic extract was found to be 181.33 ± 1.15 µg/ml and 197.00 ± 1.73 µg/ml respectively, however in stem, IC 50 of chloroform extract and ethanolic extract was found to be 187.33 ± 0.57 µg/ml and 235.66 ± 1.52 µg/ml respectively. Ascorbic acid is used as standard which showed IC 50 2.03 ± 0.06 µg/ml. In HPTLC studies the ferulic acid content was found to be 0.026% and 0.082% in S. persica stem and twig respectively. All the extracts showed significant in vitro antioxidant activity, chloroform extract showed the most potent activity followed by ethanolic extract. Ferulic acid, a potential antioxidant present in this species, has been studied through HPTLC. The presence of ferulic acid has not yet been reported and quantified in this species which may be utilized for the proper standardization of the drug.

A series of isoniazid–amidoether derivatives was synthesized and screened for their antimycobacterial activity in vitro and in vivo. Most of the compounds exhibited potent in vitro activity against the Mycobacterium tuberculosis H37Rv strain with MIC99 values ranging from 0.39 to 3.125 μM. Five compounds were equally as potent as the reference compound isoniazid. The most active compound 3b, when evaluated for in vivo activity, exhibited mild reduction in the bacillary load in lungs. However it showed a better effect in spleens. All the compounds were also evaluated for their cytotoxicity against the THP-1 cell line and no toxicity was observed up to 50 μM concentrations. The calculated ADMET parameters for the compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new anti-tuberculosis agents.

Both turmeric (Curcuma longa Linn) and honey have been popularly used for treating microbial infections in Asian countries, but their combined effect on bacterial virulence has not been tested thus far. Therefore, in this investigation, the potential of curcumin (50 μg mL−1) plus 1% of honey (ChC) in reducing QS-mediated production of virulence factors and biofilm formation in Pseudomonas aeruginosa PAO1 was studied. Treatment with ChC displayed a significant reduction in the secretion of AHLs, pyocyanin, pyoverdin, pyochelin, LasA protease, LasB elastase, and hemolysin without affecting bacterium growth. The data obtained from β-galactosidase activity revealed that ChC reduced the activity of QS-related genes, namely lasI, lasR, rhlI, and rhlR. The ChC showed strong anti-biofilm activity, inhibiting biofilm formation and also eradicating it. It was also proven that the anti-biofilm activity is associated with the inhibition of rhamnolipid and alginate, as well as the swimming, and swarming motility of PAO1 as a result of ChC treatment. Eventually, it was also documented that ChC enhanced the susceptibility of PAO1 to conventional antibiotics. The results clearly indicated that the combination of curcumin and honey is a good candidate for the development of a new antibacterial agent acting not as a cidal but as an anti-virulence agent.

In order to overcome the problem of emerging drug resistance in malarial chemotherapy, a series of highly active 4-aminoquinoline–pyrimidine hybrids were synthesized and evaluated for their antimalarial activity against CQ-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum in an in vitro assay. The most active hybrid 19f exhibited 74-fold better potency than chloroquine and 4-fold better potency than artesunate against the drug-resistant strain of P. falciparum. Compound 19e, when evaluated for in vivo activity in the P. berghei-mouse malaria model showed 93.9% parasite suppression at 30 mg kg−1 dose on Day 4 with a mean survival time of 11 days. To gain insights towards the mechanism of action of these hybrids, heme binding and molecular modelling studies were performed on the most active hybrids. It was observed that inhibition of formation of β-hematin and dihydrofolate reductase-thymidylate synthase Pf-DHFR-TS enzyme could be associated with the observed antimalarial activity of these compounds.