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The study revealed that the overall prevalence of gastrointestinal nematode (GIN) infection in cattle of Assam was 41% (134/325). Among 134 infected cattle 24 animals with >200 EPG of similar age group were selected randomly and divided into four groups (T1, T2, T3 and T4) to record the anthelmintic efficacy and haematological parameters. The animals of group T1, T2 and T3 were treated with fenbendazole @ 5 mg/kg body weight (BW), albendazole @ 7.5 mg/kg BW and levamisole @ 7.5 mg/kg BW orally, respectively and group T4 was kept as infected untreated control group. On the basis of FECRT, the efficacy of these anthelmintic was found to be 100, 81.27 and 80.00% in the animals of group T1, T2 and T3, respectively. To record the values of haemoglobin (Hb), total erythrocyte count (TEC) and total leukocyte count (TLC), blood from the each infected treated and control animal was collected before and after treatment of 10 days. The increasing values of Hb and TEC were found to be non-significant among the treated groups while infected untreated group showed the decreasing values which were found to be highly significant when compared with treated group. However, increasing value of TLC was found to be significant in group T1, non-significant in T2 and highly significant among T3 group. These three anthelmintics have wide therapeutic index and they may kill or restrain egg production of GINs. [ABSTRACT FROM AUTHOR]

The study was conducted for comparative assessment of haematology in crossbred goats infested with spontaneous gastro intestinal nematodosis treated with AAU/CI herbal formulation (MUMB). Prior to the experiment all the goats were treated with single dose of broad spectrum antibiotic to rule any bacterial infection. Forty eight crossbred goats were taken irrespective of age, sex, and fed with standard feed ration, randomly divided into eight groups of six each. The EPG was determined prior to the treatment (0 day) and every 15 days interval up to 100 days post treatment. The herbal formulation consisted of sample AAU/CI prepared by drying and grinding of the plant (leaf and stem) material incorporated in UMB and were fed to the animal @ 15 g/animal/day in group 5 (stall feeding) by licking and group 6 (grazing) individually. Blood examination for haemoglobin, PCV, RBC count, WBC count were estimated using whole blood with the help of kit (Merck Ltd). Haemoglobin concentration was significantly (P<0.05) increased on 100 day only in group 3 fed with Fenbendazole incorporated in MUMB while the other groups showed decrease in haemoglobin concentration. An significant (P<0.05) increase in PCV and RBC in group 3, 5 and 6 animals was observed on 100th day in the present study. The WBC count decreased significantly (P<0.05) on 100th day in the animals treated with Fenbendazole incorporated in MUMB (group 1) in comparison with 0 day. The range of haemoglobin, PCV, RBC count and WBC count of infested untreated animals (Group 7) were found to be 6.070.11 to 8.05±0.18 mg /dl, 18.29±0.26 to 20.12±0.19%, 9.96±0.23 to 11.67±0.31 x 106cu. mm, 11.46±0.26 to 12.71±0.28 x103cu.mm against 6.07±0.04 to 8.38±0.12 mg /dl, 18.23±0.31 to 21.84±0.21%, 11.38±0.04 to 13.50±0.35 x106cu.mm and 11.67±0.23 to 12.74±0.30 x 103cu.mm, respectively in medicated urea molasses block (stall feeding) and 6.19±0.04 to 8.18±0.18 mg/dl, 18.23±0.31 to 21.71±0.36%, 11.43±0.04 to 14.63±0.17 x106 cu.mm and 8.76±1.54 to 11.67±0.23 x103cu.mm, respectively in medicated urea molasses block (grazing feeding). From the observations it is evident that the besides feeding Fenbendazole incorporated in MUMB, the AAU/CI herbal formulation (MUMB) had also a significant effect on the hematological parameters in animals affected with nematodosis. [ABSTRACT FROM AUTHOR]

An investigation was undertaken with a view to study the effects of different concentration of soda, pre-soaking media and cooking methods on cooking parameters of muga cocoons in autumn crop in the Department of Sericulture, Assam Agricultural University, Jorhat in two consecutive years. The parameters for the study were cooking period (min), deflossing period (min), cooking efficiency (%) and reelability (%). The three different concentrations of soda were used in the study of 0.10, 0.20 and 0.30 per cent. Among three different concentrations of soda the cooking parameters of muga cocoons were recorded better in 0.30 per cent soda than the rest of two concentrations and the pre-soaked cocoons in alkaline media and cooked by sunken system showed better performance in cooking parameters. Increasing of soda concentrations there is a tendency of decreasing of the cooking period and deflossing period in both sunken and floating system. Cooking efficiency and reelability percentage was also registered higher in 0.30 per cent soda concentrations. The reelability percentage and cooking efficiency were recorded higher in pre-soaked cocoons in alkaline media and cooked by sunken system. [ABSTRACT FROM AUTHOR]

A new species, Cleistanthus nokrensis (Euphorbiaceae), was collected and described from Indian Himalaya. This species is confined to the Nokrek Biosphere Reserve where it grows on the calcareous habitat in karst topography. On the basis of the critical features of its habitat, branches, petioles, leaves, and fruits, the species is compared with the closely related allied species, C. tonkinensis Jabl. and C. balakrishnanii Chakrab. Notes on its taxonomic description, photographs, ecology, associated species, population data, and threat perspective as per latest IUCN conservation status are provided. A key to the other taxa in the genus reported from India is provided for the first time, along with their distributional records and endemism. [ABSTRACT FROM AUTHOR]

The present study documented pharmaceutically important plant resources used in primary health care of ethnic Garo tribes from Eastern Himalayas (Nokrek Biosphere Reserve [NBR], India). In order to document information on medicinal plants and to maximize the collection of indigenous knowledge of Garo tribes, 12 traditional healers were identified using the Participatory Rapid Appraisal approach. Data were collected through open-end interviews with traditional healers, between 2007 and 2011. A total of 157 plant species representing 134 genera and 81 families were found to be commonly used in the treatment of 67 health-problems. More than one-fourth of the plant species were used in the treatment of cough, flu, and cold, which are prevalent ailments in the study area. The leaves, root, rhizome, and tuber were the most commonly used plant parts while decoction was the most common method of drug preparation. [ABSTRACT FROM PUBLISHER]

Nokrek National Park, located approximately 40km from Tura town in West Garo Hills district of Meghalaya, India, was added to the list of Biosphere Reserves by UNESCO in May 2009. Since there is no previous report from this area, the pteridophytes of the Nokrek Biosphere Reserve are catalogued in the present study. The checklist consists of 113 taxa (98 ferns, 15 fern allies), of which 25 species are newly reported for the Meghalaya State (Selaginella involvens, Selaginella semicordata, Selaginella subdiaphana, Selaginella tenuifolia, Asplenium gueinzianum, Asplenium perakanse, Microlepia hancei, Microlepia rhomboidea, Dicranopteris linearis, Coniogramme procera, Bolbitis sinensis, Loxogramme chinensis, Lygodium microphyllum, Lemmaphyllum microphyllum, Lemmaphyllum rostratum, Pleopeltis macrosphaera, Pyrrosia lanceolata, Pyrrosia longifolia, Pteris biaurita ssp. walkeriana, Pteris grevilleana, Tectaria fuscipes, Cyclosorus crinipes, Pseudocyclosorus falcilobus, Diplazium apicisorum and Diplazium pseudosetigerum) and 43 species are new for all the three Garo Hill districts of the Garo Hills in the Meghalaya State. [ABSTRACT FROM AUTHOR]

The present paper focuses on the various disturbance agents such as coal mining, limestone extraction, stone quarrying, jhum cultivation, fire, grazing, over-exploitation of resources, road constructions etc., affecting the natural growth of Nepethes khasiana in the Nokrek Biosphere Reserve of India. N. khasiana is the prominent insectivorous scandent shrubs species of this biosphere reserve and is an important source of medicine and basic ornamental uses for the local garo tribal people of north-east India. The inevitable pressure due to commercialization of the N. khasiana is leading to severe destruction of the species and may create the scarcity of that species in the near future. Therefore, joint efforts need to be implemented by the local garo villagers with governmental and non-governmental agencies for conservation and sustainable use of N. khasiana. The government may also take initiative by allotting demarcated forests areas to the villagers as village forest, thus motivating the villagers to take special care for its protection and rehabilitation and for a sustainable output. [ABSTRACT FROM AUTHOR]

Context: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown.Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells.Design, Setting, and Patients: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A.Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation.Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells.Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer. [ABSTRACT FROM AUTHOR]

A study was conducted to record the histoenzymic changes in the proventricular glandular structures of local poultry naturally infected with T. mohtedai using specific substrates for succinate (SDH) and lactate dehydrogenases (LDH), cytochrome oxidase (CYO), acid phosphatase (ACPase) and alkaline phosphatase (AKPase). Variable enzyme reactions could be recorded in both the parasites, eggs and the tissues viz., intense for SDH, strong for CYO and AKPase; moderate for ACPase and reduced for LDH. The changes have been discussed and compared. [ABSTRACT FROM AUTHOR]

This article discusses a study which investigated the in vitro anthelmintic activity of some plant extracts against Paramphistomum cervi. It is noted that Paramphistomiasis is a disease of domesticated ruminants causing economic loss to the livestock industry in India. Research findings revealed that methanol extract of Corchorous fascicularis, hydroethanol extract of Zanthoxyllum nepalensis and Pongamia pinnata possessed anthelmintic activity.

Abstract Background The intersection between illicit drug use and female commercial sex work has been identified as an important factor responsible for rising HIV prevalence among female sex workers (FSW) in several northeastern states of India. But, little is know about the factors associated with the use of drugs among FSWs in this region. The objective of the paper was to describe the factors associated with history of drug use among FSWs in Dimapur, an important commercial hub of Nagaland, which is a high HIV prevalence state of India. Methods FSWs were recruited using respondent driven sampling (RDS), and were interviewed to collect data on socio-demographic characteristics and HIV risk behaviours. Biological samples were tested for HIV, syphilis gonorrhea and Chlamydia. Logistic regression analysis was performed to identify factors associated with drug use. Results Among the 426 FSWs in the study, about 25% (n = 107) reported having ever used illicit drugs. Among 107 illicit drug users, 83 (77.6%) were non-injecting and 24 (22.4%) were injecting drug users. Drug-using FSWs were significantly more likely to test positive for one or more STIs (59% vs. 33.5%), active syphilis (27.1% vs. 11.4%) and Chlamydia infection (30% vs. 19.9%) compared to their non-drug using peers. Drug-using FSWs were also significantly more likely to be currently married, widowed or separated compared with non-drug-using FSWs. In multiple logistic regression analysis, being an alcohol user, being married, having a larger volume of clients, and having sexual partners who have ever used or shared injecting drugs were found to be independently associated with illicit drug use. Conclusions Drug-using FSWs were more vulnerable to STIs including HIV compared to their non-drug using peers. Several important factors associated with being an FSW who uses drugs were identified in this study and this knowledge can be used to plan more effectively targeted harm reduction strategies and programs.

In this present study, the nuclear track detector LR-115 (II) was employed to assess radon (222Rn) exhalation rate, effective radium (226Ra) content, and the annual effective dose from coal and soil samples collected in and around the coal mining area of Tiru region of Nagaland, India. The 222Rn mass and surface exhalation rates and 226Ra contents were found to be in the ranges of 7.3-17.3 mBq kg-1 h-1, 242.9-573.6 mBq m-2 h-1 and 1.0-2.3 Bq kg-1, respectively, for coal and 15.8-22.0 mBq kg-1 h-1, 523.8-730.4 mBq m-2 h-1 and 2.1-2.9 Bq kg-1, respectively, for soil. The 222Rn exhalation rates and 226Ra contents in soils were found to be higher than in coal. The estimated annual effective doses for coal and soils were found to be in the ranges of 17.6-41.6 and 38.0-53.0 μSv y-1, respectively. This study is an important contribution to the understanding of radiation exposure in the coal mining area of the thrust-bound sedimentary sequence of the Naga Schuppen Belt, and it would have potential impact on further human health studies. However, the measured values for all the samples were found to be within the globally recognised permissible range., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A rapid, clean plasma-chemical technique is demonstrated here, for cost-effective, synthesis of surface vacancy engineered, 2D, molybdenum-oxide nanomaterials, during a one-step, integrated synthesis-hydrogenation process for biomedical applications. A laminar plasma beam populated with O and H radicals impinges on a molybdenum target, out of which molybdenum-oxide nanomaterials are very rapidly generated with controlled surface O vacancies. 2D, dark-blue coloured, nano-flake/ribbon like MoO 3- x is produced maximum up to 194 g h -1 , the core of which still remains as stoichiometric molybdenum-oxide. These nanomaterials can get heated-up by absorbing energy from a near-infrared (NIR) laser, which enable them as photothermal therapy (PTT) candidate material for the invasive precision therapy of cancer. The surface defects endows the products with robust ferromagnetism at room temperature conditions (maximum saturation-magnetization: 6.58 emu g -1 ), which is order of magnitude stronger than most other vacancy engineered nanomaterials. These nanometric metal-oxides are observed to be perfectly compatible in animal physiological environment and easily dispersed in an aqueous solution even without any pre-treatment. The MoO 3- x nanomaterials are stable against further oxidation even under prolonged atmospheric exposure. In vitro experiments confirm that they have ideal efficacy for photothermal ablation of human and murine melanoma cancer at relatively lower dose. During in vivo PTT treatments, they may be manipulated with a simple external magnetic field for targeted delivery at the malignant tumours. It is demonstrated that commensurate to the neutralization of the malignant cells, the nanomaterials themselves get self-degraded, which should get easily excreted out of the body., (© 2023 IOP Publishing Ltd.)

Evaluation of cardiotoxicity potential of new chemical entities (NCEs) has lately become one of the stringent filters in the drug discovery and development process. Cardiotoxicity is caused mainly by the inhibition of human ether-a-go-go related gene (hERG) channel protein. Inhibition of the hERG channel leads to a life-threatening condition known as cardiac arrhythmia. Knowledge of the structural behaviour of the hERG would aid greatly in the design of new drug molecules that do not interact with the protein and add to the safety index. In this study, a computational model for the active-state of hERG was developed. This model was equilibrated by performing the molecular dynamics simulations for 100 ns followed by clustering and selection of a representative structure based on the largest populated cluster. To study the changes in the protein structure on inhibition, three inhibitory ligands, namely, dofetilide, cisapride and terfenadine were docked, followed by molecular dynamics simulations of 200 ns for the apo and each ligand-bound structure. It was observed that docking and simulation studies of the hERG model exhibited noticeable conformational changes in the protein upon ligand-binding. A significant change in the kink of the S6-transmembrane helix was observed. Inter-chain distances between the crucial residues Y652 and F656 (present below the ion-selectivity filter), their side-chain orientation and hydrogen bonding indicated a probable collapse of the pore. These changes may infer the initiation in transition of hERG from an open to an inactive state. Hence, these findings would help in designing compounds devoid of hERG inhibition with reduced cardiotoxicity.Communicated by Ramaswamy H. Sarma.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC 50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kβ as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37 . Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

The Indian poultry industry is one of the fast-growing sectors of which duck farming plays an important role. Duck population in India is 33.51 million that is concentrated towards north-east and southern parts of the country who rears mainly for eggs and meat. Duck diseases are of great concern as they badly affect the financial status of the small, landless farmers. Databases such as Google Scholar, PubMed, J gate were used to search articles between 2000 and 2019 that showed the prevalence of viral, bacterial, and parasitic duck diseases. R open source software was used to derive forest plots by statistical analysis. Pooled prevalence estimates of duck diseases worldwide was found to be 20% (95%-CI:15-26). Also, continent-wise analysis of all duck diseases has revealed highest prevalence in North America, followed by Asia, Africa, Europe,Oceania and South America. This prevalence of data would be helpful to the policymakers to develop appropriate intervention strategies to prevent and control diseases in their respective locations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11 , through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34 . Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

A simple and efficient reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed for the first time for the estimation of a mosquito repellent, methyl jasmonate in a cream formulation, and validated as per the International Conference on Harmonization guidelines. Acetonitrile and water (75:25 v/v) were used as the mobile phase and the flow-rate of the mobile phase was kept constant at 1.0 mL/min. The analysis was performed isocratically on a C 18 analytical column (250 × 4.4 mm, 5 μm) using a Diode Array Detector for the detection of methyl jasmonate at 214 nm. The presence of excipients did not interfere with the quantification of methyl jasmonate. The calibration curve was linear in the concentration range of 25-300 μg/mL. The relative standard deviations for intra-day and inter-day precision, and repeatability were less than 2%. The recovery ranged from 88.5% to 90.7% with relative standard deviations not higher than 2%. The limit of detection and quantification were 9.4 μg/mL and 28.5 μg/mL, respectively. System suitability parameters were within the accepted range. The proposed method was also robust. Thus, the present report puts forward a novel analytical method for the estimation of an emerging mosquito repellent, methyl jasmonate by using the RP-HPLC technique.

Diseases by protozoan pathogens pose a significant public health concern, particularly in tropical and subtropical countries, where these are responsible for significant morbidity and mortality. Protozoan pathogens tend to establish chronic infections underscoring their competence at subversion of host immune processes, an important component of disease pathogenesis and of their virulence. Modulation of cytokine and chemokine levels, their crosstalks and downstream signaling pathways, and thereby influencing recruitment and activation of immune cells is crucial to immune evasion and subversion. Many protozoans are now known to secrete effector molecules that actively modulate host immune transcriptome and bring about alterations in host epigenome to alter cytokine levels and signaling. The complexity of multi-dimensional events during interaction of hosts and protozoan parasites ranges from microscopic molecular levels to macroscopic ecological and epidemiological levels that includes disrupting metabolic pathways, cell cycle ( Toxoplasma and Theileria sp.), respiratory burst, and antigen presentation ( Leishmania spp.) to manipulation of signaling hubs. This requires an integrative systems biology approach to combine the knowledge from all these levels to identify the complex mechanisms of protozoan evolution via immune escape during host-parasite coevolution. Considering the diversity of protozoan parasites, in this review, we have focused on Leishmania and Plasmodium infections. Along with the biological understanding, we further elucidate the current efforts in generating, integrating, and modeling of multi-dimensional data to explain the modulation of cytokine networks by these two protozoan parasites to achieve their persistence in host via immune escape during host-parasite coevolution.

Several studies reported that stress can enhance the consumption of alcohol in humans and animals. However, the combinatorial effect of stress and alcohol on cognitive function and neurochemical alterations is quite understudied. In the present study, we have elucidated the involvement of oxidative stress-PARP cascade in alcohol and restraint stress (RS)-exposed animals using a PARP inhibitor, 1,5-isoquinolinediol (3mg/kg for 14days). Male Swiss albino mice were given alcohol (ALC) or RS (2h per day) or both in ALC+RS group for 28days. Behavioral analysis revealed cognitive dysfunction in ALC+RS group. Furthermore, oxidative stress and raised level of pro-inflammatory cytokines were found in the hippocampus region of ALC+RS group. Semi-quantitative reverse transcriptase PCR showed overactivation of PARP-1 gene in ALC+RS group. 1,5-isoquinolinediol treatment significantly prevented cognitive deficits and aforementioned neurochemical alterations. Overall, our findings showed that ALC+RS exerted deleterious effects on the hippocampus which involves oxidative stress-PARP overactivation cascade., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Radon and thoron, and their progeny concentrations along with equilibrium factors for gas progeny and radiological risks to the residents have been measured in dwellings of Digboi and Mashimpur areas located on anticlines during the winter season. In this present investigation, twin-cup dosemeters fitted with LR-115 (II) nuclear detectors have been employed. The present work has shown that there exist considerable house-to-house variations in values with maximum values in mud houses and minimum values in assam type (AT) houses. It has been found that mean (and geometric standard deviations (GSD)) radon concentrations are 83.8 (1.3), 113.5 (1.1) and 157.2 (1.2) Bq m(-3) in AT, reinforced cement concrete (RCC) and mud houses in Digboi area and 63.0 (1.1), 87.1 (1.4) and 182.1 (1.2) Bq m(-3) in AT, RCC and mud houses in Mashimpur area, respectively. The overall mean radon concentrations in Digboi and Mashimpur are estimated to be 114.4 (1.4) and 100.0 (1.7) Bq m(-3). The mean radon concentrations are found to be less than the lower reference level of 200 Bq m(-3) of the International Commission on Radiological Protection (ICRP 2007). The thoron concentrations in Digboi area are estimated to be 31.1 (1.3), 50.8 (1.4) and 67.0 (1.6) Bq m(-3) in AT, RCC and mud houses, respectively, whereas in Mashimpur area, the thoron concentrations are estimated to be 26.4 (1.3), 44.4 (1.3) and 77.7 (1.3) Bq m(-3) in AT, RCC and mud houses, respectively. The mean annual effective doses in Digboi area are found to be 1.9 (1.3), 2.7 (1.2) and 4.1 (1.4) mSv y(-1) in AT, RCC and mud houses, respectively, while in the case of Mashimpur area, the mean annual effective doses are found to be 1.5 (1.4), 2.2 (1.2) and 4.9 (1.3) mSv y(-1) in AT, RCC and mud houses, respectively. Nevertheless, the obtained results are much lower than the upper reference level of 10 mSv (ICRP 2007).

The photophysical behavior of the deprotonated form of lumazine (Lum-anion) was studied in biologically relevant surfactant systems like sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB) and TritonX-100 (TX-100) and also model water soluble protein, bovine serum albumin (BSA), using steady-state and time-resolved fluorescence spectroscopy in buffer solution of pH 12.0. The association constant values were calculated from modulated fluorescence intensity of Lum-anion in different medium. The interaction of non-ionic surfactant TX-100 was found to be about 10 times greater than SDS and CTAB. However, while the driving force of binding in SDS and/or TX-100 is mainly hydrophobic in nature, electrostatic interaction with the oppositely charged micellar head group is the predominant factor in CTAB. The thermodynamic parameters like enthalpy (ΔH) and entropy (ΔS) change, etc., corresponding to the binding of Lum-anion with BSA were estimated by performing the fluorescence titration experiment at different temperatures. Thermodynamically favorable and strong binding of Lum-anion (K~10(4) M(-1)) into BSA is due to hydrophobic interaction in the ligand binding domain II. However, the binding mechanism is entirely different in presence of protein denaturing agent like urea and electrostatic interaction plays a major role under this condition., (Copyright © 2013 Elsevier B.V. All rights reserved.)

To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.

Transforming growth factor-beta (TGF-beta) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc(Min/+) mice, we show that Apc(Min/+);Tgfbr1(+/-) mice develop twice as many intestinal tumors as Apc(Min/+);Tgfbr1(+/+) mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of Apc(Min/+); Tgfbr1(+/-) mice. Smad-mediated TGF-beta signaling is preserved in both Apc(Min/+);Tgfbr1(+/+) and Apc(Min/+);Tgfbr1(+/-) intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc(Min/+);Tgfbr1(+/-) tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-beta signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer.

Background: Glycogen synthase kinase 3 beta (GSK3beta) is a multifunctional serine/threonine kinase, which plays a major role in various signaling pathways. More than two decades after its discovery, various pharmaceutical companies are focusing on this protein as a target of interest for various therapeutic conditions., Objective: To discuss the major developments in the area of GSK3beta as a therapeutic target globally and its role in disease physiology and give an overview of the classes of compounds designed for its inhibition., Results: Data generated by various workers has helped the pharmaceutical players to put GSK3beta in their portfolio. Since it is involved in various pathways of disease physiologies, understanding of the full spectrum of the role of GSK3beta in relation to its structure and function is necessary to put successful modulators into clinical use.

TGFBR1*6A is a common hypomorphic variant of the type 1 transforming growth factor beta receptor (TGFBR1), which has been associated with increased cancer risk in some studies. Although TGFBR1*6A is capable of switching TGF-beta growth-inhibitory signals into growth-stimulatory signals when stably transfected into MCF-7 breast cancer cells, the biological effects of TGFBR1*6A are largely unknown. To broadly explore the potential oncogenic properties of TGFBR1*6A, we assessed its effects on NIH-3T3 cells as well as its effect on the migration and invasion of MCF-7 cells. We found that TGFBR1*6A has decreased oncogenic properties compared with TGFBR1. However, TGFBR1*6A significantly enhances MCF-7 cell migration and invasion in a TGF-beta signaling-independent manner. Gene expression profiling studies identified two down-regulated genes involved in cell migration and invasion: ARHGAP5, encoding ARHGAP5, and FN1, encoding fibronectin-1 (FN1). ARHGAP5 and FN1 expression was similarly down-regulated in MCF-7 cells stably transfected with a kinase-inactivated TGFBR1*6A construct. Functional assays show that TGFBR1*6A-mediated decreased ARHGAP5 expression is associated with higher RhoA activation, a crucial mediator of cell migration. Extracellular signal-regulated kinase (ERK) activation is also higher in cells that harbor the TGFBR1*6A allele. We conclude that TGFBR1*6A is not an oncogene but enhances MCF-7 cell migration and invasion through RhoA and ERK pathway activation and down-regulates two crucial mediators of this phenotype. These results provide the first evidence that TGFBR1*6A may contribute to cancer progression in a TGF-beta signaling-independent manner.

Liver X receptors (LXRs) are a member of the nuclear hormone receptor superfamily of ligand activated transcription factors. LXRs have gained importance as therapeutic targets because of their involvement in many diseases. Analysis of the protein-ligand complexes of X-ray crystallography-derived structures revealed that residues His435 and Trp457 act as a switch that mediates ligand activation. These residues show conservation for main chain (phi, psi) in His435 and moderate movement for Trp457. His435 in Helix11 (H11) is conserved in relation to Trp457 in Helix12 (H12). This shows that some induced fit effect can be incorporated while designing ligands for activation of LXR with relation to Trp457 rather than that of His435. Similarly, main chain movement in Phe329 and Leu330 showed significant conformational mobility leading to flexibility in the ligand-binding domain (LBD) along with Arg319 which has a moderate movement in (phi and psi) angles. It is interesting to know that for some sequence-ligand complex crystallizations using different conditions show considerable main chain and side chain mobility indicating plasticity in LBD of LXRbeta. This study supports our understanding the relative movement of residues in the LBD of LXRs upon ligand binding which can provide insight for designing of LXRs modulators.

We present molecular docking studies on the inhibitors of GSK-3beta kinase in the enzyme binding sites of the X-ray complexes (1H8F, 1PYX, 1O9U, 1Q4L, 1Q5K, and 1UV5) using the Schrödinger docking tool Glide. Cognate and cross-docking studies using standard precision (SP) and extraprecision (XP) algorithms have been carried out. Cognate docking studies demonstrate that docked poses similar to X-ray poses (root-mean-square deviations of less than 2 A) are found within the top four ranks of the GlideScore and E-model scores. However, cross-docking studies typically produce poses that are significantly deviated from X-ray poses in all but a couple of cases, implying potential for induced fit effects in ligand binding. In this light, we have also carried out induced fit docking studies in the active sites of 1O9U, 1Q4L, and 1Q5K. Specifically, conformational changes have been effected in the active sites of these three protein structures to dock noncognate ligands. Thus, for example, the active site of 1O9U has been induced to fit the ligands of 1Q4L, 1Q5K, and 1UV5. These studies produce ligand docked poses which have significantly lower root-mean-square deviations relative to their X-ray crystallographic poses, when compared to the corresponding values from the cross-docking studies. Furthermore, we have used an ensemble of the induced fit models and X-ray structures to enhance the retrieval of active GSK-3beta inhibitors seeded in a decoy database, normally used in Glide validation studies. Thus, our studies provide valuable insights into computational strategies useful for the identification of potential GSK-3beta inhibitors.

Litsea salicifolia is one of the many plants used as phytopesticide, traditionally by various tribes of Assam. Of the five extracts of L. salicifolia tested for the bioactivity against Aedes aegypti and Culex quinquefasciatus, the aqueous extract was more effective compared to other extracts exhibiting bioactivity at 72 ppm against A. aegypti. The hexane extract (2000 ppm) exhibited 70% repellent activity for 3 hr against A. aegypti and 46% activity for 3 hr against C. quinquefasciatus. This is the first report on the insecticidal properties of L. salicifolia which can be further developed as an eco-friendly biopesticides of the future.

There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.