ENTADA PHASEOLOIDES ATTENUATES SCOPOLAMINE INDUCED MEMORY IMPAIRMENT, NEURO-INFLAMMATION AND NEURO-DEGENERATION VIA BDNF/TRKB/NFΚB P65 PATHWAY IN RADIAL ARM MAZE

Objective: The present study investigates the protective effects of crude extract from seeds of Entada phaseoloides and isolated compounds in enhancing cognition in Scopolamine induced learning and memory impairments in the radial arm maze model.Methods: Two doses (100 and 200 mg/kg) of the crude methanolic extract of Entada phaseoloides (MEEP) were evaluated for amnesic activity by Radial Arm Maze memory model. Scopolamine (0.4 mg/kg i. p.), an amnestic drug was used for impairing memory. Tacrine (3 mg/kg, i. p.) was used as the standard drug. Animals were sacrificed to evaluate biochemical parameters viz. lipid peroxidase (LPO), nitrite oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), cytokine levels by ELISA, Catecholamine levels by high performance liquid chromatography (HPLC), Caspase-3 activity by Fluorogenic assay, Gene (BDNF, TrkB, NF-κB p65, BAX) expression studies by Western Blotting and AChE, α7nAchR, Caspase-3, Nrf2 and HO-1 by Reverse Transcriptase Polymerase Chain Reaction.Results: Treatment with MEEP significantly decreases escape latency and reference memory error (RME). MEEP treatment reversed the Scopolamine-induced hyperactivation of Acetylcholinesterase activity and overexpression of proteins NF-κB p65 BAX and also Caspase-3 activity in the hippocampus of rats. The level of BDNF, TrkB and α7nAchR were significantly up-regulated and AChE, Caspase-3, Nrf2, HO-1 were down-regulated in the MEEP treated rat. The extract increased the activity of SOD, GSH, Catalase, 5-HT, NE, Dopamine and decreased the levels of LPO and NO in rat hippocampus. Different active components of the seeds have been isolated.Conclusion: These results indicated that seeds of Entada phaseoloides might become a promising therapeutic agent for the treatment of cognitive dysfunction in addition to its already established medicinal properties

Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region

SummaryEvidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope

Induction of Fc-Mediated Effector Functions Against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region

Recent clinical trials and studies using nonhuman primates (NHPs) suggest that antibody-mediated protection against HIV-1 will require α-HIV envelope humoral immunity beyond direct neutralization to include Fc-receptor (FcR) mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC). There is also strong evidence indicating that the most potent ADCC response in humans is directed toward transitional non-neutralizing epitopes associated with the gp41-interactive face of gp120, particularly those within the first and second constant (C1–C2) region (A32-like epitopes). These epitopes were shown to be major targets of ADCC responses during natural infection and have been implicated in vaccine-induced protective immunity. Here we describe the immunogenicity of ID2, an immunogen consisting of the inner domain of the clade A/E 93TH057 HIV-1 gp120 expressed independently of the outer domain (OD) and stabilized in the CD4-bound conformation to harbor conformational A32 region epitopes within a minimal structural unit of HIV-1 Env. ID2 induced A32-specific antibody responses in BALB/c mice when injected alone or in the presence of the adjuvants Alum or GLA-SE. Low α-ID2 titers were detected in mice immunized with ID2 alone whereas robust responses were observed with ID2 plus adjuvant, with the greatest ID2 and A32-specific titers observed in the GLA-SE group. Only sera from groups immunized in the presence of GLA-SE were capable of mediating significant ADCC using NKr cells sensitized with recombinant BaL gp120 as targets and human PBMCs as effectors. A neutralization response to a tier 2 virus was not observed. Altogether, our studies demonstrate that ID2 is highly immunogenic and elicits A32-specific ADCC responses in an animal host. The ID2 immunogen has significant translational value as it can be used in challenge studies to evaluate the role of non-neutralizing antibodies directed at the A32 subregion in HIV-1 protection

Timescapes of Himalayan hydropower: promises, project life cycles, and precarities

In this paper, we review the existing social science scholarship focused on hydropower development in the Himalayan region, using an interpretive lens attuned to issues of time and temporality. While the spatial politics of Himalayan hydropower are well examined in the literature, an explicit examination of temporal politics is lacking. In this paper, we present a conceptual framework organized around the heuristic of timescapes, highlighting temporal themes implicit in the existing literature. In three sections, we explore the temporal politics of anticipation that shape hydropower dreams, the intersecting temporalities and rhythms that modulate the life cycles of hydropower projects, and the ways that geological and hydrological time affect both hydropower development and broader Himalayan futures. Along the way, we pose a series of questions useful for framing future research given the significant climatic, geophysical, and sociopolitical changes underway in the Himalayan bioregion, calling for greater analytical attention to time, temporality, and temporal ethics in future studies of hydropower in the Himalayas and beyond.Austin Lord, Georgina Drew, Mabel Denzin Gerga

Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Background Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. Methods The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). Findings Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80). Interpretation Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care

Evaluation of Theils U: A Naïve Forecast Application

The reliability of any forecast needs to be tested effectively with an empirical data. Simple or complicated forecast methods have many a time failed subjected to empirical examination. There is no agreement among scholars as to which metric is the best for determining the best forecasting method. So this paper evaluates the basic of forecast techniques of predicting the future values and comparing its accuracy by Theil's U statistic. The predicted values were estimated by Naïve's method and the errors are calculated to verify the accuracy of the forecasted values as well. The testing has been done with a set of fictitious data set which helps to explain the steps in establishing the accuracy of the projected model