Brokering justice: global indigenous rights and struggles over hydropower in Nepal

This article explores the dynamics of brokerage at the intersection between the justice conceptions enshrined in global norms and the notions of justice asserted in specific socio-environmental struggles. Using the case of a small hydropower project in Nepal, we trace the attempts of an indigenous activist to enrol villagers in his campaign against the background of villagers’ everyday negotiations with the hydropower company. The study shows how global norms, such as indigenous peoples’ rights, may fail to gain traction on the ground or even become sources of injustice in particular contexts

Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors

Evaluation of glucose challenge test using cut off values 130mg/dl and 140 mg/dl for gestational diabetes mellitus screening

Background: Gestational Diabetes Mellitus (GDM) is associated with several adverse maternal and perinatal outcomes. Thus, screening for early detection of GDM and its treatment is important.Methods: This was hospital based descriptive study done over one year in department of Obstetrics and Gynecology, TUTH, Nepal. Six hundred ninety-seven women fulfilling the inclusion criteria were enrolled at 18-22 weeks of gestation. High risk factors were assessed and GCT was performed in women with risk factors during enrollment. Diagnostic OGTT was performed in women who screened positive (GCT ≥130mg/dl). Screen negative high-risk women were re-screened at 24-28 weeks. In women without known risk factors, GCT was performed at 24-28 weeks and OGTT was performed when screen positive. The diagnosis of GDM was made according to Carpenter and Coustan criteria.Results: Out of 697 enrolled women, 12 were excluded for various reasons and 685 women were analyzed. Women having risk of GDM were 28.9%. The prevalence of GDM was 2.92% and 2.48% with GCT cut off 130 mg/dl and 140 mg/dl respectively. Lowering the threshold to 130 mg/dl identified three extra cases (p=0.010). The prevalence among high risk group was 8.58% and 7.07% with the cut off value 130 mg/dl and 140 mg/dl respectively with three extra cases detected on taking cut off value 130 mg/dl (p=0.014). Among low risk women the prevalence of GDM was same i.e. 0.61% with both the cut off values.Conclusions: Lowering threshold of GCT to 130 mg/dl could identify significant percentage of extra cases of GDM especially in high risk women

Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach

Inhibitors of the p53-MDM2 protein-protein interaction are emerging as a novel and validated approach to treating cancer. In this work we describe the synthesis and inhibitory evaluation of a series of isoquinolin-1-one analogues, and highlight the utility of an initial growth rates STD NMR approach supported by protein-ligand docking to investigate p53-MDM2 inhibition. The approach is illustrated by the study of compound 1, providing key insights into the binding mode of this kind of MDM2 ligands and, more importantly, readily unveiling the previously proposed three finger pharmacophore requirement for p53-MDM2 inhibition

Quaternary time scales for the Pontocaspian domain: interbasinal connectivity and faunal evolution

The Pontocaspian (Black Sea - Caspian Sea) region has a very dynamic history of basin development and biotic evolution. The region is the remnant of a once vast Paratethys Sea. It contains some of the best Eurasian geological records of tectonic, climatic and paleoenvironmental change. The Pliocene-Quaternary co-evolution of the Black Sea-Caspian Sea is dominated by major changes in water (lake and sea) levels resulting in a pulsating system of connected and isolated basins. Understanding the history of the region, including the drivers of lake level and faunal evolution, is hampered by indistinct stratigraphic nomenclature and contradicting time constraints for regional sedimentary successions. In this paper we review and update the late Pliocene to Quaternary stratigraphic framework of the Pontocaspian domain, focusing on the Black Sea Basin, Caspian Basin, Marmara Sea and the terrestrial environments surrounding these large, mostly endorheic lake-sea systems

Situation Analysis of Patients Attending TU Teaching Hospital after Medical Abortion with Problems and Complications

Introduction: In Nepal medical abortion has been approved for use since 2009. There were many cases coming to Tribhuvan University Teaching Hospital coming with problems and complications following medical abortion. Thus the objective of this study was to analyze the cases that came to TUTH following medical abortion with problems and complications. Methods: This is a prospective study conducted in the Department of Obstetrics and Gynecology of TUTH. Study was carried from 1st August 2011 to 30th November 2012. Women who came to TUTH with any complaints following medical abortion were interviewed, examined and treatment provided. Relevant clinical finding were noted. Results: There were a total of 57 cases during the study. Most (66.6%) of the women were in age group 20-29 years age. There were 45 (79%) women who had abortion up to 9 weeks. Medical shop was the main place where most of the women (45.6%) directly come to know about medical abortion. More than 34 (77.2%) received the service from medical shops without any supervision. Most 31 (54.4%) presented with incomplete abortion. There were three cases of continuing pregnancy and four presented with ectopic pregnancy. Eighteen (31.6%) cases needed admission. Fifty six percent of the cases were treated with manual vacuum aspiration, six cases underwent laparotomy and there was one maternal mortality. Conclusions: There is a need for proper dissemination and implementation of guideline for management of these women and adequate supervision to reduce the problems and complications. _______________________________________________________________________________________ Keywords: complications; incomplete abortion; medical abortion; problems

Tubulin Binds to the Cytoplasmic Loop of TRESK Background K+ Channel In Vitro.

The cytoplasmic loop between the second and third transmembrane segments is pivotal in the regulation of TRESK (TWIK-related spinal cord K+ channel, K2P18.1, KCNK18). Calcineurin binds to this region and activates the channel by dephosphorylation in response to the calcium signal. Phosphorylation-dependent anchorage of 14-3-3 adaptor protein also modulates TRESK at this location. In the present study, we identified molecular interacting partners of the intracellular loop. By an affinity chromatography approach using the cytoplasmic loop as bait, we have verified the specific association of calcineurin and 14-3-3 to the channel. In addition to these known interacting proteins, we observed substantial binding of tubulin to the intracellular loop. Successive truncation of the polypeptide and pull-down experiments from mouse brain cytosol narrowed down the region sufficient for the binding of tubulin to a 16 amino acid sequence: LVLGRLSYSIISNLDE. The first six residues of this sequence are similar to the previously reported tubulin-binding region of P2X2 purinergic receptor. The tubulin-binding site of TRESK is located close to the protein kinase A (PKA)-dependent 14-3-3-docking motif of the channel. We provide experimental evidence suggesting that 14-3-3 competes with tubulin for the binding to the cytoplasmic loop of TRESK. It is intriguing that the 16 amino acid tubulin-binding sequence includes the serines, which were previously shown to be phosphorylated by microtubule-affinity regulating kinases (MARK kinases) and contribute to channel inhibition. Although tubulin binds to TRESK in vitro, it remains to be established whether the two proteins also interact in the living cell

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205

Charging of drops impacting onto superhydrophobic surfaces

When neutral water drops impact and rebound from superhydrophobic surfaces, they acquire a positive electrical charge. To measure the charge, we analyzed the trajectory of rebounding drops in an external electric field by high-speed video imaging. Although this charging phenomenon has been observed in the past, little is known about the controlling parameters for the amount of drop charging. Here we investigate the relative importance of five of these potential variables: impact speed, drop contact area, contact line retraction speed, drop size, and type of surface. We additionally apply our previously reported model for sliding drop electrification to the case of impacting drops, suggesting that the two cases contain the same charge separation mechanism at the contact line. Both our experimental results and our theoretical model indicate that maximum contact area is the dominant control parameter for charge separation