Synthesis, characterization and biological evaluation of sulfonamide based transition metal complexes

In the present study a noval 4-oxo-4-(4-sulfamoylphenylamino)but-2-enoic acid (OSPAB) was prepared by reaction of maleic anhydride with sulphanilamide. The prepared ligand was characterized by elemental analysis and spectral studies. The transition metal complexes viz. Cu2+, Ni2+ , Co2+ , Mn2+ and  Zn2+  of OSPAB were prepared and characterized by metal-ligand (M:L) ratio, IR, reflectance spectroscopies and magnetic properties. All the prepared metal complexes and ligand were studies as antimicrobial agent. Among all the metal complexes, Zn2+ and Cu2+ metal complexes have shown significant activity. Â

Profile of patients with intellectual disability visiting a tertiary care center in western India

Background:Intellectual disability is commonly associated with variety of etio-pathological and co-morbid conditions influencing outcome of rehabilitative measures. Understanding of these factors helps in better management of disabled condition.Methods:A qualitative retrospective case record review, of patients with intellectual disability, visiting psychiatry department of a tertiary care hospital, within a period of one year, was conducted to assess their epidemiological and clinical profile.Results: Patients with Intellectual disability are brought to the hospital at all ages and commonly by their parents. Etiologically related various peri-natal factors (delayed birth cry and seizures being most common) as well as childhood medical conditions (epilepsy and recurrent respiratory/GI infections being most common) were commonly found in these patients. Milestones are delayed in almost 60-70% of cases whereas various physical and psychiatric conditions commonly co-existed with disability.Conclusion:Clinical profile of these patients demands a comprehensive evaluation and management apart from routine IQ assessment

The benzodiazepine class of compounds as a potential for the treatment of cutaneous leishmaniasis

Cutaneous leishmaniasis is endemic in over 70 countries in the tropics and neotropics. Several Leishmania species are the causative agent of this form of the disease and are transmitted to humans and animals by a bite of a phlebotomies sandfly. Antileishmanial drugs including antimonials, Amphotericin B, pentamidine, paromomycin, allupurinol and miltefosine have been the treatment of choice over recent years. However, toxicity, difficulty of administration and emergence of resistance have limited the number of chemotherapeutic options available hence underlying the urgency for the identification of new classes of compounds with antileishmanial activity. The benzodiazepine class of compounds whose core structure entails the fusion of a benzene and diazepine ring have been used over the past 50 years as psychoactive drugs in the treatment of anxiety, insomnia and as an anticonvulsants. The aim of this study was to explore the antileishmanial effects of this class of compounds on stationary phase promastigotes of old and new world Leishmania species (L. aethiopica, L. major, L. tropica and L. mexicana) using the 3-(4,5-dimethylthiazol+2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) assay for assessing parasite viability. An array of compounds with modifications brought about at the benzene and diazepine structures were tested over a range of concentrations over a 24-hour period for all species mentioned above. The three most active compounds (RRP223, RRP262 and RRP 199) displayed a different range of activity with inhibition of parasite growth at micromolar range in all 4 species. These findings implicate selective activity and demonstrate Leishmanicidal potential in the benzodiazepine class of compounds

A defined synthetic substrate for serum-free culture of human stem cell derived cardiomyocytes with improved functional maturity identified using combinatorial materials microarrays

Cardiomyocytes from human stem cells have applications in regenerative medicine and can provide models for heart disease and toxicity screening. Soluble components of the culture system such as growth factors within serum and insoluble components such as the substrate on which cells adhere to are important variables controlling the biological activity of cells. Using a combinatorial materials approach we develop a synthetic, chemically defined cellular niche for the support of functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) in a serum-free fully defined culture system. Almost 700 polymers were synthesized and evaluated for their utility as growth substrates. From this group, 20 polymers were identified that supported cardiomyocyte adhesion and spreading. The most promising 3 polymers were scaled up for extended culture of hESC-CMs for 15 days and were characterized using patch clamp electrophysiology and myofibril analysis to find that functional and structural phenotype was maintained on these synthetic substrates without the need for coating with extracellular matrix protein. In addition, we found that hESC-CMs cultured on a co-polymer of isobornyl methacrylate and tert-butylamino-ethyl methacrylate exhibited significantly longer sarcomeres relative to gelatin control. The potential utility of increased structural integrity was demonstrated in an in vitro toxicity assay that found an increase in detection sensitivity of myofibril disruption by the anti-cancer drug doxorubicin at a concentration of 0.05 ?M in cardiomyocytes cultured on the co-polymer compared to 0.5 ?M on gelatin. The chemical moieties identified in this large-scale screen provide chemically defined conditions for the culture and manipulation of hESC-CMs, as well as a framework for the rational design of superior biomaterials

Negotiating power relations, gender equality, and collective agency: are village health committees transformative social spaces in northern India?

BACKGROUND: Participatory health initiatives ideally support progressive social change and stronger collective agency for marginalized groups. However, this empowering potential is often limited by inequalities within communities and between communities and outside actors (i.e. government officials, policymakers). We examined how the participatory initiative of Village Health, Sanitation, and Nutrition Committees (VHSNCs) can enable and hinder the renegotiation of power in rural north India. METHODS: Over 18 months, we conducted 74 interviews and 18 focus groups with VHSNC members (including female community health workers and local government officials), non-VHSNC community members, NGO staff, and higherlevel functionaries. We observed 54 VHSNC-related events (such as trainings and meetings). Initial thematic network analysis supported further examination of power relations, gendered “social spaces,” and the “discourses of responsibility” that affected collective agency. RESULTS: VHSNCs supported some re-negotiation of intra-community inequalities, for example by enabling some women to speak in front of men and perform assertive public roles. However, the extent to which these new gender dynamics transformed relations beyond the VHSNC was limited. Furthermore, inequalities between the community and outside stakeholders were re-entrenched through a “discourse of responsibility”: The comparatively powerful outside stakeholders emphasized community responsibility for improving health without acknowledging or correcting barriers to effective VHSNC action. In response, some community members blamed peers for not taking up this responsibility, reinforcing a negative collective identity where participation was futile because no one would work for the greater good. Others resisted this discourse, arguing that the VHSNC alone was not responsible for taking action: Government must also intervene. This counter-narrative also positioned VHSNC participation as futile. CONCLUSIONS: Interventions to strengthen participation in health systems can engender social transformation. However they must consider how changing power relations can be sustained outside participatory spaces, and how discourse frames the rationale for community participation.ISIScopu

High throughput screening for discovery of materials that control stem cell fate

Insights into the complex stem cell niche have identified the cell–material interface to be a potent regulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this, materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicit specific cellular responses. To accelerate materials discovery, high throughput screening platforms have been designed which can rapidly evaluate combinatorial material libraries in two and three-dimensional environments. In this review, we present screening platforms for the discovery of material properties that influence stem cell behavior

Drug delivery across length scales

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future

A Gain-of-Function Germline Mutation in Drosophila ras1 Affects Apoptosis and Cell Fate during Development

The RAS/MAPK signal transduction pathway is an intracellular signaling cascade that transmits environmental signals from activated receptor tyrosine kinases (RTKs) on the cell surface and other endomembranes to transcription factors in the nucleus, thereby linking extracellular stimuli to changes in gene expression. Largely as a consequence of its role in oncogenesis, RAS signaling has been the subject of intense research efforts for many years. More recently, it has been shown that milder perturbations in Ras signaling during embryogenesis also contribute to the etiology of a group of human diseases. Here we report the identification and characterization of the first gain-of-function germline mutation in Drosophila ras1 (ras85D), the Drosophila homolog of human K-ras, N-ras and H-ras. A single amino acid substitution (R68Q) in the highly conserved switch II region of Ras causes a defective protein with reduced intrinsic GTPase activity, but with normal sensitivity to GAP stimulation. The ras1R68Q mutant is homozygous viable but causes various developmental defects associated with elevated Ras signaling, including cell fate changes and ectopic survival of cells in the nervous system. These biochemical and functional properties are reminiscent of germline Ras mutants found in patients afflicted with Noonan, Costello or cardio-facio-cutaneous syndromes. Finally, we used ras1R68Q to identify novel genes that interact with Ras and suppress cell death

Beyond form and functioning: Understanding how contextual factors influence village health committees in northern India

Health committees are a common strategy to foster community participation in health. Efforts to strengthen committees often focus on technical inputs to improve committee form (e.g. representative membership) and functioning (e.g. meeting procedures). However, porous and interconnected contextual spheres also mediate committee effectiveness. Using a framework for contextual analysis, we explored the contextual features that facilitated or hindered Village Health, Sanitation and Nutrition Committee (VHSNC) functionality in rural north India. We conducted interviews (n = 74), focus groups (n = 18) and observation over 1.5 years. Thematic content analysis enabled the identification and grouping of themes, and detailed exploration of sub-themes. While the intervention succeeded in strengthening committee form and functioning, participant accounts illuminated the different ways in which contextual influences impinged on VHSNC efficacy. Women and marginalized groups navigated social hierarchies that curtailed their ability to assert themselves in the presence of men and powerful local families. These dynamics were not static and unchanging, illustrated by pre-existing cross-caste problem solving, and the committee's creation of opportunities for the careful violation of social norms. Resource and capacity deficits in government services limited opportunities to build relationships between health system actors and committee members and engendered mistrust of government institutions. Fragmented administrative accountability left committee members bearing responsibility for improving local health without access to stakeholders who could support or respond to their efforts. The committee's narrow authority was at odds with widespread community needs, and committee members struggled to involve diverse government services across the health, sanitation, and nutrition sectors. Multiple parallel systems (political decentralization, media and other village groups) presented opportunities to create more enabling VHSNC contexts, although the potential to harness these opportunities was largely unmet. This study highlights the urgent need for supportive contexts in which people can not only participate in health committees, but also access the power and resources needed to bring about actual improvements to their health and wellbeing.IS