Evidence for a High Affinity, Saturable, Prenylation-Dependent p21(Ha- Ras) Binding Site in Plasma Membranes

Oncogenic p21(ras) proteins can only exert their stimulation of cellular proliferation when plasma membrane-associated. This membrane association has an absolute requirement for post-translational modification with isoprenoids. The mechanism by which isoprenoids participate in the specific association of p21(ras) with plasma membranes is the subject of this report. We present in vitro evidence for a plasma membrane binding protein for p21(ras) that can recognize the isoprenoid substituent and, therefore, may facilitate the localization of p21(ras)

Protective effects of Sm-p80 in the presence of resiquimod as an adjuvant against challenge infection with Schistosoma mansoni in mice

SummaryObjectivesTo determine the prophylactic efficacy of an Sm-p80-based vaccine formulation against challenge infection with Schistosoma mansoni in mice using an approach comprising of initial priming with DNA and boosting with recombinant protein in the presence of resiquimod (R848) as an adjuvant.MethodsIn the first experiment (prime–boost approach), mice were primed with Sm-p80–pcDNA3 (week 0) and boosted at weeks 4 and 8 with recombinant Sm-p80 formulated in resiquimod (R848). Each mouse in the control group first received only pcDNA3 and was boosted with R848. In the second set of experiments (recombinant protein approach), mice were immunized (week 0) and boosted (weeks 4 and 8) with rSm-p80 formulated in R848. Animals of the control group in this series of experiments received only R848 at 0, 4, and 8 weeks. All of the animals from both the ‘prime–boost’ and ‘recombinant protein’ groups were challenged with cercariae of S. mansoni, 4 weeks after the last immunization. The mice were sacrificed 6 weeks post-challenge and the reductions in worm burden and egg production were determined. Sm-p80-specific antibody titers were estimated in the mice sera by ELISA. Cytokine mRNA and protein production by proliferating splenocytes in response to in vitro stimulation with Sm-p80, were estimated via RT-PCR and ELISA, respectively.ResultsVaccination with Sm-p80 (prime–boost approach) showed 49% reduction in worm burden; with the recombinant protein approach the protection was found to be 50%. The protection levels were correlated with antibody production. Upon antigenic stimulation with recombinant Sm-p80, splenocytes secreted significant levels of interferon (IFN)-γ and interleukin (IL)-2, indicating that the immune responses were Th1-biased and this was further supported in terms of distribution of antibody isotypes and mRNA expression of cytokines.ConclusionsIn conclusion the present study clearly demonstrates that Sm-p80 consistently maintained its protective nature, and resiquimod as an immunopotentiating agent slightly boosted the protective effects of Sm-p80 in both ‘DNA prime–protein boost’ and ‘recombinant protein’ immunization approaches in a murine model

Birds population in different coastal areas of Sindh

Coastal areas of Karachi and Thatta districts including Sandspit, Cape Monze, Gidyani, Korangi Creek, Pitti Creek, Rohri Creek, Shah Bunder, Sando Bunder and Ketti Bunder were surveyed. The coastal areas of Thatta (Shah Bunder, Sando Bunder and Ketti Bunder) are richly populated

Flow of a Second Grade Fluid through Constricted Tube using Integral Method

The steady flow of a second grade fluid through constricted tube for mild stenosis is modeled and analyzed theoretically. The governing equations are simplified by implying an order-of-magnitude analysis. Based on Karman Pohlhausen procedure polynomial solution for velocity profile is presented. Expressions for pressure gradient, shear stress, separation and reattachment points are also calculated. The effects of nondimensional parameters emerging in the model on the velocity profile, shear stress, pressure gradient are discussed and depicted graphically. The effect of non-Newtonian parameter on velocity profile, wall shear stress and pressure gradient is also analyzed. It is found that the Reynolds number strongly effect the wall shear stress, separation and reattachment points

Effectiveness of Solvent Vapor Annealing over Thermal Annealing on the Photovoltaic Performance of Non-Fullerene Acceptor Based BHJ Solar Cells

We explore two small molecules containing arms of dicyano-n-hexylrhodanine and diathiafulvalene wings terminated with benzothiadiazole linker, denoted as BAF-4CN and BAF-2HDT, respectively, as small molecule non-fullerene acceptors (SMNFAs) in organic solar cells. The proposed materials are mixed with a low band gap polymer donor PTB7-Th having broad absorption in the range of 400–750 nm to form solution-processed bulk heterojunctions (BHJs). The photoluminescence (PL) measurements show that both donor and acceptor can quench each other’s PL effectively, implying that not only electrons are transferred from PTB7-Th → SMNFAs but also holes are transferred from SMNFAs → PTB7-Th for efficient photocurrent generation. Furthermore, solvent vapor annealing (SVA) processing is shown to yield a more balanced hole and electron mobility and thus suppresses the trap-assisted recombination significantly. With this dual charge transfer enabled via fine-tuning of end-groups and SVA treatment, power conversion efficiency of approximately 10% is achieved, demonstrating the feasibility of the proposed approach

Root-Cause Analysis of Persistently High Maternal Mortality in a Rural District of Indonesia: Role of Clinical Care Quality and Health Services Organizational Factors

Background: Despite significant reduction in maternal mortality, there are still many regions in the world that suffer from high mortality. District Kutai Kartanegara, Indonesia, is one such region where consistently high maternal mortality was observed despite high rate of delivery by skilled birth attendants.Method: Thirty maternal deaths were reviewed using verbal autopsy interviews, terminal event reporting, medical records\u27 review, and Death Audit Committee reports, using a comprehensive root-cause analysis framework including Risk Identification, Signal Services, Emergency Obstetrics Care Evaluation, Quality, and 3 Delays.Findings: The root causes were found in poor quality of care, which caused hospital to be unprepared to manage deteriorating patients. In hospital, poor implementation of standard operating procedures was rooted in inadequate skills, lack of forward planning, ineffective communication, and unavailability of essential services. In primary care, root causes included inadequate risk management, referrals to facilities where needed services are not available, and lack of coordination between primary healthcare and hospitals.Conclusion: There is an urgent need for a shift in focus to quality of care through knowledge, skills, and support for consistent application of protocols, making essential services available, effective risk assessment and management, and facilitating timely referrals to facilities that are adequately equipped

Pro-poor intervention strategies in irrigated agriculture in Asia: poverty in irrigated agriculture: issues and options: Bangladesh

Irrigated farming / Poverty / Irrigation management / Water resource management / Policy / Planning / Institutions / Organizations / Local government / Non-governmental organizations / Legislation / Water users / Participatory management / Public sector / Water allocation / Cost recovery / Households / Income / Expenditure / Irrigation canals / Bangladesh

Recent Advances and Methodological Considerations on Vaccine Candidates for Human Schistosomiasis

Schistosomiasis remains a neglected tropical disease of major public health concern with high levels of morbidity in various parts of the world. Although considerable efforts in implementing mass drug administration programs utilizing praziquantel have been deployed, schistosomiasis is still not contained. A vaccine may therefore be an essential part of multifaceted prevention control efforts. In the 1990s, a joint United Nations committee promoting parasite vaccines shortlisted promising candidates including for schistosomiasis discussed below. After examining the complexity of immune responses in human hosts infected with schistosomes, we review and discuss the antigen design and preclinical and clinical development of the four leading vaccine candidates: Sm-TSP-2 in Phase 1b/2b, Sm14 in Phase 2a/2b, Sm-p80 in Phase 1 preparation, and Sh28GST in Phase 3. Our assessment of currently leading vaccine candidates revealed some methodological issues that preclude a fair comparison between candidates and the rationale to advance in clinical development. These include (1) variability in animal models - in particular non-human primate studies - and predictive values of each for protection in humans; (2) lack of consensus on the assessment of parasitological and immunological parameters; (3) absence of reliable surrogate markers of protection; (4) lack of well-designed parasitological and immunological natural history studies in the context of mass drug administration with praziquantel. The controlled human infection model - while promising and unique - requires validation against efficacy outcomes in endemic settings. Further research is also needed on the impact of advanced adjuvants targeting specific parts of the innate immune system that may induce potent, protective and durable immune responses with the ultimate goal of achieving meaningful worm reduction.</jats:p

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings.

Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. We conducted a prospective, clinical study to compare the efficacy and safety of a 7-day course of oral albendazole with a single dose of oral ivermectin, or double doses, given 2 weeks apart, of ivermectin in Thai patients who developed this infection. Patients were regularly followed-up after initiation of treatment, until one year after treatment. Ninety patients were studied (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). The average duration of follow-up were 19 (range 2–76) weeks in albendazole group, 39 ( range 2–74) weeks in single dose ivermectin group, and 26 ( range 2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively. No serious adverse event associated with treatment was found in any of the groups. Therefore this study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis