228 research outputs found

    Determination of the structure of papaya protease omega

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    Sustainability of donor programs: evaluating and informing the transition of a large HIV prevention program in India to local ownership

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    Sustainability is the holy grail of many development projects, yet there is limited evidence about strategies that effectively support transition of programs from donor funding to national governments. The first phase of Avahan, the India AIDS Initiative supported by the Bill and Melinda Gates Foundation (2003–2009), aimed to demonstrate an HIV/AIDS prevention program at scale, primarily targeted at high-risk groups. During the second phase (2009–2013), this large-scale program will be transitioned to its natural owners: the Government of India and local communities. This paper describes the evaluation design for the Avahan transition strategy.A detailed logic model for the transition was developed. The Avahan transition strategy focuses on three activities: 1 enhancing capacities among communities, non-governmental organizations (NGOs), and government entities, in line with India's national AIDS control strategy; 2 aligning technical and managerial aspects of Avahan programs with government norms and standards; and 3 promoting and sustaining commitment to services for most-at-risk populations. It is anticipated that programs will then transfer smoothly to government and community ownership, become institutionalized within the government system, and support a sustained HIV/AIDS response.The research design evaluates the implementation and effectiveness of 1 activities undertaken by the program; 2 intermediate effects including the process of institutionalization and the extent to which key Avahan organizational procedures and behaviors are integrated into government systems; and 3 overarching effects namely the impact of the transition process on the sustained delivery of HIV/AIDS prevention services to high-risk groups. Both qualitative and quantitative research approaches are employed so that the evaluation will both assess outcomes and explain why they have occurred.It is unusual for donor-supported projects in low- and middle-income countries to carefully plan transition processes, and prospectively evaluate these. This evaluation is designed so as to both inform decision making throughout the transition process and answer larger questions about the transition and sustainability of donor programs

    Assessing community perspectives of the community based education and service model at Makerere University, Uganda: a qualitative evaluation

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    <p>Abstract</p> <p>Background</p> <p>Community partnerships are defined as groups working together with shared goals, responsibilities, and power to improve the community. There is growing evidence that these partnerships contribute to the success and sustainability of community-based education and service programs (COBES), facilitating change in community actions and attitudes. Makerere University College of Health Sciences (MakCHS) is forging itself as a transformational institution in Uganda and the region. The College is motivated to improve the health of Ugandans through innovative responsive teaching, provision of service, and community partnerships. Evaluating the COBES program from the community perspective can assist the College in refining an innovative and useful model that has potential to improve the health of Ugandans.</p> <p>Methods</p> <p>A stratified random sample of 11 COBES sites was selected to examine the community’s perception of the program. Key Informant Interviews of 11 site tutors and 33 community members were completed. The data was manually analyzed and themes developed.</p> <p>Results</p> <p>Communities stated the students consistently engaged with them with culturally appropriate behaviour. They rated the student’s communication as very good even though translators were frequently needed. Half the community stated they received some feedback from the students, but some communities interpreted any contact after the initial visit as feedback. Communities confirmed and appreciated that the students provided a number of interventions and saw positive changes in health and health seeking behaviours. The community reflected that some programs were more sustainable than others; the projects that needed money to implement were least sustainable. The major challenges from the community included community fatigue, and poor motivation of community leaders to continue to take students without compensation.</p> <p>Conclusions</p> <p>Communities hosting Makerere students valued the students’ interventions and the COBES model. They reported witnessing health benefits of fewer cases of disease, increased health seeking behavior and sustainable healthcare programs. The evidence suggests that efforts to standardize objectives, implement structural adjustments, and invest in development of the program would yield even more productive community interactions and a healthcare workforce with public health skills needed to work in rural communities.</p

    LMS-Verify: abstraction without regret for verified systems programming

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    Performance critical software is almost always developed in C, as programmers do not trust high-level languages to deliver the same reliable performance. This is bad because low-level code in unsafe languages attracts security vulnerabilities and because development is far less productive, with PL advances mostly lost on programmers operating under tight performance constraints. High-level languages provide memory safety out of the box, but they are deemed too slow and unpredictable for serious system software. Recent years have seen a surge in staging and generative programming: the key idea is to use high-level languages and their abstraction power as glorified macro systems to compose code fragments in first-order, potentially domain-specific, intermediate languages, from which fast C can be emitted. But what about security? Since the end result is still C code, the safety guarantees of the high-level host language are lost. In this paper, we extend this generative approach to emit ACSL specifications along with C code. We demonstrate that staging achieves ``abstraction without regret'' for verification: we show how high-level programming models, in particular higher-order composable contracts from dynamic languages, can be used at generation time to compose and generate first-order specifications that can be statically checked by existing tools. We also show how type classes can automatically attach invariants to data types, reducing the need for repetitive manual annotations. We evaluate our system on several case studies that varyingly exercise verification of memory safety, overflow safety, and functional correctness. We feature an HTTP parser that is (1) fast (2) high-level: implemented using staged parser combinators (3) secure: with verified memory safety. This result is significant, as input parsing is a key attack vector, and vulnerabilities related to HTTP parsing have been documented in all widely-used web servers.</jats:p

    In Silico and Structural Analyses Demonstrate That Intrinsic Protein Motions Guide T Cell Receptor Complementarity Determining Region Loop Flexibility.

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    T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 Å in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions

    Structure and in silico simulations of a cold-active esterase reveals its prime cold-adaptation mechanism

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    Here we determined the structure of a cold active family IV esterase (EstN7) cloned from Bacillus cohnii strain N1. EstN7 is a dimer with a classical α/β hydrolase fold. It has an acidic surface that is thought to play a role in cold-adaption by retaining solvation under changed water solvent entropy at lower temperatures. The conformation of the functionally important cap region is significantly different to EstN7's closest relatives, forming a bridge-like structure with reduced helical content providing greater access to the active site through more than one substrate access tunnel. However, dynamics do not appear to play a major role in cold adaption. Molecular dynamics at different temperatures, rigidity analysis, normal mode analysis and geometric simulations of motion confirm the flexibility of the cap region but suggest that the rest of the protein is largely rigid. Rigidity analysis indicates the distribution of hydrophobic tethers is appropriate to colder conditions, where the hydrophobic effect is weaker than in mesophilic conditions due to reduced water entropy. Thus, it is likely that increased substrate accessibility and tolerance to changes in water entropy are important for of EstN7's cold adaptation rather than changes in dynamics

    Positive functional synergy of structurally integrated artificial protein dimers assembled by Click chemistry

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    Construction of artificial higher order protein complexes allows sampling of structural architectures and functional features not accessible by classical monomeric proteins. Here, we combine in silico modelling with expanded genetic code facilitated strain promoted azide-alkyne cycloaddition to construct artificial complexes that are structurally integrated protein dimers and demonstrate functional synergy. Using fluorescent proteins sfGFP and Venus as models, homodimers and heterodimers are constructed that switched ON once assembled and display enhanced spectral properties. Symmetrical crosslinks are found to be important for functional enhancement. The determined molecular structure of one artificial dimer shows that a new long-range polar network comprised mostly of organised water molecules links the two chromophores leading to activation and functional enhancement. Single molecule analysis reveals the dimer is more resistant to photobleaching spending longer times in the ON state. Thus, genetically encoded bioorthogonal chemistry can be used to generate truly integrated artificial protein complexes that enhance function
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