944 research outputs found
"The difference that makes a difference": highlighting the role of variable contexts within an HIV Prevention Community Randomised Trial (HPTN 071/PopART) in 21 study communities in Zambia and South Africa.
This paper explores contextual heterogeneity within a community randomised trial HPTN 071 (Population Effects of Antiretroviral Treatment to Reduce HIV Transmission) carried out in 21 study communities (12 Zambian, 9 South African). The trial evaluates the impact of a combination HIV prevention package (including household-based HIV counselling and testing and anti-retroviral treatment (ART) eligibility regardless of CD4-count) on HIV incidence. The selection, matching and randomisation of study communities relied on key epidemiological and demographic variables and community and stakeholder support. In 2013, following the selection of study communities, a "Broad Brush Survey" (BBS) approach was used to rapidly gather qualitative data on each study community, prior to the implementation of the trial intervention. First-year process indicator intervention data (2014-2015) were collected during the household-based intervention by community lay workers. Using an open/closed typology of urban communities (indicating more or less heterogeneity), this qualitative inquiry presents key features of 12 Zambian communities using a list of four meta-indicators (physical features, social organisation, networks and community narratives). These indicators are then compared with four intervention process indicators in a smaller set of four study communities. The process indicators selected for this analysis indicate response to the intervention (uptake) amongst adults. The BBS qualitative data are used to interpret patterns of similarity and variability in the process indicators across four communities. We found that meta-indicators of local context helped to interpret patterns of similarity and variability emerging across and within the four communities. Features especially significant for influencing heterogeneity in process indicators include proportion of middle-class residents, proximity to neighbouring communities and town centre, the scale of the informal economy, livelihood-linked mobility, presence of HIV stakeholders over time and commitment to community action. Future interdisciplinary analysis is needed to explore if these patterns of difference continue to hold up over the full intervention period and all intervention communities
Structural motifs of biomolecules
Biomolecular structures are assemblies of emergent anisotropic building
modules such as uniaxial helices or biaxial strands. We provide an approach to
understanding a marginally compact phase of matter that is occupied by proteins
and DNA. This phase, which is in some respects analogous to the liquid crystal
phase for chain molecules, stabilizes a range of shapes that can be obtained by
sequence-independent interactions occurring intra- and intermolecularly between
polymeric molecules. We present a singularityfree self-interaction for a tube
in the continuum limit and show that this results in the tube being positioned
in the marginally compact phase. Our work provides a unified framework for
understanding the building blocks of biomolecules.Comment: 13 pages, 5 figure
Investigating the Relationship between hs-CRP Serum Level and Insulin Resistance (HOMA IR) Six Weeks after Childbirth in Patients with Gestational Diabetes Mellitus
Background: Some patients with GDM (Gestational Diabetes Mellitus) still experience impaired glucose tolerance after childbirth and will be affected by diabetes mellitus type 2.
Objectives: The aim of this study is to investigate the relationship between hs-CRP serum levels with insulin resistance six weeks after childbirth in patients with gestational diabetes mellitus type 2.
Methods: In this descriptive cross-sectional study, 110 patients with GDM were evaluated in terms of the insulin resistance index (HOMA), hs-CRP serum, and the oral glucose tolerance test (OGTT) six weeks after childbirth. Their anthropometric indices were measured in the early pregnancy. Spearman’s rank correlation coefficient and linear regression analysis were used to analyze data in SPSS 16.
Results: The mean of hs-CRP was 8.72 µg/ml among the patients in this study. It is higher than the normal range. Moreover, 24.5% of the patients were suffering from impaired glucose tolerance, and hs-CRP levels were higher than the normal range in 92.6% of these patients. Furthermore, 41.8% of patients showed insulin resistance, and hs-CRP levels were high among 73.9% of them. After age adjustment, the increase in hs-CRP serum level was significantly correlated with insulin resistance (HOMA) and the one-hour and two-hour OGTTs (p=0.007 and p<0.001, respectively).
Conclusion: It appears that age adjustment can help us figure out the relationship between the increase in hs-CRP serum and insulin resistance in pregnant mothers with diabetes six weeks after childbirth
Making justice more accessible
From the point of view of the Citizen, Justice is not always readily
accessible. Either because it is a lengthy process, potentially
expensive, sometimes unclear or simply scary, people will often
avoid or withdraw from a judicial process, especially in those
cases that involve relatively small amounts. This results in the
giving up of a basic right, with the potential loss of rightful
benefits. In this paper we briefly analyze the main aspects that
impair access to Justice nowadays. We then move on to look at
recent technological developments in the field of Online Dispute
Resolution to argue that these can, in the near future, have a
significant role in improving access to Justice. Specifically, we
analyze the UMCourt Conflict Resolution Framework, developed
by our research team, and address the different dimensions in
which such tools contribute to make Justice more accessible,
namely through better access to useful information, support in
decision-making or more cost-effective processes.Development Fund through the COMPETE Programme
(operational programme for competitiveness) and by National
Funds through the FCT - Fundação para a Ciência e a Tecnologia
(Portuguese Foundation for Science and Technology) within
projects FCOMP-01-0124-FEDER-028980 (PTDC/EEISII/1386/
2012) and PEst-OE/EEI/UI0752/201
Effect of molecular chaperones on aberrant protein oligomers in vitro: super- versus sub-stoichiometric chaperone concentrations
Living systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 μm, of two molecular chaperones, namely αB-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. αB-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasizes the efficiency and versatility of these protein molecules
Discrete molecular dynamics simulations of peptide aggregation
We study the aggregation of peptides using the discrete molecular dynamics
simulations. At temperatures above the alpha-helix melting temperature of a
single peptide, the model peptides aggregate into a multi-layer parallel
beta-sheet structure. This structure has an inter-strand distance of 0.48 nm
and an inter-sheet distance of 1.0 nm, which agree with experimental
observations. In this model, the hydrogen bond interactions give rise to the
inter-strand spacing in beta-sheets, while the Go interactions among side
chains make beta-strands parallel to each other and allow beta-sheets to pack
into layers. The aggregates also contain free edges which may allow for further
aggregation of model peptides to form elongated fibrils.Comment: 15 pages, 8 figure
Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide
Understanding the influence of macromolecular crowding and nanoparticles on
the formation of in-register -sheets, the primary structural component
of amyloid fibrils, is a first step towards describing \emph{in vivo} protein
aggregation and interactions between synthetic materials and proteins. Using
all atom molecular simulations in implicit solvent we illustrate the effects of
nanoparticle size, shape, and volume fraction on oligomer formation of an
amyloidogenic peptide from the transthyretin protein. Surprisingly, we find
that inert spherical crowding particles destabilize in-register -sheets
formed by dimers while stabilizing -sheets comprised of trimers and
tetramers. As the radius of the nanoparticle increases crowding effects
decrease, implying smaller crowding particles have the largest influence on the
earliest amyloid species. We explain these results using a theory based on the
depletion effect. Finally, we show that spherocylindrical crowders destabilize
the ordered -sheet dimer to a greater extent than spherical crowders,
which underscores the influence of nanoparticle shape on protein aggregation
The Effect of Nanoparticles on Amyloid Aggregation Depends on the Protein Stability and Intrinsic Aggregation Rate
Nanoparticles interfere with protein amyloid formation. Catalysis of the process may occur due to increased local protein concentration and nucleation on the nanoparticle surface, whereas tight binding or a large particle/protein surface area may lead to inhibition of protein aggregation. Here we show a clear correlation between the intrinsic protein stability and the nanoparticle effect on the aggregation rate. The results were reached for a series of five mutants of single-chain monellin differing in intrinsic stability toward denaturation, for which a correlation between protein stability and aggregation propensity has been previously documented by Szczepankiewicz et al. [Mol. Biosyst 2010 7 (2), 521-532]. The aggregation process was monitored by thioflavin T fluorescence in the absence and presence of copolyrneric nanoparticles with different hydrophobic characters. For mutants with a high intrinsic stability and low intrinsic aggregation rate, we find that amyloid fibril formation is accelerated by nanoparticles. For find the opposite-a retardation of amyloid fibril formation by nanoparticles. Moreover, both catalytic and inhibitory effects are most pronounced with the least hydrophobic nanoparticles, which have a larger surface accessibility of hydrogen-bonding groups in the polymer backbone
Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers
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