Ring-like N-fold Models of Aβ42 fibrils

When assembling as fibrils Aβ40 peptides can only assume U-shaped conformations while Aβ42 can also arrange as S-shaped three-stranded chains. We show that this allows Aβ42 peptides to assemble pore-like structures that may explain their higher toxicity. For this purpose, we develop a scalable model of ring-like assemblies of S-shaped Aβ1–42 chains and study the stability and structural properties of these assemblies through atomistic molecular dynamics simulations. We find that the proposed arrangements are in size and symmetry compatible with experimentally observed Aβ assemblies. We further show that the interior pore in our models allows for water leakage as a possible mechanism of cell toxicity of Aβ42 amyloids.Simulations were done on the SCHOONER cluster of the University of Oklahoma and the Extreme Science and Engineering Discovery Environment (XSEDE) which is supported by NSF under grant ACI-1053575. We acknowledge financial support from NSF CHE-1266256. Open access fees fees for this article provided whole or in part by OU Libraries Open Access Fund.Ye

Preliminary analysis of immune activation in early onset type 2 diabetes

Introduction. First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n=8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)-matched controls without T2D (n=8). Methods. Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 µM). Culture supernatants were evaluated for the amount of TNF-α and IL-1β produced by PBMC. Results. Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p<0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-α and IL-1β after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1β synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1β synthesis in PBMCs isolated from youth with T2D versus controls (p<0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort. Conclusion. These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1β activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people

Major agricultural changes required to mitigate phosphorus losses under climate change

Phosphorus losses from land to water will be impacted by climate change and land management for food production, with detrimental impacts on aquatic ecosystems. Here we use a unique combination of methods to evaluate the impact of projected climate change on future phosphorus transfers, and to assess what scale of agricultural change would be needed to mitigate these transfers. We combine novel high-frequency phosphorus flux data from three representative catchments across the UK, a new high-spatial resolution climate model, uncertainty estimates from an ensemble of future climate simulations, two phosphorus transfer models of contrasting complexity and a simplified representation of the potential intensification of agriculture based on expert elicitation from land managers. We show that the effect of climate change on average winter phosphorus loads (predicted increase up to 30% by 2050s) will be limited only by large-scale agricultural changes (e.g., 20–80% reduction in phosphorus inputs)

Travel-related schistosomiasis, strongyloidiasis, filariasis, and toxocariasis: the risk of infection and the diagnostic relevance of blood eosinophilia

<p>Abstract</p> <p>Background</p> <p>This study prospectively assessed the occurrence of clinical and subclinical schistosomiasis, strongyloidiasis, filariasis, and toxocariasis, and the screening value of eosinophilia in adult short-term travelers to helminth-endemic countries.</p> <p>Methods</p> <p>Visitors of a pre-travel health advice centre donated blood samples for serology and blood cell count before and after travel. Samples were tested for eosinophilia, and for antibodies against schistosomiasis, strongyloidiasis, filariasis, and toxocariasis. Previous infection was defined as seropositivity in pre- and post-travel samples. Recent infection was defined as a seroconversion. Symptoms of parasitic disease were recorded in a structured diary.</p> <p>Results</p> <p>Previous infection was found in 112 of 1207 subjects: schistosomiasis in 2.7%, strongyloidiasis in 2.4%, filariasis in 3.4%, and toxocariasis in 1.8%. Recent schistosomiasis was found in 0.51% of susceptible subjects at risk, strongyloidiasis in 0.25%, filariasis in 0.09%, and toxocariasis in 0.08%. The incidence rate per 1000 person-months was 6.4, 3.2, 1.1, and 1.1, respectively. Recent infections were largely contracted in Asia. The positive predictive value of eosinophilia for diagnosis was 15% for previous infection and 0% for recent infection. None of the symptoms studied had any positive predictive value.</p> <p>Conclusion</p> <p>The chance of infection with schistosomiasis, strongyloidiasis, filariasis, and toxocariasis during one short-term journey to an endemic area is low. However, previous stay leads to a cumulative risk of infection. Testing for eosinophilia appeared to be of no value in routine screening of asymptomatic travelers for the four helminthic infections. Findings need to be replicated in larger prospective studies.</p

Reservoir stress path and induced seismic anisotropy: Results from linking coupled fluid-flow/geomechanical simulation with seismic modelling

We present a workflow linking coupled fluid-flow and geomechanical simulation with seismic modelling to predict seismic anisotropy induced by nonhydrostatic stress changes. We generate seismic models from coupled simulations to examine the relationship between reservoir geometry, stress path and seismic anisotropy. The results indicate that geometry influences the evolution of stress, which leads to stress-induced seismic anisotropy. Although stress anisotropy is high for the small reservoir, the effect of stress arching and the ability of the side-burden to support the excess load limit the overall change in effective stress and hence seismic anisotropy. For the extensive reservoir, stress anisotropy and induced seismic anisotropy are high. The extensive and elongate reservoirs experience significant compaction, where the inefficiency of the developed stress arching in the side-burden cannot support the excess load. The elongate reservoir displays significant stress asymmetry, with seismic anisotropy developing predominantly along the long-edge of the reservoir. We show that the link between stress path parameters and seismic anisotropy is complex, where the anisotropic symmetry is controlled not only by model geometry but also the nonlinear rock physics model used. Nevertheless, a workflow has been developed to model seismic anisotropy induced by non-hydrostatic stress changes, allowing field observations of anisotropy to be linked with geomechanical models

Artificial Polyploidy Improves Bacterial Single Cell Genome Recovery

BACKGROUND: Single cell genomics (SCG) is a combination of methods whose goal is to decipher the complete genomic sequence from a single cell and has been applied mostly to organisms with smaller genomes, such as bacteria and archaea. Prior single cell studies showed that a significant portion of a genome could be obtained. However, breakages of genomic DNA and amplification bias have made it very challenging to acquire a complete genome with single cells. We investigated an artificial method to induce polyploidy in Bacillus subtilis ATCC 6633 by blocking cell division and have shown that we can significantly improve the performance of genomic sequencing from a single cell. METHODOLOGY/PRINCIPAL FINDINGS: We inhibited the bacterial cytoskeleton protein FtsZ in B.subtilis with an FtsZ-inhibiting compound, PC190723, resulting in larger undivided single cells with multiple copies of its genome. qPCR assays of these larger, sorted cells showed higher DNA content, have less amplification bias, and greater genomic recovery than untreated cells. SIGNIFICANCE: The method presented here shows the potential to obtain a nearly complete genome sequence from a single bacterial cell. With millions of uncultured bacterial species in nature, this method holds tremendous promise to provide insight into the genomic novelty of yet-to-be discovered species, and given the temporary effects of artificial polyploidy coupled with the ability to sort and distinguish differences in cell size and genomic DNA content, may allow recovery of specific organisms in addition to their genomes

Improving pneumonia case-management in Benin: a randomized trial of a multi-faceted intervention to support health worker adherence to Integrated Management of Childhood Illness guidelines

<p>Abstract</p> <p>Background</p> <p>Pneumonia is a leading cause of death among children under five years of age. The Integrated Management of Childhood Illness strategy can improve the quality of care for pneumonia and other common illnesses in developing countries, but adherence to these guidelines could be improved. We evaluated an intervention in Benin to support health worker adherence to the guidelines after training, focusing on pneumonia case management.</p> <p>Methods</p> <p>We conducted a randomized trial. After a health facility survey in 1999 to assess health care quality before Integrated Management of Childhood Illness training, health workers received training plus either study supports (job aids, non-financial incentives and supervision of workers and supervisors) or "usual" supports. Follow-up surveys were conducted in 2001, 2002 and 2004. Outcomes were indicators of health care quality for Integrated Management-defined pneumonia. Further analyses included a graphical pathway analysis and multivariable logistic regression modelling to identify factors influencing case-management quality.</p> <p>Results</p> <p>We observed 301 consultations of children with non-severe pneumonia that were performed by 128 health workers in 88 public and private health facilities. Although outcomes improved in both intervention and control groups, we found no statistically significant difference between groups. However, training proceeded slowly, and low-quality care from untrained health workers diluted intervention effects. Per-protocol analyses suggested that health workers with training plus study supports performed better than those with training plus usual supports (20.4 and 19.2 percentage-point improvements for recommended treatment [p = 0.08] and "recommended or adequate" treatment [p = 0.01], respectively). Both groups tended to perform better than untrained health workers. Analyses of treatment errors revealed that incomplete assessment and difficulties processing clinical findings led to missed pneumonia diagnoses, and missed diagnoses led to inadequate treatment. Increased supervision frequency was associated with better care (odds ratio for recommended treatment = 2.1 [95% confidence interval: 1.13.9] per additional supervisory visit).</p> <p>Conclusion</p> <p>Integrated Management of Childhood Illness training was useful, but insufficient, to achieve high-quality pneumonia case management. Our study supports led to additional improvements, although large gaps in performance still remained. A simple graphical pathway analysis can identify specific, common errors that health workers make in the case-management process; this information could be used to target quality improvement activities, such as supervision (ClinicalTrials.gov number NCT00510679).</p

CCL3L1 copy number, CCR5 genotype and susceptibility to tuberculosis

Background: Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1α and its receptor CCR5 play a role in susceptibility to TB. Thus by measuring copy number variation of CCL3L1, one of the genes that encode MIP-1α, and genotyping a functional promoter polymorphism -2459A > G in CCR5 (rs1799987) we investigate the influence of MIP-1α and CCR5, independently and combined, in susceptibility to clinically active TB in three populations, a Peruvian population (n = 1132), a !Xhosa population (n = 605) and a South African Coloured population (n = 221). The three populations include patients with clinically diagnosed pulmonary TB, as well as other, less prevalent forms of extrapulmonary TB. Methods and results: Copy number of CCL3L1 was measured using the paralogue ratio test and exhibited ranges between 0–6 copies per diploid genome (pdg) in Peru, between 0–12 pdg in !Xhosa samples and between 0–10 pdg in South African Coloured samples. The CCR5 promoter polymorphism was observed to differ significantly in allele frequency between populations (*A; Peru f = 0.67, !Xhosa f = 0.38, Coloured f = 0.48). Conclusions: The case–control association studies performed however find, surprisingly, no evidence for an influence of variation in genes coding for MIP-1α or CCR5 individually or together in susceptibility to clinically active TB in these populations

Cattle transhumance and agropastoral nomadic herding practices in central Cameroon

Abstract Background In sub-Saharan Africa, livestock transhumance represents a key adaptation strategy to environmental variability. In this context, seasonal livestock transhumance also plays an important role in driving the dynamics of multiple livestock infectious diseases. In Cameroon, cattle transhumance is a common practice during the dry season across all the main livestock production zones. Currently, the little recorded information of the migratory routes, grazing locations and nomadic herding practices adopted by pastoralists, limits our understanding of pastoral cattle movements in the country. GPS-tracking technology in combination with a questionnaire based-survey were used to study a limited pool of 10 cattle herds from the Adamawa Region of Cameroon during their seasonal migration, between October 2014 and May 2015. The data were used to analyse the trajectories and movement patterns, and to characterize the key animal health aspects related to this seasonal migration in Cameroon. Results Several administrative Regions of the country were visited by the transhumant herds over more than 6 months. Herds travelled between 53 and 170 km to their transhumance grazing areas adopting different strategies, some travelling directly to their destination areas while others having multiple resting periods and grazing areas. Despite their limitations, these are among the first detailed data available on transhumance in Cameroon. These reports highlight key livestock health issues and the potential for multiple types of interactions between transhumant herds and other domestic and wild animals, as well as with the formal livestock trading system. Conclusion Overall, these findings provide useful insights into transhumance patterns and into the related animal health implications recorded in Cameroon. This knowledge could better inform evidence-based approaches for designing infectious diseases surveillance and control measures and help driving further studies to improve the understanding of risks associated with livestock movements in the region

Association of Carotid Plaque Lp-PLA2 with Macrophages and Chlamydia pneumoniae Infection among Patients at Risk for Stroke

BACKGROUND: We previously showed that the burden of Chlamydia pneumoniae in carotid plaques was significantly associated with plaque interleukin (IL)-6, and serum IL-6 and C-reactive protein (CRP), suggesting that infected plaques contribute to systemic inflammatory markers in patients with stroke risk. Since lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mediates inflammation in atherosclerosis, we hypothesized that serum Lp-PLA(2) mass and activity levels and plaque Lp-PLA(2) may be influenced by plaque C. pneumoniae infection. METHODOLOGY/PRINCIPAL FINDINGS: Forty-two patients underwent elective carotid endarterectomy. Tissue obtained at surgery was stained by immunohistochemistry for Lp-PLA(2) grade, macrophages, IL-6, C. pneumoniae and CD4+ and CD8+ cells. Serum Lp-PLA(2) activity and mass were measured using the colorimetric activity method (CAM) and ELISA, respectively. Serum homocysteine levels were measured by HPLC. Eleven (26.2%) patients were symptomatic with transient ischemic attacks. There was no correlation between patient risk factors (smoking, coronary artery disease, elevated cholesterol, diabetes, obesity, hypertension and family history of genetic disorders) for atherosclerosis and serum levels or plaque grade for Lp-PLA(2). Plaque Lp-PLA(2) correlated with serum homocysteine levels (p = 0.013), plaque macrophages (p<0.01), and plaque C. pneumoniae (p<0.001), which predominantly infected macrophages, co-localizing with Lp-PLA(2). CONCLUSIONS: The significant association of plaque Lp-PLA(2) with plaque macrophages and C. pneumoniae suggests an interactive role in accelerating inflammation in atherosclerosis. A possible mechanism for C. pneumoniae in the atherogenic process may involve infection of macrophages that induce Lp-PLA(2) production leading to upregulation of inflammatory mediators in plaque tissue. Additional in vitro and in vivo research will be needed to advance our understanding of specific C. pneumoniae and Lp-PLA(2) interactions in atherosclerosis