Regional-scale climate-variability synchrony of cholera epidemics in West Africa

BACKGROUND: The relationship between cholera and climate was explored in Africa, the continent with the most reported cases, by analyzing monthly 20-year cholera time series for five coastal adjoining West African countries: Côte d'Ivoire, Ghana, Togo, Benin and Nigeria. METHODS: We used wavelet analyses and derived methods because these are useful mathematical tools to provide information on the evolution of the periodic component over time and allow quantification of non-stationary associations between time series. RESULTS: The temporal variability of cholera incidence exhibits an interannual component, and a significant synchrony in cholera epidemics is highlighted at the end of the 1980's. This observed synchrony across countries, even if transient through time, is also coherent with both the local variability of rainfall and the global climate variability quantified by the Indian Oscillation Index. CONCLUSION: Results of this study suggest that large and regional scale climate variability influence both the temporal dynamics and the spatial synchrony of cholera epidemics in human populations in the Gulf of Guinea, as has been described for two other tropical regions of the world, western South America and Bangladesh

Cow's Milk Fat Obesity pRevention Trial (CoMFORT): a primary care embedded randomised controlled trial protocol to determine the effect of cow's milk fat on child adiposity.

INTRODUCTION: Cow's milk is a dietary staple for children in North America. Though clinical guidelines suggest children transition from whole (3.25% fat) milk to reduced (1% or 2%) fat milk at age 2 years, recent epidemiological evidence supports a link between whole milk consumption and lower adiposity in children. The purpose of this trial is to determine which milk fat recommendation minimises excess adiposity and optimises child nutrition and growth. METHODS AND ANALYSIS: Cow's Milk Fat Obesity pRevention Trial will be a pragmatic, superiority, parallel group randomised controlled trial involving children receiving routine healthcare aged 2 to 4-5 years who are participating in the TARGet Kids! practice-based research network in Toronto, Canada. Children (n=534) will be randomised to receive one of two interventions: (1) a recommendation to consume whole milk or (2) a recommendation to consume reduced (1%) fat milk. The primary outcome is adiposity measured by body mass index z-score and waist circumference z-score; secondary outcomes will be cognitive development (using the Ages and Stages Questionnaire), vitamin D stores, cardiometabolic health (glucose, high-sensitivity C-reactive protein, non-high density lipoprotein (non-HDL), low density lipoprotein (LDL), triglyceride, HDL and total cholesterol, insulin and diastolic and systolic blood pressure), sugary beverage and total energy intake (measured by 24 hours dietary recall) and cost effectiveness. Outcomes will be measured 24 months postrandomisation and compared using analysis of covariance (ANCOVA), adjusting for baseline measures. ETHICS AND DISSEMINATION: Ethics approval has been obtained from Unity Health Toronto and The Hospital for Sick Children. Results will be presented locally, nationally and internationally and published in a peer-reviewed journal. The findings may be helpful to nutrition guidelines for children in effort to reduce childhood obesity using a simple, inexpensive and scalable cow's milk fat intervention. TRIAL REGISTRATION NUMBER: NCT03914807; pre-results

The TCF7L2 locus and type 1 diabetes

<p>Abstract</p> <p>Background</p> <p><it>TCF7L2 </it>belongs to a subfamily of TCF7-like HMG box-containing transcription factors, and maps to human chromosome 10q25.3. A recent study identified genetic association of type 2 diabetes (T2D) with this gene, correlated with diminished insulin secretion. This study aimed to investigate the possibility of genetic association between <it>TCF7L2 </it>and type 1 diabetes (T1D).</p> <p>Methods</p> <p>The SNP most significantly associated with T2D, rs7903146, was genotyped in 886 T1D nuclear family trios with ethnic backgrounds of mixed European descent.</p> <p>Results</p> <p>This study found no T1D association with, and no age-of-onset effect from rs7903146.</p> <p>Conclusion</p> <p>This study suggests that a T2D mechanism mediated by <it>TCF7L2 </it>does not participate in the etiology of T1D.</p

Study of Transcriptional Effects in Cis at the IFIH1 Locus

Background: The Thr allele at the non-synonymous single-nucleotide polymorphism (nsSNP) Thr946Ala in the IFIH1 gene confers risk for Type 1 diabetes (T1D). The SNP is embedded in a 236 kb linkage disequilibrium (LD) block that includes four genes: IFIH1, GCA, FAP and KCNH7. The absence of common nsSNPs in the other genes makes the IFIH1 SNP the strongest functional candidate, but it could be merely a marker of association, due to LD with a variant regulating expression levels of IFIH1 or neighboring genes. Methodology/Principal Findings: We investigated the effect of the T1D-associated variation on mRNA transcript expression of these genes. Heterozygous mRNA from lymphoblastoid cell lines (LCLs), pancreas and thymus was examined by allelic expression imbalance, to detect effects in cis on mRNA expression. Using single-nucleotide primer extension, we found no difference between mRNA transcripts in 9 LCLs, 6 pancreas and 13 thymus samples, suggesting that GCA and FAP are not involved. On the other hand, KCNH7 was not expressed at a detectable level in all tissues examined. Moreover, the association of the Thr946Ala SNP with T1D is not due to modulation of IFIH1 expression in organs involved in the disease, pointing to the IFIH1 nsSNP as the causal variant. Conclusions/Significance: The mechanism of the association of the nsSNP with T1D remains to be determined, but does not involve mRNA modulation. It becomes necessary to study differential function of the IFIH1 protein alleles at Thr946Al

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Inactivation and sub-lethal injury of salmonella typhi, salmonella typhimurium and vibrio cholerae in copper water storage vessels

Background: This study provides information on the antibacterial effect of copper against the water-borne pathogens Salmonella Typhi, Salmonella Typhimurium and Vibrio cholerae. Methods: Suspensions of each pathogen were kept in water within a traditional copper vessel at 30°C for 24 h. Samples were withdrawn, diluted and plated onto suitable growth media. Conventional enumeration of healthy (uninjured) bacteria was carried out using standard aerobic incubation conditions. Additionally, reactive oxygen species-neutralised (ROS-n) conditions were achieved by adding the peroxide scavenger sodium pyruvate to the medium with anaerobic incubation, to enumerate uninjured (ROS-insensitive) and injured (ROS-sensitive) bacteria. Differences between log-transformed means of conventional (aerobic) and ROS-n counts were statistically evaluated using t tests. Results: Overall, all three pathogens were inactivated by storage in copper vessels for 24 h. However, for shorter-term incubation (4-12 h), higher counts were observed under ROS-n conditions than under aerobic conditions, which demonstrate the presence of substantial numbers of sub-lethally injured cells prior to their complete inactivation. Conclusions: The present study has for the first time confirmed that these bacterial pathogens are inactivated by storage in a copper vessel within 24 h. However, it has also demonstrated that it is necessary to account for short-term sub-lethal injury, manifest as ROS-sensitivity, in order to more fully understand the process. This has important practical implications in terms of the time required to store water within a copper vessel to completely inactivate these bacteria and thereby remove the risk of water-borne disease transmission by this route

Expanding the Understanding of Biases in Development of Clinical-Grade Molecular Signatures: A Case Study in Acute Respiratory Viral Infections

The promise of modern personalized medicine is to use molecular and clinical information to better diagnose, manage, and treat disease, on an individual patient basis. These functions are predominantly enabled by molecular signatures, which are computational models for predicting phenotypes and other responses of interest from high-throughput assay data. Data-analytics is a central component of molecular signature development and can jeopardize the entire process if conducted incorrectly. While exploratory data analysis may tolerate suboptimal protocols, clinical-grade molecular signatures are subject to vastly stricter requirements. Closing the gap between standards for exploratory versus clinically successful molecular signatures entails a thorough understanding of possible biases in the data analysis phase and developing strategies to avoid them.Using a recently introduced data-analytic protocol as a case study, we provide an in-depth examination of the poorly studied biases of the data-analytic protocols related to signature multiplicity, biomarker redundancy, data preprocessing, and validation of signature reproducibility. The methodology and results presented in this work are aimed at expanding the understanding of these data-analytic biases that affect development of clinically robust molecular signatures.Several recommendations follow from the current study. First, all molecular signatures of a phenotype should be extracted to the extent possible, in order to provide comprehensive and accurate grounds for understanding disease pathogenesis. Second, redundant genes should generally be removed from final signatures to facilitate reproducibility and decrease manufacturing costs. Third, data preprocessing procedures should be designed so as not to bias biomarker selection. Finally, molecular signatures developed and applied on different phenotypes and populations of patients should be treated with great caution

M tuberculosis in the adjuvant modulates time of appearance of CNS-specific effector T cells in the spleen through a polymorphic site of TLR2

DC deliver information regulating trafficking of effector T cells along T-cell priming. However, the role of pathogen-derived motives in the regulation of movement of T cells has not been studied. We hereinafter report that amount of M tuberculosis in the adjuvant modulates relocation of PLP139-151 specific T cells. In the presence of a low dose of M tuberculosis in the adjuvant, T cells (detected by CDR3 BV-BJ spectratyping, the so-called "immunoscope") mostly reach the spleen by day 28 after immunization ("late relocation") in the SJL strain, whereas T cells reach the spleen by d 14 with a high dose of M tuberculosis ("early relocation"). The C57Bl/6 background confers a dominant "early relocation" phenotype to F1 (SJL 7C57Bl/6) mice, allowing early relocation of T cells in the presence of low dose M tuberculosis. A single non-synonymous polymorphism of TLR2 is responsible for "early/late" relocation phenotype. Egress of T lymphocytes is regulated by TLR2 expressed on T cells. Thus, pathogens engaging TLR2 on T cells regulate directly T-cell trafficking, and polymorphisms of TLR2 condition T-cell trafficking upon a limiting concentration of ligand

Activated Platelets in Carotid Artery Thrombosis in Mice Can Be Selectively Targeted with a Radiolabeled Single-Chain Antibody

BACKGROUND: Activated platelets can be found on the surface of inflamed, rupture-prone and ruptured plaques as well as in intravascular thrombosis. They are key players in thrombosis and atherosclerosis. In this study we describe the construction of a radiolabeled single-chain antibody targeting the LIBS-epitope of activated platelets to selectively depict platelet activation and wall-adherent non-occlusive thrombosis in a mouse model with nuclear imaging using in vitro and ex vivo autoradiography as well as small animal SPECT-CT for in vivo analysis. METHODOLOGY/PRINCIPAL FINDINGS: LIBS as well as an unspecific control single-chain antibody were labeled with (111)Indium ((111)In) via bifunctional DTPA ( = (111)In-LIBS/(111)In-control). Autoradiography after incubation with (111)In-LIBS on activated platelets in vitro (mean 3866 ± 28 DLU/mm(2), 4010 ± 630 DLU/mm(2) and 4520 ± 293 DLU/mm(2)) produced a significantly higher ligand uptake compared to (111)In-control (2101 ± 76 DLU/mm(2), 1181 ± 96 DLU/mm(2) and 1866 ± 246 DLU/mm(2)) indicating a specific binding to activated platelets; P<0.05. Applying these findings to an ex vivo mouse model of carotid artery thrombosis revealed a significant increase in ligand uptake after injection of (111)In-LIBS in the presence of small thrombi compared to the non-injured side, as confirmed by histology (49630 ± 10650 DLU/mm(2) vs. 17390 ± 7470 DLU/mm(2); P<0.05). These findings could also be reproduced in vivo. SPECT-CT analysis of the injured carotid artery with (111)In-LIBS resulted in a significant increase of the target-to-background ratio compared to (111)In-control (1.99 ± 0.36 vs. 1.1 ± 0.24; P < 0.01). CONCLUSIONS/SIGNIFICANCE: Nuclear imaging with (111)In-LIBS allows the detection of platelet activation in vitro and ex vivo with high sensitivity. Using SPECT-CT, wall-adherent activated platelets in carotid arteries could be depicted in vivo. These results encourage further studies elucidating the role of activated platelets in plaque pathology and atherosclerosis and might be of interest for further developments towards clinical application

Membrane-mediated interactions

Interactions mediated by the cell membrane between inclusions, such as membrane proteins or antimicrobial peptides, play important roles in their biological activity. They also constitute a fascinating challenge for physicists, since they test the boundaries of our understanding of self-assembled lipid membranes, which are remarkable examples of two-dimensional complex fluids. Inclusions can couple to various degrees of freedom of the membrane, resulting in different types of interactions. In this chapter, we review the membrane-mediated interactions that arise from direct constraints imposed by inclusions on the shape of the membrane. These effects are generic and do not depend on specific chemical interactions. Hence, they can be studied using coarse-grained soft matter descriptions. We deal with long-range membrane-mediated interactions due to the constraints imposed by inclusions on membrane curvature and on its fluctuations. We also discuss the shorter-range interactions that arise from the constraints on membrane thickness imposed by inclusions presenting a hydrophobic mismatch with the membrane.Comment: 38 pages, 10 figures, pre-submission version. In: Bassereau P., Sens P. (eds) Physics of Biological Membranes. Springer, Cha