Mixed liposomes containing gram-positive bacteria lipids:Lipoteichoic acid (LTA) induced structural changes

Lipoteichoic acid (LTA), a surface associated polymer amphiphile tethered directly to the Gram-positive bacterial cytoplasmic membrane, is a key structural and functional membrane component. Its composition in the membrane is regulated by bacteria under different physiological conditions. How such LTA compositional variations modulate the membrane structural stability and integrity is poorly understood. Here, we have investigated structural changes in mixed liposomes mimicking the lipid composition of Gram-positive bacteria membranes, in which the concentration of Bacillus Subtilis LTA was varied between 0–15 mol%. Small-angle neutron scattering (SANS) and dynamic light scattering (DLS) measurements indicated formation of mixed unilamellar vesicles, presumably stabilized by the negatively charged LTA polyphosphates. The vesicle size increased with the LTA molar concentration up to ∼6.5 mol%, accompanied by a broadened size distribution, and further increasing the LTA concentration led to a decrease in the vesicle size. At 80 °C, SANS analyses showed the formation of larger vesicles with thinner shells. Complementary Cryo-TEM imaging confirmed the vesicle formation and the size increase with LTA addition, as well as the presence of interconnected spherical aggregates of smaller size at higher LTA concentrations. The results are discussed in light of the steric and electrostatic interactions of the bulky LTA molecules with increased chain fluidity at the higher temperature, which affect the molecular packing and interactions, and thus depend on the LTA composition, in the membrane

Associations between gestational anthropometry, maternal HIV, and fetal and early infancy growth in a prospective rural/semi-rural Tanzanian cohort, 2012-13.

BACKGROUND: Healthcare access and resources differ considerably between urban and rural settings making cross-setting generalizations difficult. In resource-restricted rural/semi-rural environments, identification of feasible screening tools is a priority. The objective of this study was to evaluate gestational anthropometry in relation to birth and infant growth in a rural/semi-rural Tanzanian prospective cohort of mothers and their infants. METHODS: Mothers (n = 114: 44 HIV-positive) attending antenatal clinic visits were recruited in their second or third trimester between March and November, 2012, and followed with their infants through 6-months post-partum. Demographic, clinical, and infant feeding data were obtained using questionnaires administered by a Swahili-speaking research nurse on demographic, socioeconomic, clinical, and infant feeding practices. Second or third trimester anthropometry (mid-upper arm circumference [MUAC], triceps skinfold thickness, weight, height), pregnancy outcomes, birth (weight, length, head circumference) and infant anthropometry (weight-for-age z-score [WAZ], length-for-age z-score [LAZ]) were obtained. Linear regression and mixed effect modeling were used to evaluate gestational factors in relation to pregnancy and infant outcomes. RESULTS AND DISCUSSION: Gestational MUAC and maternal HIV status (HIV-positive mothers = 39%) were associated with infant WAZ and LAZ from birth to 6-months in multivariate models, even after adjustment for infant feeding practices. The lowest gestational MUAC tertile was associated with lower WAZ throughout early infancy, as well as lower LAZ at 3 and 6-months. In linear mixed effects models through 6-months, each 1 cm increase in gestational MUAC was associated with a 0.11 increase in both WAZ (P < 0.001) and LAZ (P = 0.001). Infant HIV-exposure was negatively associated with WAZ (β = -0.65, P < 0.001) and LAZ (β = -0.49, P < 0.012) from birth to 6-months. CONCLUSIONS: Lower gestational MUAC, evaluated using only a tape measure and minimal training that is feasible in non-urban clinic and community settings, was associated with lower infant anthropometric measurements. In this rural and semi-rural setting, HIV-exposure was associated with poorer anthropometry through 6-months despite maternal antiretroviral access. Routine assessment of MUAC has the potential to identify at-risk women in need of additional health interventions designed to optimize pregnancy outcomes and infant growth. Further research is needed to establish gestational MUAC reference ranges and to define interventions that successfully improve MUAC during pregnancy

All-cause admissions following a first-ever exacerbation-related hospitalization in COPD

Background Hospital admissions are important contributors to the overall burden of chronic obstructive pulmonary disease (COPD). Understanding the patterns and causes of hospital admissions will help to identify targets for preventive interventions. This study aimed to determine the 5-year all-cause hospital admission trajectories of patients with COPD following their first ever exacerbation-related hospitalisation. Methods Patients with COPD were identified from the Danish national registries. Patients experiencing their first ever exacerbation-related hospitalisation, defined as the index event, between 2000 and 2014 were included. All-cause hospital admissions were examined during a subsequent 5-year follow-up period, and categorised using the International Classification of Diseases, 10th revision. Results In total, 82 964 patients with COPD were included. The mean±sd age was 72±10 years and 48% were male. Comorbidities were present in 58%, and 65% of the patients collected inhalation medication ≤6 months prior to the index event. In total, 337 066 all-cause hospital admissions were identified, resulting in a 5-year admission rate of 82%. Most admissions were due to nonrespiratory causes (59%), amongst which cardiac events were most common (19%). Conclusion Hospital admissions following a first exacerbation-related hospitalisation are common; nonrespiratory events constitute the majority of admissions. Besides the respiratory causes, treatment targeting the nonrespiratory causes of hospital admission should be considered to effectively decrease the burden of hospitalisation in COPD

Priority interventions to improve maternal and child diets in Sub-Saharan Africa and South Asia.

Nutrition-sensitive interventions to improve overall diet quality are increasingly needed to improve maternal and child health. This study demonstrates feasibility of a structured process to leverage local expertise in formulating programmes tailored for current circumstances in South Asia and Africa. We assembled 41 stakeholders in 2 regional workshops and followed a prespecified protocol to elicit programme designs listing the human and other resources required, the intervention's mechanism for impact on diets, target foods and nutrients, target populations, and contact information for partners needed to implement the desired programme. Via this protocol, participants described 48 distinct interventions, which we then compared against international recommendations and global goals. Local stakeholders' priorities focused on postharvest food systems to improve access to nutrient-dense products (75% of the 48 programmes) and on production of animal sourced foods (58%), as well as education and social marketing (23%) and direct transfers to meet food needs (12.5%). Each programme included an average of 3.2 distinct elements aligned with those recommended by United Nations system agencies in the Framework for Action produced by the Second International Conference on Nutrition in 2014 and the Compendium of Actions for Nutrition developed for the Renewed Efforts Against Child Hunger initiative in 2016. Our results demonstrate that a participatory process can help local experts identify their own priorities for future investments, as a first step in a novel process of rigorous, transparent, and independent priority setting to improve diets among those at greatest risk of undernutrition

DNA evidence of bowhead whale exploitation by Greenlandic Paleo-Inuit 4,000 years ago

The demographic history of Greenland is characterized by recurrent migrations and extinctions since the first humans arrived 4,500 years ago. Our current understanding of these extinct cultures relies primarily on preserved fossils found in their archaeological deposits, which hold valuable information on past subsistence practices. However, some exploited taxa, though economically important, comprise only a small fraction of these sub-fossil assemblages. Here we reconstruct a comprehensive record of past subsistence economies in Greenland by sequencing ancient DNA from four well-described midden deposits. Our results confirm that the species found in the fossil record, like harp seal and ringed seal, were a vital part of Inuit subsistence, but also add a new dimension with evidence that caribou, walrus and whale species played a more prominent role for the survival of Paleo-Inuit cultures than previously reported. Most notably, we report evidence of bowhead whale exploitation by the Saqqaq culture 4,000 years ago.Full Tex

DNA evidence of bowhead whale exploitation by Greenlandic Paleo-Inuit 4,000 years ago.

The demographic history of Greenland is characterized by recurrent migrations and extinctions since the first humans arrived 4,500 years ago. Our current understanding of these extinct cultures relies primarily on preserved fossils found in their archaeological deposits, which hold valuable information on past subsistence practices. However, some exploited taxa, though economically important, comprise only a small fraction of these sub-fossil assemblages. Here we reconstruct a comprehensive record of past subsistence economies in Greenland by sequencing ancient DNA from four well-described midden deposits. Our results confirm that the species found in the fossil record, like harp seal and ringed seal, were a vital part of Inuit subsistence, but also add a new dimension with evidence that caribou, walrus and whale species played a more prominent role for the survival of Paleo-Inuit cultures than previously reported. Most notably, we report evidence of bowhead whale exploitation by the Saqqaq culture 4,000 years ago

Ancient diversity in host-parasite interaction genes in a model parasitic nematode

Abstract Host-parasite interactions exert strong selection pressures on the genomes of both host and parasite. These interactions can lead to negative frequency-dependent selection, a form of balancing selection that is hypothesised to explain the high levels of polymorphism seen in many host immune and parasite antigen loci. Here, we sequence the genomes of several individuals of Heligmosomoides bakeri, a model parasite of house mice, and Heligmosomoides polygyrus, a closely related parasite of wood mice. Although H. bakeri is commonly referred to as H. polygyrus in the literature, their genomes show levels of divergence that are consistent with at least a million years of independent evolution. The genomes of both species contain hyper-divergent haplotypes that are enriched for proteins that interact with the host immune response. Many of these haplotypes originated prior to the divergence between H. bakeri and H. polygyrus, suggesting that they have been maintained by long-term balancing selection. Together, our results suggest that the selection pressures exerted by the host immune response have played a key role in shaping patterns of genetic diversity in the genomes of parasitic nematodes

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny