A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. Methods We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Results Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95 % CI = 0.96–0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Conclusions Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome

Deuterium in marine organic biomarkers: toward a new tool for quantifying aquatic mixotrophy

The traditional separation between primary producers (autotrophs) and consumers (heterotrophs) at the base of the marine food web is being increasingly replaced by the paradigm that mixoplankton, planktonic protists with the nutritional ability to use both phago (hetero)trophy and photo(auto)trophy to access energy are widespread globally. Thus, many ‘phytoplankton’ eat, while 50% of ‘protozooplankton’ also perform photosynthesis. Mixotrophy may enhance primary production, biomass transfer to higher trophic levels and the efficiency of the biological pump to sequester atmospheric CO2 into the deep ocean. Although this view is gaining traction, science lacks a tool to quantify the relative contributions of autotrophy and heterotrophy in planktonic protists. This hinders our understanding of their impacts on carbon cycling within marine pelagic ecosystems. It has been shown that the hydrogen (H) isotopic signature of lipids is uniquely sensitive to heterotrophy relative to autotrophy in plants and bacteria. Here, we explored whether it is also sensitive to the trophic status in protists. The new understanding of H isotope signature of lipid biomarkers suggests it offers great potential as a novel tool for quantifying the prevalence of mixotrophy in diverse marine microorganisms and thus for investigating the implications of the ‘mixoplankton’ paradigm

Reconciliation of the carbon budget in the ocean’s twilight zone

Photosynthesis in the surface ocean produces approximately 100 gigatonnes of organic carbon per year, of which 5 to 15 per cent is exported to the deep ocean1, 2. The rate at which the sinking carbon is converted into carbon dioxide by heterotrophic organisms at depth is important in controlling oceanic carbon storage3. It remains uncertain, however, to what extent surface ocean carbon supply meets the demand of water-column biota; the discrepancy between known carbon sources and sinks is as much as two orders of magnitude4, 5, 6, 7, 8. Here we present field measurements, respiration rate estimates and a steady-state model that allow us to balance carbon sources and sinks to within observational uncertainties at the Porcupine Abyssal Plain site in the eastern North Atlantic Ocean. We find that prokaryotes are responsible for 70 to 92 per cent of the estimated remineralization in the twilight zone (depths of 50 to 1,000 metres) despite the fact that much of the organic carbon is exported in the form of large, fast-sinking particles accessible to larger zooplankton. We suggest that this occurs because zooplankton fragment and ingest half of the fast-sinking particles, of which more than 30 per cent may be released as suspended and slowly sinking matter, stimulating the deep-ocean microbial loop. The synergy between microbes and zooplankton in the twilight zone is important to our understanding of the processes controlling the oceanic carbon sink

Planetary population synthesis

In stellar astrophysics, the technique of population synthesis has been successfully used for several decades. For planets, it is in contrast still a young method which only became important in recent years because of the rapid increase of the number of known extrasolar planets, and the associated growth of statistical observational constraints. With planetary population synthesis, the theory of planet formation and evolution can be put to the test against these constraints. In this review of planetary population synthesis, we first briefly list key observational constraints. Then, the work flow in the method and its two main components are presented, namely global end-to-end models that predict planetary system properties directly from protoplanetary disk properties and probability distributions for these initial conditions. An overview of various population synthesis models in the literature is given. The sub-models for the physical processes considered in global models are described: the evolution of the protoplanetary disk, the planets' accretion of solids and gas, orbital migration, and N-body interactions among concurrently growing protoplanets. Next, typical population synthesis results are illustrated in the form of new syntheses obtained with the latest generation of the Bern model. Planetary formation tracks, the distribution of planets in the mass-distance and radius-distance plane, the planetary mass function, and the distributions of planetary radii, semimajor axes, and luminosities are shown, linked to underlying physical processes, and compared with their observational counterparts. We finish by highlighting the most important predictions made by population synthesis models and discuss the lessons learned from these predictions - both those later observationally confirmed and those rejected.Comment: 47 pages, 12 figures. Invited review accepted for publication in the 'Handbook of Exoplanets', planet formation section, section editor: Ralph Pudritz, Springer reference works, Juan Antonio Belmonte and Hans Deeg, Ed

Familial history of diabetes and clinical characteristics in Greek subjects with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>A lot of studies have showed an excess maternal transmission of type 2 diabetes (T2D). The aim, therefore, of the present study was to estimate the prevalence of familial history of T2D in Greek patients, and to evaluate its potential effect on the patient's metabolic control and the presence of diabetic complications.</p> <p>Methods</p> <p>A total of 1,473 T2D patients were recruited. Those with diabetic mothers, diabetic fathers, diabetic relatives other than parents and no known diabetic relatives, were considered separately.</p> <p>Results</p> <p>The prevalence of diabetes in the mother, the father and relatives other than parents, was 27.7, 11.0 and 10.7%, respectively. Patients with paternal diabetes had a higher prevalence of hypertension (64.8 vs. 57.1%, P = 0.05) and lower LDL-cholesterol levels (115.12 ± 39.76 vs. 127.13 ± 46.53 mg/dl, P = 0.006) than patients with diabetes in the mother. Patients with familial diabetes were significantly younger (P < 0.001), with lower age at diabetes diagnosis (P < 0.001) than those without diabetic relatives. Patients with a diabetic parent had higher body mass index (BMI) (31.22 ± 5.87 vs. 30.67 ± 5.35 Kg/m², P = 0.08), higher prevalence of dyslipidemia (49.8 vs. 44.6%, P = 0.06) and retinopathy (17.9 vs. 14.5%, P = 0.08) compared with patients with no diabetic relatives. No difference in the degree of metabolic control and the prevalence of chronic complications were observed.</p> <p>Conclusion</p> <p>The present study showed an excess maternal transmission of T2D in a sample of Greek diabetic patients. However, no different influence was found between maternal and paternal diabetes on the clinical characteristics of diabetic patients except for LDL-cholesterol levels and presence of hypertension. The presence of a family history of diabetes resulted to an early onset of the disease to the offspring.</p

The epidemiology of postpartum malaria: a systematic review

Pregnant women are more susceptible to malaria than their non-pregnant counterparts. Less is known about the risk of malaria in the postpartum period. The epidemiology of postpartum malaria was systematically reviewed. Eleven articles fitted the inclusion criteria. Of the 10 studies that compared malaria data from the postpartum period with pregnancy data, nine studies suggested that the risk for malaria infection decreased after delivery. All three studies that compared postpartum data with non-pregnant non-postpartum women concluded that the risk did not return to pre-pregnancy levels immediately after delivery. The results of this review have to be carefully interpreted, as the majority of studies were not designed to study postpartum malaria, and there was large variability in study designs and reported outcomes. Current evidence suggests an effort should be made to detect and radically cure malaria during pregnancy so that women do not enter the postpartum period with residual parasites

The crystal structure of the Sgt1-Skp1 complex: the link between Hsp90 and both SCF E3 ubiquitin ligases and kinetochores

The essential cochaperone Sgt1 recruits Hsp90 chaperone activity to a range of cellular factors including SCF E3 ubiquitin ligases and the kinetochore in eukaryotes. In these pathways Sgt1 interacts with Skp1, a small protein that heterodimerizes with proteins containing the F-box motif. We have determined the crystal structure of the interacting domains of Saccharomyces cerevisiae Sgt1 and Skp1 at 2.8 Å resolution and validated the interface in the context of the full-length proteins in solution. The BTB/POZ domain of Skp1 associates with Sgt1 via the concave surface of its TPR domain using residues that are conserved in humans. Dimerization of yeast Sgt1 occurs via an insertion that is absent from monomeric human Sgt1. We identify point mutations that disrupt dimerization and Skp1 binding in vitro and find that the interaction with Skp1 is an essential function of Sgt1 in yeast. Our data provide a structural rationale for understanding the phenotypes of temperature-sensitive Sgt1 mutants and for linking Skp1-associated proteins to Hsp90-dependent pathways

Targeting of Pseudorabies Virus Structural Proteins to Axons Requires Association of the Viral Us9 Protein with Lipid Rafts

The pseudorabies virus (PRV) Us9 protein plays a central role in targeting viral capsids and glycoproteins to axons of dissociated sympathetic neurons. As a result, Us9 null mutants are defective in anterograde transmission of infection in vivo. However, it is unclear how Us9 promotes axonal sorting of so many viral proteins. It is known that the glycoproteins gB, gC, gD and gE are associated with lipid raft microdomains on the surface of infected swine kidney cells and monocytes, and are directed into the axon in a Us9-dependent manner. In this report, we determined that Us9 is associated with lipid rafts, and that this association is critical to Us9-mediated sorting of viral structural proteins. We used infected non-polarized and polarized PC12 cells, a rat pheochromocytoma cell line that acquires many of the characteristics of sympathetic neurons in the presence of nerve growth factor (NGF). In these cells, Us9 is highly enriched in detergent-resistant membranes (DRMs). Moreover, reducing the affinity of Us9 for lipid rafts inhibited anterograde transmission of infection from sympathetic neurons to epithelial cells in vitro. We conclude that association of Us9 with lipid rafts is key for efficient targeting of structural proteins to axons and, as a consequence, for directional spread of PRV from pre-synaptic to post-synaptic neurons and cells of the mammalian nervous system

The effectiveness of ω-3 polyunsaturated fatty acid interventions during pregnancy on obesity measures in the offspring: an up-to-date systematic review and meta-analysis.

BACKGROUND: The potential role of ω-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on subsequent risk of obesity outcomes in the offspring is not clear and there is a need to synthesise this evidence. OBJECTIVE: A systematic review and meta-analysis of randomised controlled trials (RCTs), including the most recent studies, was conducted to assess the effectiveness of ω-3 LCPUFA interventions during pregnancy on obesity measures, e.g. BMI, body weight, fat mass in offspring. METHODS: Included RCTs had a minimum of 1-month follow-up post-partum. The search included CENTRAL, MEDLINE, SCOPUS, WHO's International Clinical Trials Reg., E-theses and Web of Science databases. Study quality was evaluated using the Cochrane Collaboration's risk of bias tool. RESULTS: Eleven RCTs, from ten unique trials, (3644 children) examined the effectiveness of ω-3 LCPUFA maternal supplementation during pregnancy on the development of obesity outcomes in offspring. There were heterogeneities between the trials in terms of their sample, type and duration of intervention and follow-up. Pooled estimates did not show an association between prenatal intake of fatty acids and obesity measures in offspring. CONCLUSION: These results indicate that maternal supplementation with ω-3 LCPUFA during pregnancy does not have a beneficial effect on obesity risk. Due to the high heterogeneity between studies along with small sample sizes and high rates of attrition, the effects of ω-3 LCPUFA supplementation during pregnancy for prevention of childhood obesity in the long-term remains unclear. Large high-quality RCTs are needed that are designed specifically to examine the effect of prenatal intake of fatty acids for prevention of childhood obesity. There is also a need to determine specific sub-groups in the population that might get a greater benefit and whether different ω-3 LCPUFA, i.e. eicosapentaenoic (EPA) vs. docosahexanoic (DHA) acids might potentially have different effects