Low anti-staphylococcal IgG responses in granulomatosis with polyangiitis patients despite long-term Staphylococcus aureus exposure

Chronic nasal carriage of the bacterium Staphylococcus aureus in patients with the autoimmune disease granulomatosis with polyangiitis (GPA) is a risk factor for disease relapse. To date, it was neither known whether GPA patients show similar humoral immune responses to S. aureus as healthy carriers, nor whether specific S. aureus types are associated with GPA. Therefore, this study was aimed at assessing humoral immune responses of GPA patients against S. aureus antigens in relation to the genetic diversity of their nasal S. aureus isolates. A retrospective cohort study was conducted, including 85 GPA patients and 18 healthy controls (HC). Humoral immune responses against S. aureus were investigated by determining serum IgG levels against 59 S. aureus antigens. Unexpectedly, patient sera contained lower anti-staphylococcal IgG levels than sera from HC, regardless of the patients' treatment, while total IgG levels were similar or higher. Furthermore, 210 S. aureus isolates obtained from GPA patients were characterized by different typing approaches. This showed that the S. aureus population of GPA patients is highly diverse and mirrors the general S. aureus population. Our combined findings imply that GPA patients are less capable of mounting a potentially protective antibody response to S. aureus than healthy individuals

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia

Root anchorage and its significance for submerged plants in shallow lakes.

Submerged plants in shallow lakes are subject to pulling forces arising from waves, currents and grazing birds. Such forces can cause anchorage failure (mainly dislodgement of the root system) or breaking failure of the stems. Both lead to loss of fitness but uprooting is more damaging because many perennial species can replace broken shoot systems. We investigated 12 abundant species (Ceratophyllum demersum, Chara sp., Eleogiton fluitans, Elodea canadensis, Myriophyllum spicatum, Najas marina, Potamogeton natans, P. obtusifolius, P. pectinatus, P. pusillus, Utricularia vulgaris and Zannichellia palustris) in 28 shallow lakes in the UK and the Netherlands. We measured the anchorage and breaking strengths of individual plants of different sizes. Anchorage strength depends on the cohesive strength of the sediment and the size of the root system. The undrained shear-strength of sediments in shallow lakes varied more than 50-fold, but all were substantially weaker than terrestrial soils. Anchorage strength was modelled using the product of sediment cohesive strength and four measures of root-system size. A transformation of plan-form area (raising it to the power 2/3) that represented the hemispherical surface area of the root ball was consistently the best predictor of anchorage strength. Breaking strength was a linear function of stem cross-sectional area in all species. Breaking stresses were comparable with those of marine algae and non-lignified terrestrial plants. The results were used, in combination with plant allometric relationships, to predict the fates of four of the species when challenged with the largest waves likely to be encountered in a 10-year period, and the even greater forces exerted by grazing birds. We show that sediment strength and plant size determine whether plants break or uproot. A careful balance between investment in anchorage and in breakage resistance is needed to survive in the fluctuating physical environment of lakes. Pulling forces experienced by aquatic plants are distinct from the mainly bending forces on more rigid land plants. We provide the first theoretical and quantitative framework for understanding their effects. Anchorage failure associated with the soft sediments of eutrophic lakes is likely to be a factor in the loss of macrophyte communities and an important factor in their restoration