2,6,9-Trisubstituted purine derivatives as protein A mimetics for the treatment of autoimmune diseases

A series of 9-substituted and 2,9-disubstituted 6-(3-aminophenylamino) purines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure–activity relationship (SAR) demonstrates that the 6-(3-aminoanilinyl) purine component was essential for activity. Purine 14 demonstrated significant activity, compared to protein A. These compounds may prove useful for the treatment of autoimmune diseases.     

KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST

The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro-intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour.     

Beryllium Increases the CD14dimCD16+ Subset in the Lung of Chronic Beryllium Disease

CD14^dimCD16+ and CD14^brightCD16+ cells, which compose a minor population of monocytes in human peripheral blood mononuclear cells (PBMC), have been implicated in several inflammatory diseases. The aim of this study was to investigate whether this phenotype was present as a subset of lung infiltrative alveolar macrophages (AMs) in the granulomatous lung disease, chronic beryllium disease (CBD). The monocytes subsets was determined from PBMC cells and bronchoalveolar lavage (BAL) cells from CBD, beryllium sensitized Non-smoker (BeS-NS) and healthy subjects (HS) using flow cytometry. The impact of smoking on the AMs cell phenotype was determined by using BAL cells from BeS smokers (BeS-S). In comparison with the other monocyte subpopulations, CD14^dimCD16+ cells were at decreased frequency in PBMCs of both BeS-NS and CBD and showed higher HLA-DR expression, compared to HS. The AMs from CBD and BeS-NS demonstrated a CD14^dimCD16+phenotype, while CD14^brightCD16+ cells were found at increased frequency in AMs of BeS, compared to HS. Fresh AMs from BeS-NS and CBD demonstrated significantly greater CD16, CD40, CD86 and HLA-DR than HS and BeS-S. The expression of CD16 on AMs from both CBD and BeS-NS was downregulated significantly after 10μM BeSO₄ stimulation. The phagocytic activity of AMs decreased after 10μM BeSO₄ treatment in both BeS-NS and CBD, although was altered or reduced in HS and BeS-S. These results suggest that Be increases the CD14^dimCD16+ subsets in the lung of CBD subjects. We speculate that Be-stimulates the compartmentalization of a more mature CD16+ macrophage phenotype and that in turn these macrophages are a source of Th1 cytokines and chemokines that perpetuate the Be immune response in CBD. The protective effect of cigarette smoking in BeS-S may be due to the low expression of co-stimulatory markers on AMs from smokers as well as the decreased phagocytic function.     

ProteINSIDE to Easily Investigate Proteomics Data from Ruminants: Application to Mine Proteome of Adipose and Muscle Tissues in Bovine Foetuses

Genomics experiments are widely acknowledged to produce a huge amount of data to be analysed. The challenge is to extract meaningful biological context for proteins or genes which is currently difficult because of the lack of an integrative workflow that hinders the efficiency and the robustness of data mining performed by biologists working on ruminants. Thus, we designed ProteINSIDE, a free web service (www.proteinside.org) that (I) provides an overview of the biological information stored in public databases or provided by annotations according to the Gene Ontology, (II) predicts proteins that are secreted to search for proteins that mediate signalisation between cells or tissues, and (III) analyses protein-protein interactions to identify proteins contributing to a process or to visualize functional pathways. Using lists of proteins or genes as a unique input, ProteINSIDE is an original all-in-one tool that merges data from these searches to present a fast overview and integrative analysis of genomic and proteomic data from Bovine, Ovine, Caprine, Human, Rat, and Murine species. ProteINSIDE was bench tested with 1000 proteins identifiers from each species by comparison with DAVID, BioMyn, AgBase, PrediSi, and Phobius. Compared to DAVID or BioMyn, identifications and annotations provided by ProteINSIDE were similar from monogastric proteins but more numerous and relevant for ruminants proteins. ProteINSIDE, thanks to SignalP, listed less proteins potentially secreted with a signal peptide than PrediSi and Phobius, in agreement with the low false positive rate of SignalP. In addition ProteINSIDE is the only resource that predicts proteins secreted by cellular processes that do not involve a signal peptide. Lastly, we reported the usefulness of ProteINSIDE to bring new biological hypotheses of research from proteomics data: the biological meaning of the uptake of adiponectin by the foetal muscle and a role for autophagy during ontogenesis of adipose and muscle tissues.     

Livestock-Associated MRSA in Household Members of Pig Farmers: Transmission and Dynamics of Carriage,A Prospective Cohort Study

This prospective cohort study describes carriage of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in household members from 49 farrowing pig farms in the Netherlands (2010–2011). Of 171 household members, 4% were persistent MRSA nasal carriers, and the MRSA prevalence on any given sampling moment was 10% (range 7-11%). Working in the stables (of which 98% was MRSA-positive, prevalence ratio (PR) = 2.11 per 10 hours), working with sows (PR=1.97), and living with an MRSA-positive pig farmer (PR=4.63) were significant determinants for MRSA carriage. Significant protective factors were carriage of methicillin-susceptible Staphylococcus aureus (MSSA) (PR=0.50), and wearing a facemask when working in the stables (37% decreased prevalence). All MRSA strains during the study period were known livestock-associated types. The bacteriophage φ3 was not found in household members. Transmission from pigs and the environment appeared to be important determinants; human-to-human transmission could not sufficiently be differentiated. Wearing a facemask when working in the stables and carriage of MSSA are potential interventional targets.     

Modelling the Contributions of Malaria,HIV, Malnutrition and Rainfall to the Decline in Paediatric Invasive Non-typhoidal Salmonella Disease in Malawi

Introduction

Nontyphoidal Salmonellae (NTS) are responsible for a huge burden of bloodstream infection in Sub-Saharan African children. Recent reports of a decline in invasive NTS (iNTS) disease from Kenya and The Gambia have emphasised an association with malaria control. Following a similar decline in iNTS disease in Malawi, we have used 9 years of continuous longitudinal data to model the interrelationships between iNTS disease, malaria, HIV and malnutrition.

Methods

Trends in monthly numbers of childhood iNTS disease presenting at Queen’s Hospital, Blantyre, Malawi from 2002 to 2010 were reviewed in the context of longitudinal monthly data describing malaria slide-positivity among paediatric febrile admissions, paediatric HIV prevalence, nutritional rehabilitation unit admissions and monthly rainfall over the same 9 years, using structural equation models (SEM).

Results

Analysis of 3,105 iNTS episodes identified from 49,093 blood cultures, showed an 11.8% annual decline in iNTS (p < 0.001). SEM analysis produced a stable model with good fit, revealing direct and statistically significant seasonal effects of malaria and malnutrition on the prevalence of iNTS disease. When these data were smoothed to eliminate seasonal cyclic changes, these associations remained strong and there were additional significant effects of HIV prevalence.

Conclusions

These data suggest that the overall decline in iNTS disease observed in Malawi is attributable to multiple public health interventions leading to reductions in malaria, HIV and acute malnutrition. Understanding the impacts of public health programmes on iNTS disease is essential to plan and evaluate interventions.     

Repair of DNA Damage Induced by the Cytidine Analog Zebularine Requires ATR and ATM in Arabidopsis

DNA damage repair is an essential cellular mechanism that maintains genome stability. Here, we show that the nonmethylable cytidine analog zebularine induces a DNA damage response in Arabidopsis thaliana, independent of changes in DNA methylation. In contrast to genotoxic agents that induce damage in a cell cycle stage-independent manner, zebularine induces damage specifically during strand synthesis in DNA replication. The signaling of this damage is mediated by additive activity of ATAXIA TELANGIECTASIA MUTATED AND RAD3-RELATED and ATAXIA TELANGIECTASIA MUTATED kinases, which cause postreplicative cell cycle arrest and increased endoreplication. The repair requires a functional STRUCTURAL MAINTENANCE OF CHROMOSOMES5 (SMC5)-SMC6 complex and is accomplished predominantly by synthesis-dependent strand-annealing homologous recombination. Here, we provide insight into the response mechanism for coping with the genotoxic effects of zebularine and identify several components of the zebularine-induced DNA damage repair pathway.     

Climate Change on Twitter: Topics,Communities and Conversations about the 2013 IPCC Working Group 1 Report

In September 2013 the Intergovernmental Panel on Climate Change published its Working Group 1 report, the first comprehensive assessment of physical climate science in six years, constituting a critical event in the societal debate about climate change. This paper analyses the nature of this debate in one public forum: Twitter. Using statistical methods, tweets were analyzed to discover the hashtags used when people tweeted about the IPCC report, and how Twitter users formed communities around their conversational connections. In short, the paper presents the topics and tweeters at this particular moment in the climate debate. The most used hashtags related to themes of science, geographical location and social issues connected to climate change. Particularly noteworthy were tweets connected to Australian politics, US politics, geoengineering and fracking. Three communities of Twitter users were identified. Researcher coding of Twitter users showed how these varied according to geographical location and whether users were supportive, unsupportive or neutral in their tweets about the IPCC. Overall, users were most likely to converse with users holding similar views. However, qualitative analysis suggested the emergence of a community of Twitter users, predominantly based in the UK, where greater interaction between contrasting views took place. This analysis also illustrated the presence of a campaign by the non-governmental organization Avaaz, aimed at increasing media coverage of the IPCC report.