Smad4 is critical for self-renewal of hematopoietic stem cells

Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4−/− primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal

Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non-random Process.

Genomic data generated from clinical Vibrio cholerae O1 isolates collected over a five year period in an area of Kolkata, India with seasonal cholera outbreaks allowed a detailed genetic analysis of serotype switching that occurred from Ogawa to Inaba and back to Ogawa. The change from Ogawa to Inaba resulted from mutational disruption of the methyltransferase encoded by the wbeT gene. Re-emergence of the Ogawa serotype was found to result either from expansion of an already existing Ogawa clade or reversion of the mutation in an Inaba clade. Our data suggests that such transitions are not random events but rather driven by as yet unidentified selection mechanisms based on differences in the structure of the O1 antigen or in the serotype-determining wbeT gene

Towards improved cover glasses for photovoltaic devices

For the solar energy industry to increase its competitiveness there is a global drive to lower the cost of solar generated electricity. Photovoltaic (PV) module assembly is material-demanding and the cover glass constitutes a significant proportion of the cost. Currently, 3 mm thick glass is the predominant cover material for PV modules, accounting for 10-25% of the total cost. Here we review the state-of-the-art of cover glasses for PV modules and present our recent results for improvement of the glass. These improvements were demonstrated in terms of mechanical, chemical and optical properties by optimizing the glass composition, including addition of novel dopants, to produce cover glasses that can provide: (i) enhanced UV protection of polymeric PV module components, potentially increasing module service lifetimes; (ii) re-emission of a proportion of the absorbed UV photon energy as visible photons capable of being absorbed by the solar cells, thereby increasing PV module efficiencies; (iii) Successful laboratory-scale demonstration of proof-of-concept, with increases of 1-6% in Isc and 1-8% Ipm. Improvements in both chemical and crack resistance of the cover glass were also achieved through modest chemical reformulation, highlighting what may be achievable within existing manufacturing technology constraints

Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome

<p>Abstract</p> <p>Background</p> <p>This study aimed to profile levels of blood cells and serum cytokines during afebrile and febrile phases of periodic fever, aphthous <b>s</b>tomatitis, pharyngitis and adenitis (PFAPA) syndrome to advance pathophysiological understanding of this pediatric disease.</p> <p>Methods</p> <p>A cohort of patients with a median age of 4.9 years experiencing 'typical PFAPA' episodes participated in this study. Blood cells and serum cytokines were analyzed by CBC analysis and multiplex ELISA.</p> <p>Results</p> <p>Oscillations in the concentration of blood cells during the afebrile and febrile phases of typical PFAPA syndrome were observed; novel findings include increased monocytes and decreased eosinophils during a febrile episode and increased thrombocytes in the afebrile interval. Relatively modest levels of pro-inflammatory cytokines were present in sera. IFNγ-induced cytokine IP10/CXCL10 was increased after the onset of fever while T cell-associated cytokines IL7 and IL17 were suppressed during afebrile and febrile periods.</p> <p>Conclusions</p> <p>Identification of dysregulated blood cells and serum cytokines is an initial step towards the identification of biomarkers of PFAPA disease and/or players in disease pathogenesis. Future investigations are required to conclusively discern which mediators are associated specifically with PFAPA syndrome.</p

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing

EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients (EVA-TRISP) registry: basis and methodology of a pan-European prospective ischaemic stroke revascularisation treatment registry.

PURPOSE The Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration was a concerted effort initiated in 2010 with the purpose to address relevant research questions about the effectiveness and safety of intravenous thrombolysis (IVT). The collaboration also aims to prospectively collect data on patients undergoing endovascular treatment (EVT) and hence the name of the collaboration was changed from TRISP to EVA-TRISP. The methodology of the former TRISP registry for patients treated with IVT has already been published. This paper focuses on describing the EVT part of the registry. PARTICIPANTS All centres committed to collecting predefined variables on consecutive patients prospectively. We aim for accuracy and completeness of the data and to adapt local databases to investigate novel research questions. Herein, we introduce the methodology of a recently constructed academic investigator-initiated open collaboration EVT registry built as an extension of an existing IVT registry in patients with acute ischaemic stroke (AIS). FINDINGS TO DATE Currently, the EVA-TRISP network includes 20 stroke centres with considerable expertise in EVT and maintenance of high-quality hospital-based registries. Following several successful randomised controlled trials (RCTs), many important clinical questions remain unanswered in the (EVT) field and some of them will unlikely be investigated in future RCTs. Prospective registries with high-quality data on EVT-treated patients may help answering some of these unanswered issues, especially on safety and efficacy of EVT in specific patient subgroups. FUTURE PLANS This collaborative effort aims at addressing clinically important questions on safety and efficacy of EVT in conditions not covered by RCTs. The TRISP registry generated substantial novel data supporting stroke physicians in their daily decision making considering IVT candidate patients. While providing observational data on EVT in daily clinical practice, our future findings may likewise be hypothesis generating for future research as well as for quality improvement (on EVT). The collaboration welcomes participation of further centres willing to fulfill the commitment and the outlined requirements