Probing the growth of supermassive black holes at z>6 with LOFAR

HII regions surrounding supermassive black holes (BHs) in an otherwise still neutral intergalactic medium (IGM) are likely to be the most easily detectable sources by future 21cm experiments like LOFAR. We have made predictions for the size distribution of such HII regions for several physically motivated models for BH growth at high redshift and compared this to the expected LOFAR sensitivity to these sources. The number of potentially detectable HII regions does not only depend on the ionisation state of the intergalactic medium and the decoupling of the spin temperature of the neutral hydrogen from the cosmic microwave background (CMB) temperature, but is also strongly sensitive to the rate of growth of BHs at high redshift. If the supermassive BHs at redshift 6 were built up via continuous Eddington-limited accretion from low mass seed BHs at high redshift, then LOFAR is not expected to detect isolated QSO HII regions at redshifts much larger than 6, and only if the IGM is still significantly neutral. If the high-redshift growth of BHs starts with massive seed BHs and is driven by short-lived accretion events following the merging of BH hosting galaxies then the detection of HII regions surrounding supermassive BHs may extend to redshifts as large as 8-9 but is still very sensitive to the redshift to which the IGM remains significantly neutral. The most optimistic predictions are for a model where the supermassive BHs at z>6 have grown slowly. HII regions around supermassive BHs may then be detected to significantly larger redshifts.Comment: 11 pages, 6 figures, accepted for publication in MNRA

Secretory vesicles are preferentially targeted to areas of low molecular SNARE density

Intercellular communication is commonly mediated by the regulated fusion, or exocytosis, of vesicles with the cell surface. SNARE (soluble N-ethymaleimide sensitive factor attachment protein receptor) proteins are the catalytic core of the secretory machinery, driving vesicle and plasma membrane merger. Plasma membrane SNAREs (tSNAREs) are proposed to reside in dense clusters containing many molecules, thus providing a concentrated reservoir to promote membrane fusion. However, biophysical experiments suggest that a small number of SNAREs are sufficient to drive a single fusion event. Here we show, using molecular imaging, that the majority of tSNARE molecules are spatially separated from secretory vesicles. Furthermore, the motilities of the individual tSNAREs are constrained in membrane micro-domains, maintaining a non-random molecular distribution and limiting the maximum number of molecules encountered by secretory vesicles. Together our results provide a new model for the molecular mechanism of regulated exocytosis and demonstrate the exquisite organization of the plasma membrane at the level of individual molecular machines

Optimising the management of bone disease for coeliac patients in a dietetic-led clinic

Coeliac disease (CD) is a chronic autoimmune inflammatory condition of the small bowel; the only treatment is lifelong adherence to a gluten free diet (GFD). Adherence to a GFD also minimises the risk of associated conditions such as osteoporosis in CD patients. The present study aimed to evaluate and optimise management of bone disease in CD patients in a dietetic-led clinic. This study was conducted in two parts: study 1 utilised retrospective data to evaluate management of bone disease with reference to British Society of Gastroenterology (BSG) guidelines in 229 CD patients. Based on the results from study 1, study 2 developed a tool to estimate dietary calcium intake in CD patients, which was then trialled on 50 patients. There were no significant differences between the population demographics for study 1 and study 2. 65% of patients had a diagnosis of osteopenia or osteoporosis, in a female predominant population (74.6%). Reported mean dietary calcium intake was over estimated at 1239.6mg/day (SD ± 377.1mg) in study 1 and corrected to 852mg/day (SD ± 264.57mg) using improved methodology (study 2) (p≤0.05). Understanding and compliance with dietary advice correlated positively with GFD (p≤0.001) but not osteoporosis or fracture risk. Overall patients attending the clinic did not meet the BSG recommended calcium intake. However, 30% of patients could meet the 2014 BSG target from oral diet alone. Utilising individual dietary prescriptions and targeted use of calcium supplementation maximised the opportunity to reduce risk of bone disease and improved compliance with BSG recommendations.http://pubs.sciepub.com/ijcd/4/2/6

Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4

The fibronectin receptors α5β1 integrin and syndecan-4 cocluster in focal adhesions and coordinate cell migration by making individual contributions to the suppression of RhoA activity during matrix engagement. p190Rho–guanosine triphosphatase–activating protein (GAP) is known to inhibit RhoA during the early stages of cell spreading in an Src-dependent manner. This paper dissects the mechanisms of p190RhoGAP regulation and distinguishes the contributions of α5β1 integrin and syndecan-4. Matrix-induced tyrosine phosphorylation of p190RhoGAP is stimulated solely by engagement of α5β1 integrin and is independent of syndecan-4. Parallel engagement of syndecan-4 causes redistribution of the tyrosine-phosphorylated pool of p190RhoGAP between membrane and cytosolic fractions by a mechanism that requires direct activation of protein kinase C α by syndecan-4. Activation of both pathways is necessary for the efficient regulation of RhoA and, as a consequence, focal adhesion formation. Accordingly, we identify p190RhoGAP as the convergence point for adhesive signals mediated by α5β1 integrin and syndecan-4. This molecular mechanism explains the cooperation between extracellular matrix receptors during cell adhesion

Essential requirement for polypyrimidine tract binding proteins 1 and 3 in the maturation and maintenance of mature B cells in mice

Abstract: The maturation of immature B cells and the survival of mature B cells is stringently controlled to maintain a diverse repertoire of antibody specificities while avoiding self‐reactivity. At the molecular level this is regulated by signaling from membrane Ig and the BAFF‐receptor that sustain a pro‐survival program of gene expression. Whether and how posttranscriptional mechanisms contribute to B cell maturation and survival remains poorly understood. Here, we show that the polypyrimidine tract binding proteins (PTBP) PTBP1 and PTBP3 bind to a large and overlapping set of transcripts in B cells. Both PTBP1 and PTBP3 bind to introns and exons where they are predicted to regulate alternative splicing. Moreover, they also show high‐density of binding to 3’ untranslated regions suggesting they influence the transcriptome in diverse ways. We show that PTBP1 and PTBP3 are required in B cells beyond the immature cell stage to sustain transitional B cells and the B1, marginal zone and follicular B cell lineages. Therefore, PTBP1 and PTBP3 promote the maturation of quiescent B cells by regulating gene expression at the posttranscriptional level

Peripheral inflammation in prodromal Alzheimer's and Lewy body dementias.

OBJECTIVES: There is growing evidence for the role of systemic inflammation in Alzheimer's disease (AD) and other neurodegenerative diseases; however the systemic inflammatory profile in dementia with Lewy bodies (DLB) has never before been investigated. This study aimed to characterise systemic inflammatory mediators in established DLB and AD, as well as in their prodromal, mild cognitive impairment (MCI) phases. METHODS: We obtained plasma samples from patients with DLB (n=37), AD (n=20), MCI with DLB profile (n=38), MCI with AD profile (n=20) and healthy control subjects (n=20). The following inflammatory biomarkers were measured using Roche cobas c702 and Meso Scale Discovery V-Plex Plus: high-sensitivity C-reactive protein, interferon-gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8 and tumour necrosis factor-alpha. RESULTS: We found significantly higher levels of IL-10, IL-1beta, IL-4 and IL-2 in both MCI groups (P<0.001), while there was no significant difference in inflammatory markers between dementia groups and controls. Furthermore, increased disease severity was associated with lower levels of IL-1beta, IL-2 and IL-4 (P<0.05). INTERPRETATION: We have shown for the first time that in both DLB and AD, increased peripheral inflammation occurs early at the MCI disease stages. These data support a role for inflammation early in the disease process, and have important implications for the stage of disease where trials of anti-inflammatory medication should be focused.We would like to acknowledge our funders; the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne NHS Foundation Trust and Newcastle University. Thanks to The Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Eleanor King is also grateful to the Royal College of Psychiatrists Pathfinder Fellowship for the grant that was provided for this project. We would also like to thank Melanie Maitland and friends for their donations to our research in Lewy Body Dementi