The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model

<p>Abstract</p> <p>Background</p> <p>Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.</p> <p>Methods</p> <p>To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.</p> <p>Results</p> <p>By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.</p> <p>Conclusions</p> <p>This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.</p

Satellites around Milky Way Analogs: Tension in the Number and Fraction of Quiescent Satellites Seen in Observations versus Simulations

We compare the star-forming properties of satellites around Milky Way (MW) analogs from the Stage II release of the Satellites Around Galactic Analogs Survey (SAGA-ii) to those from the APOSTLE and Auriga cosmological zoom-in simulation suites. We use archival GALEX UV imaging as a star formation indicator for the SAGA-ii sample and derive star formation rates (SFRs) to compare with those from APOSTLE and Auriga. We compare our detection rates from the NUV and FUV bands to the SAGA-ii Hα detections and find that they are broadly consistent with over 85% of observed satellites detected in all three tracers. We apply the same spatial selection criteria used around SAGA-ii hosts to select satellites around the MW-like hosts in APOSTLE and Auriga. We find very good overall agreement in the derived SFRs for the star-forming satellites as well as the number of star-forming satellites per host in observed and simulated samples. However, the number and fraction of quenched satellites in the SAGA-ii sample are significantly lower than those in APOSTLE and Auriga below a stellar mass of M ∗ ∼ 108 M o˙, even when the SAGA-ii incompleteness and interloper corrections are included. This discrepancy is robust with respect to the resolution of the simulations and persists when alternative star formation tracers are employed. We posit that this disagreement is not readily explained by vagaries in the observed or simulated samples considered here, suggesting a genuine discrepancy that may inform the physics of satellite populations around MW analogs

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Cholesterol Homeostasis in Two Commonly Used Human Prostate Cancer Cell-Lines, LNCaP and PC-3

BACKGROUND:Recently, there has been renewed interest in the link between cholesterol and prostate cancer. It has been previously reported that in vitro, prostate cancer cells lack sterol-mediated feedback regulation of the major transcription factor in cholesterol homeostasis, sterol-regulatory element binding protein 2 (SREBP-2). This could explain the accumulation of cholesterol observed in clinical prostate cancers. Consequently, perturbed feedback regulation to increased sterol levels has become a pervasive concept in the prostate cancer setting. Here, we aimed to explore this in greater depth. METHODOLOGY/PRINCIPAL FINDINGS:After altering the cellular cholesterol status in LNCaP and PC-3 prostate cancer cells, we examined SREBP-2 processing, downstream effects on promoter activity and expression of SREBP-2 target genes, and functional activity (low-density lipoprotein uptake, cholesterol synthesis). In doing so, we observed that LNCaP and PC-3 cells were sensitive to increased sterol levels. In contrast, lowering cholesterol levels via statin treatment generated a greater response in LNCaP cells than PC-3 cells. This highlighted an important difference between these cell-lines: basal SREBP-2 activity appeared to be higher in PC-3 cells, reducing sensitivity to decreased cholesterol levels. CONCLUSION/SIGNIFICANCE:Thus, prostate cancer cells are sensitive to changing sterol levels in vitro, but the extent of this regulation differs between prostate cancer cell-lines. These results shed new light on the regulation of cholesterol metabolism in two commonly used prostate cancer cell-lines, and emphasize the importance of establishing whether or not cholesterol homeostasis is perturbed in prostate cancer in vivo

How equitable are GP practice prescribing rates for statins?: an ecological study in four primary care trusts in North West England

BACKGROUND: There is a growing body of literature highlighting inequities in GP practice prescribing rates for a number of drug therapies. The small amount of research on statin prescribing has either focussed on variations rather than equity per se, been based on populations other than GP practices or has used cost-based prescribing rates. AIM: To explore the equity of GP practice prescribing rates for statins, using the theoretical framework of equity of treatment (also known as horizontal equity or comparative need). METHODS: The study involved a cross-sectional secondary analysis in four primary care trusts (PCTs 1–4) in the North West of England, including 132 GP practices. Prescribing rates and health care needs indicators (HCNIs) were developed for all GP practices. RESULTS: Scatter-plots revealed large differences between individual GP practices, both within and between PCTs, in terms of the relationship between statin prescribing and healthcare need. In addition, there were large differences between GP practices in terms of the relationship between actual and expected prescribing rates for statins. Multiple regression analyses explained almost 30% of the variation in prescribing rates in the combined dataset, 25% in PCT1, 31% in PCT3, 51% in PC4 and 58% in PCT2. There were positive associations with variables relating to CHD hospital diagnoses and procedures and negative associations with variables relating to ethnicity, material deprivation, the proportion of patients aged over 75 years and single-handed GP practices. CONCLUSION: Overall, this study found inequitable relationships between actual and expected prescribing rates, and possible inequities in statin prescribing rates on the basis of ethnicity, deprivation, single-handed practices and the proportion of patients aged over 75 years

Long-Term Persistence of Functional Thymic Epithelial Progenitor Cells In Vivo under Conditions of Low FOXN1 Expression

Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro

CMS Data Processing Workflows during an Extended Cosmic Ray Run

Peer reviewe

Aligning the CMS Muon Chambers with the Muon Alignment System during an Extended Cosmic Ray Run

Peer reviewe