miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development

MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes

1,5-Anhydroglucitol as a marker of maternal glycaemic control and predictor of neonatal birthweight in pregnancies complicated by type 1 diabetes mellitus

AIMS/HYPOTHESIS: Most pregnant women with type 1 diabetes mellitus achieve HbA(1c) targets; however, macrosomia remains prevalent and better pregnancy glycaemic markers are therefore needed. 1,5-Anhydroglucitol (1,5-AG) is a short-term marker of glycaemia, reflecting a period of 1 to 2 weeks. Its excretion rate depends on the renal glucose threshold and thus it is unclear whether it may be used in pregnant type 1 diabetes women. We evaluated 1,5-AG as a glycaemic marker and birthweight predictor in pregnant women with type 1 diabetes, and compared its performance with HbA(1c). METHODS: 1,5-AG and HbA(1c) were measured in 82 pregnant women with type 1 diabetes. In addition, 58 continuous glucose monitoring system (CGMS) records were available. Macrosomia was defined as birthweight >90th centile. The data were analysed with Pearson’s correlations, and linear and logistic regression models. Receiver operating characteristic (ROC) analysis was used to evaluate third trimester 1,5-AG as a predictor of macrosomia. RESULTS: Unlike HbA(1c), 1,5-AG strongly correlated with CGMS indices: the AUC above 7.8 mmol/l (r = −0.66; p < 0.001), average maximum glucose (r = −0.58; p < 0.001) and mean glucose (r = −0.54; p < 0.001). In the third trimester, 1,5-AG was the strongest predictor of macrosomia, with ROC AUC 0.81 (95% CI 0.70, 0.89). In contrast, HbA(1c) in the third trimester had a ROC AUC of 0.69 (95% CI 0.58, 0.81). The best discrimination was achieved when both markers were used jointly, yielding a ROC AUC of 0.84 (95% CI 0.76, 0.93). CONCLUSIONS/INTERPRETATION: In pregnant women with type 1 diabetes, 1,5-AG is a better glycaemic marker than HbA(1c), as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA(1c), is a strong predictor of macrosomia

A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

The authors gratefully thank Marion Müller, Christiane Palissa, Yvonne Weber, Bettina Sonnenburg, and Beate Anders for the excellent technical assistance and Franziska Rohr for her help within the animal facility. We also thank Prof. Judith E. Allen for her expertise, critical advice, and intellectual discussion of the topic.Peer reviewe

Texture analysis of the liver at MDCT for assessing hepatic fibrosis

PURPOSE: To evaluate CT texture analysis (CTTA) for staging of hepatic fibrosis (stages F0-F4) METHODS: Quantitative texture analysis (QTA) of the liver was performed on abdominal MDCT scans using commercially available software (TexRAD), which uses a filtration-histogram statistic-based technique. Single-slice ROI measurements of the total liver, Couinaud segments IV-VIII, and segments I-III were obtained. CTTA parameters were correlated against fibrosis stage (F0-F4), with biopsy performed within one year for all cases with intermediate fibrosis (F1-F3). RESULTS: The study cohort consisted of 289 adults (158M/131W; mean age, 51 years), including healthy controls (F0, n = 77), and patients with increasing stages of fibrosis (F1, n = 42; F2 n = 37; F3 n = 53; F4 n = 80). Mean gray-level intensity increased with fibrosis stage, demonstrating an ROC AUC of 0.78 at medium filtration for F0 vs F1-4, with sensitivity and specificity of 74% and 74% at cutoff 0.18. For significant fibrosis (≥F2), mean showed AUCs ranging from 0.71-0.73 across medium- and coarse- filtered textures with sensitivity and specificity of 71% and 68% at cutoff of 0.3, with similar performance also observed for advanced fibrosis (≥F3). Entropy showed a similar trend. Conversely, kurtosis and skewness decreased with increasing fibrosis, particularly in cirrhotic patients. For cirrhosis (≥F4), kurtosis and skewness showed AUCs of 0.86 and 0.87, respectively, at coarse-filtered scale, with skewness showing a sensitivity and specificity of 84% and 75% at cutoff of 1.3. CONCLUSION: CTTA may be helpful in detecting the presence of hepatic fibrosis and discriminating between stages of fibrosis, particularly at advanced levels

Concurrent chemoradiotherapy in limited-stage small-cell lung cancer. Results of a pilot study

Between January 1994 and February 1998, 32, limited-stage small-cell lung cancer patients were treated with concurrent chemoradiotherapy. Follow-up time ranged from 4 to 34 months, (median 14 months). Complete regression was obtained in 22 of the 30 patients, who received at least four courses of EP chemotherapy and a tumour dose of 50 Gy or more. In all, 2-year actuarial disease-free survival was 21 %. Brain metastases occurred in 8 (36.4 %) patients with CR, in 5/7 (71.4 %) patients without prophylactic cranial irradiation (PCI) and in 3/15 (20 %) patients after PCI. The survival rate was lower in patients with PCI, in Whom chest irradiation was started later than one month from the beginning of course 1 of EP chemotherapy. We have suggested a modification of the treatment protocol

The linearization of the Kodama state

We study the question of whether the linearization of the Kodama state around classical deSitter spacetime is normalizable in the inner product of the theory of linearized gravitons on deSitter spacetime. We find the answer is no in the Lorentzian theory. However, in the Euclidean theory the corresponding linearized Kodama state is delta-functional normalizable. We discuss whether this result invalidates the conjecture that the full Kodama state is a good physical state for quantum gravity with positive cosmological constant.Comment: 14 pages, statement on the corresponding Yang-Mills case correcte

Between male variation in semen characteristics and preliminary results on the dilution of semen in the ostrich

Abstract This study is part of an ongoing project on artificial insemination in ostriches. The physical output of neat semen from four ostrich males was investigated and the effect of reconstituting semen with: 1) seminal plasma of the same male (SPS); 2) seminal plasma of another male (SPD), and 3) Dulbecco&apos;s Modified Eagles Medium (DMEM). Semen was collected daily from one or two pairs of males using the dummy female method, each pair being replicated twice. Spermatozoa viability in neat semen, SPS, SPD and DMEM was assessed using nigrosin-eosin staining and the proportions of live normal, live abnormal and dead sperm were determined. Semen volume (mean ± SE) was 1.27 ± 0.13 mL, the concentration of spermatozoa 3.68 ± 0.17 x 10 9 /mL and the number of spermatozoa 4.92 ± 0.64 x 10 9 /ejaculate. Furthermore, the live normal, live abnormal and dead spermatozoa in the neat semen were 61.2 ± 4.5%, 21.2 ± 2.7% and 17.7 ± 4.3% respectively. The ejaculate volume and the number of dead spermatozoa were not affected by collection time. However, the number of live abnormal spermatozoa increased through the day causing a reduction in live normal spermatozoa. Furthermore, re-suspending spermatozoa in DMEM reduced the number of live normal (31.4 ± 4.6%) and live abnormal spermatozoa (11.0 ± 2.7%) and increased the number of dead spermatozoa (57.6 ± 4.4%). In contrast, numbers of live spermatozoa were higher when suspended in seminal plasma and similar in SPS (53.9 ± 4.6%) and SPD (50.7 ± 4.6%). These are the first crucial steps to determining the optimum semen collection time and to improving the viability of diluted spermatozoa

Chaos in an Exact Relativistic 3-body Self-Gravitating System

We consider the problem of three body motion for a relativistic one-dimensional self-gravitating system. After describing the canonical decomposition of the action, we find an exact expression for the 3-body Hamiltonian, implicitly determined in terms of the four coordinate and momentum degrees of freedom in the system. Non-relativistically these degrees of freedom can be rewritten in terms of a single particle moving in a two-dimensional hexagonal well. We find the exact relativistic generalization of this potential, along with its post-Newtonian approximation. We then specialize to the equal mass case and numerically solve the equations of motion that follow from the Hamiltonian. Working in hexagonal-well coordinates, we obtaining orbits in both the hexagonal and 3-body representations of the system, and plot the Poincare sections as a function of the relativistic energy parameter $\eta$. We find two broad categories of periodic and quasi-periodic motions that we refer to as the annulus and pretzel patterns, as well as a set of chaotic motions that appear in the region of phase-space between these two types. Despite the high degree of non-linearity in the relativistic system, we find that the the global structure of its phase space remains qualitatively the same as its non-relativisitic counterpart for all values of $\eta$ that we could study. However the relativistic system has a weaker symmetry and so its Poincare section develops an asymmetric distortion that increases with increasing $\eta$. For the post-Newtonian system we find that it experiences a KAM breakdown for $\eta \simeq 0.26$: above which the near integrable regions degenerate into chaos.Comment: latex, 65 pages, 36 figures, high-resolution figures available upon reques

Examining the Connections within the Startup Ecosystem: A Case Study of St. Louis

This paper documents the resurgence of entrepreneurial activity in St. Louis by reporting on the collaboration and local learning within the startup community. This activity is happening both between entrepreneurs and between organizations that provide support, such as mentoring and funding, to entrepreneurs. As these connections deepen, the strength of the entrepreneurial ecosystem grows. Another finding from the research is that activity-based events, where entrepreneurs have the chance to use and practice the skills needed to grow their businesses, are most useful. St. Louis provides a multitude of these activities, such as Startup Weekend, 1 Million Cups, Code Until Dawn, StartLouis, and GlobalHack. Some of these are St. Louis specific, but others have nationwide or global operations, providing important implications for other cities