Acoustic Emissions in Rock Deformation and Failure: New Insights from Q-Statistical Analysis.

We propose a new statistical analysis of the Acoustic Emissions (AE) produced in a series of triaxial deformation experiments leading to fractures and failure of two different rocks, namely, Darley Dale Sandstone (DDS) and AG Granite (AG). By means of q-statistical formalism, we are able to characterize the pre-failure processes in both types of rocks. In particular, we study AE inter-event time and AE inter-event distance distributions. Both of them can be reproduced with q-exponential curves, showing universal features that are observed here for the first time and could be important in order to understand more in detail the dynamics of rock fractures.

The Phosphatase PHLPP2 Plays a Key Role in the Regulation of Pancreatic Beta-Cell Survival.

Currently available antidiabetic treatments fail to halt, and may even exacerbate, pancreatic ß-cell exhaustion, a key feature of type 2 diabetes pathogenesis; thus, strategies to prevent, or reverse, ß-cell failure should be actively sought. The serine threonine kinase Akt has a key role in the regulation of ß-cell homeostasis; among Akt modulators, a central role is played by pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) family. Here, taking advantage of an in vitro model of chronic exposure to high glucose, we demonstrated that PHLPPs, particularly the second family member called PHLPP2, are implicated in the ability of pancreatic ß cells to deal with glucose toxicity. We observed that INS-1 rat pancreatic ß cell line maintained for 12-15 passages at high (30 mM) glucose concentrations (INS-1 HG) showed increased expression of PHLPP2 and PHLPP1 both at mRNA and protein level as compared to INS-1 maintained for the same number of passages in the presence of normal glucose levels (INS-1 NG). These changes were paralleled by decreased phosphorylation of Akt and by increased expression of apoptotic and autophagic markers. To investigate if PHLPPs had a casual role in the alteration of INS-1 homeostasis observed upon chronic exposure to high glucose concentrations, we took advantage of shRNA technology to specifically knock-down PHLPPs. We obtained proof-of-concept evidence that modulating PHLPPs expression may help to restore a healthy ß cell mass, as the reduced expression of PHLPP2/1 was accompanied by a recovered balance between pro- and antiapoptotic factor levels. In conclusion, our data provide initial support for future studies aimed to identify pharmacological PHLPPs modulator to treat beta-cell survival impairment. They also contribute to shed some light on ß-cell dysfunction, a complex and unsatisfactorily characterized phenomenon that has a central causative role in the pathogenesis of type 2 diabetes.

A polymorphism at IGF1 locus is associated with carotid intima media thickness and endothelium-dependent vasodilatation.

OBJECTIVE: Whether IGF-1 has a protective or a detrimental role in vascular homeostasis remains unsettled. There is evidence that the C/T polymorphism rs35767 near the promoter region of the IGF1 gene located in chromosome 12 is associated with plasma IGF-1 levels. We investigated the effects of this polymorphism on circulating IGF-1 levels, carotid intima media thickness (cIMT) and endothelial-dependent vasodilation. METHODS: Two samples of adult nondiabetic Whites were studied. Sample 1 comprised 1124 individuals in whom cIMT was measured by ultrasonography. Sample 2 included 162 drug-naïve hypertensive individuals in whom endothelium-dependent and endothelium-independent vasodilation were assessed by intra-arterial infusion of acetylcholine (ACh), and sodium nitroprusside (SNP), respectively. IGF-1 was determined by chemiluminescent immunoassay. rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. RESULTS: In sample 1, IGF-1 levels were higher in subjects carrying the T allele compared with CC carriers (178 ± 78 vs. 166 ± 60 ng/mL, respectively; P = 0.007 adjusted for age, gender, and BMI). cIMT was lower in subjects carrying the T allele compared with CC carriers (0.71 ± 0.20 vs. 0.76 ± 0.22 mm, respectively; P < 0.0001 adjusted for age, gender, and BMI). In sample 2, maximally ACh-stimulated forearm blood flow was higher in subjects carrying the T allele compared with CC carriers (343 ± 191 vs. 281 ± 125%, respectively; P = 0.02 adjusted for age, gender, and BMI). CONCLUSION: Subjects carrying the T allele exhibited significantly higher levels of circulating IGF-1, lower values of cIMT, and higher endothelium-dependent vasodilatation compared with CC carriers. These findings support the idea that IGF-1 plays a role in the pathogenesis of atherosclerosis.

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with chronic kidney disease.

OBJECTIVE: Studies reported a relationship between elevated asymmetric dimethylarginine (ADMA) concentrations and adverse renal outcomes. There is evidence that the rs9267551 variant in the DDAH2 gene has a functional impact with the C allele having a higher transcriptional activity resulting in increased expression of DDAH2 in endothelial cells and lower plasma ADMA levels in C allele carriers. METHODS: To address whether this variant is associated with chronic kidney disease (CDK), 2852 White European were studied. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). RESULTS: The proportion of subjects with CKD was significantly lower in C allele carriers than in GG genotype carriers (OR 0.49, 95%CI 0.25-0.97; P = 0.03). In a logistic regression model adjusted for age, gender, BMI, blood pressure, total and HDL cholesterol, triglyceride, and fasting plasma glucose, C allele carriers have a lower risk of CKD compared with GG genotype carriers (OR 0.38, 95%CI 0.18-0.78; P = 0.008). This association was maintained after addition to the logistic regression model of other confounders including glucose tolerance status, presence of dyslipidemia, anti-hypertensive and antidiabetic drugs (OR 0.35, 95%CI 0.15-0.80; P = 0.01). CONCLUSION: The rs9267551 functional variant of the DDAH2 gene is associated with CKD with carriers of the C allele having a lower risk of renal dysfunction independently from several confounders. Because ADMA predicted progression of renal disease, it is possible that, in GG carriers, ADMA may accumulate at the renal level causing endothelial dysfunction as a consequence of reduced nitric oxide availability and potentiating micro-vascular damage.

Variants of insulin-signaling inhibitor genes in type 2 diabetes and related metabolic abnormalities.

Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis.

A fasting insulin-raising allele at IGF1 locus is associated with circulating levels of IGF-1 and insulin sensitivity.

BACKGROUND: A meta-analysis of genome-wide data reported the discovery of the rs35767 polymorphism near IGF1 with genome-wide significant association with fasting insulin levels. However, it is unclear whether the effects of this polymorphism on fasting insulin are mediated by a reduced insulin sensitivity or impaired insulin clearance. We investigated the effects of the rs35767 polymorphism on circulating IGF-1 levels, insulin sensitivity, and insulin clearance. METHODOLOGY/PRINCIPAL FINDINGS: Two samples of adult nondiabetic white Europeans were studied. In sample 1 (n=569), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (190±77 vs. 218±97 ng/ml, respectively; P=0.007 after adjusting for age, gender, and BMI). Insulin sensitivity assessed by euglycaemic-hyperinsulinemic clamp was lower in GG genotype carriers compared with A allele carriers (8.9±4.1 vs. 10.1±5.1 mg x Kg(-1) free fat mass x min(-1), respectively; P=0.03 after adjusting for age, gender, and BMI). The rs35767 polymorphism did not show significant association with insulin clearance. In sample 2 (n=859), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (155±60 vs. 164±63 ng/ml, respectively; P=0.02 after adjusting for age, gender, and BMI). Insulin sensitivity, as estimated by the HOMA index, was lower in GG genotype carriers compared with A allele carriers (2.8±2.2 vs. 2.5±1.3, respectively; P=0.03 after adjusting for age, gender, and BMI). CONCLUSION/SIGNIFICANCE: The rs35767 polymorphism near IGF1 was associated with circulating IGF-1 levels, and insulin sensitivity with carriers of the GG genotype exhibiting lower IGF-1 concentrations and insulin sensitivity as compared with subjects carrying the A allele.