Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Aims/hypothesis Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. Methods Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. Results βACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. Conclusions/interpretation Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood

Circulating Zonulin, a Marker of Intestinal Permeability, Is Increased in Association with Obesity-Associated Insulin Resistance

Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA) was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity). Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002) contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01) contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase

Blood culture status and mortality among patients with suspected community-acquired bacteremia: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Comparison of mortality among patients with positive and negative blood cultures may indicate the contribution of bacteremia to mortality. This study (1) compared mortality among patients with community-acquired bacteremia with mortality among patients with negative blood cultures and (2) determined the effects of bacteremia type and comorbidity level on mortality among patients with positive blood cultures.</p> <p>Methods</p> <p>This cohort study included 29,273 adults with blood cultures performed within the first 2 days following hospital admission to an internal medical ward in northern Denmark during 1995-2006. We computed product limit estimates and used Cox regression to compute adjusted mortality rate ratios (MRRs) within 0-2, 3-7, 8-30, and 31-180 days following admission for bacteremia patients compared to culture-negative patients.</p> <p>Results</p> <p>Mortality in 2,648 bacteremic patients and 26,625 culture-negative patients was 4.8% vs. 2.0% 0-2 days after admission, 3.7% vs. 2.7% 3-7 days after admission, 5.6% vs. 5.1% 8-30 days after admission, and 9.7% vs. 8.7% 31-180 days after admission, corresponding to adjusted MRRs of 1.9 (95% confidence interval (CI): 1.6-2.2), 1.1 (95% CI: 0.9-1.5), 0.9 (95% CI: 0.8-1.1), and 1.0 (95% CI: 0.8-1.1), respectively. Mortality was higher among patients with Gram-positive (adjusted 0-2-day MRR 1.9, 95% CI: 1.6-2.2) and polymicrobial bacteremia (adjusted 0-2-day MRR 3.5, 95% CI: 2.2-5.5) than among patients with Gram-negative bacteremia (adjusted 0-2-day MRR 1.5, 95% CI 1.2-2.0). After the first 2 days, patients with Gram-negative bacteremia had the same risk of dying as culture-negative patients (adjusted MRR 0.8, 95% CI: 0.5-1.1). Only patients with polymicrobial bacteremia had increased mortality within 31-180 days following admission (adjusted MRR 1.3, 95% CI: 0.8-2.1) compared to culture-negative patients. The association between blood culture status and mortality did not differ substantially by level of comorbidity.</p> <p>Conclusions</p> <p>Community-acquired bacteremia was associated with an increased risk of mortality in the first week of medical ward admission. Higher mortality among patients with Gram-positive and polymicrobial bacteremia compared with patients with Gram-negative bacteremia and negative cultures emphasizes the prognostic importance of these infections.</p

Kinematics of the Southern Rhodope Core Complex (North Greece)

The Southern Rhodope Core Complex is a wide metamorphic dome exhumed in the northern Aegean as a result of large-scale extension from mid-Eocene to mid-Miocene times. Its roughly triangular shape is bordered on the SW by the Jurassic and Cretaceous metamorphic units of the Serbo-Macedonian in the Chalkidiki peninsula and on the N by the eclogite bearing gneisses of the Sideroneron massif. The main foliation of metamorphic rocks is flat lying up to 100 km core complex width. Most rocks display a stretching lineation trending NEâ SW. The Kerdylion detachment zone located at the SW controlled the exhumation of the core complex from middle Eocene to mid-Oligocene. From late Oligocene to mid-Miocene exhumation is located inside the dome and is accompanied by the emplacement of the synkinematic plutons of Vrondou and Symvolon. Since late Miocene times, extensional basin sediments are deposited on top of the exhumed metamorphic and plutonic rocks and controlled by steep normal faults and flat-ramp-type structures. Evidence from Thassos Island is used to illustrate the sequence of deformation from stacking by thrusting of the metamorphic pile to ductile extension and finally to development of extensional Plio-Pleistocene sedimentary basin. Paleomagnetic data indicate that the core complex exhumation is controlled by a 30� dextral rotation of the Chalkidiki block. Extensional displacements are restored using a pole of rotation deduced from the curvature of stretching lineation trends at core complex scale. It is argued that the Rhodope Core Complex has recorded at least 120 km of extension in the North Aegean, since the last 40 My

Behavior and Impact of Zirconium in the Soil–Plant System: Plant Uptake and Phytotoxicity

Because of the large number of sites they pollute, toxic metals that contaminate terrestrial ecosystems are increasingly of environmental and sanitary concern (Uzu et al. 2010, 2011; Shahid et al. 2011a, b, 2012a). Among such metals is zirconium (Zr), which has the atomic number 40 and is a transition metal that resembles titanium in physical and chemical properties (Zaccone et al. 2008). Zr is widely used in many chemical industry processes and in nuclear reactors (Sandoval et al. 2011; Kamal et al. 2011), owing to its useful properties like hardness, corrosion-resistance and permeable to neutrons (Mushtaq 2012). Hence, the recent increased use of Zr by industry, and the occurrence of the Chernobyl and Fukashima catastrophe have enhanced environmental levels in soil and waters (Yirchenko and Agapkina 1993; Mosulishvili et al. 1994 ; Kruglov et al. 1996)

Zebrafish hoxd4a Acts Upstream of meis1.1 to Direct Vasculogenesis, Angiogenesis and Hematopoiesis

10.1371/journal.pone.0058857PLoS ONE83

Intervention in gene regulatory networks via greedy control policies based on long-run behavior

<p>Abstract</p> <p>Background</p> <p>A salient purpose for studying gene regulatory networks is to derive intervention strategies, the goals being to identify potential drug targets and design gene-based therapeutic intervention. Optimal stochastic control based on the transition probability matrix of the underlying Markov chain has been studied extensively for probabilistic Boolean networks. Optimization is based on minimization of a cost function and a key goal of control is to reduce the steady-state probability mass of undesirable network states. Owing to computational complexity, it is difficult to apply optimal control for large networks.</p> <p>Results</p> <p>In this paper, we propose three new greedy stationary control policies by directly investigating the effects on the network long-run behavior. Similar to the recently proposed mean-first-passage-time (MFPT) control policy, these policies do not depend on minimization of a cost function and avoid the computational burden of dynamic programming. They can be used to design stationary control policies that avoid the need for a user-defined cost function because they are based directly on long-run network behavior; they can be used as an alternative to dynamic programming algorithms when the latter are computationally prohibitive; and they can be used to predict the best control gene with reduced computational complexity, even when one is employing dynamic programming to derive the final control policy. We compare the performance of these three greedy control policies and the MFPT policy using randomly generated probabilistic Boolean networks and give a preliminary example for intervening in a mammalian cell cycle network.</p> <p>Conclusion</p> <p>The newly proposed control policies have better performance in general than the MFPT policy and, as indicated by the results on the mammalian cell cycle network, they can potentially serve as future gene therapeutic intervention strategies.</p

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