Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels

Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered.     

Peroxisome proliferator-activated receptor {alpha} is responsible for the up-regulation of hepatic glucose-6-phosphatase gene expression in fasting and db/db Mice

Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase gene expression during fasting or T2DM animal models.     

Reproductive biology and implications for management of the painted sweetlips Diagramma pictum in the southern Arabian Gulf

The reproductive biology of the painted sweetlips Diagramma pictum was determined from 487 individuals collected between January and December 2010 in the southern Arabian Gulf. There was no evidence of sex change and the combination of histological results with the sex composition of the size and age structures indicated a gonochoristic sexual pattern. There were peaks in gonado-somatic indices for females in March and October with spawning occurring during two seasons (April to May and November). The mean size and age at sexual maturity (L(m50) and A(m50) ) were 35·7 cm fork length (L(F) ) and 2·9 years for females and 26·7 cm L(F) and 0·5 years for males. The maximum recorded age (11 years) and small mean size and young age at sexual maturity for males may be a direct result of intensive demersal fishing in the southern Arabian Gulf. There was an exponential increase in the cumulative reproductive potential with size and a linear increase with age for both sexes. The mean L(F) (L(c50) ) at which D. pictum became vulnerable to capture was 33·3 cm, which corresponded to only 3 and 7% of the cumulative reproductive potential of males and females, respectively. Size-specific and age-specific reproductive potential indicated that conventional regulations that equate the mean size at first capture to sexual maturation are unsuitable for the management of D. pictum.     

Comparison of the Diversilab® system with multi-locus sequence typing and pulsed-field gel electrophoresis for the characterization of Streptococcus agalactiae invasive strains

Streptococcus agalactiae (or group B streptococcus; GBS) is a leading cause of neonatal morbidity and mortality in the developed countries. Several epidemiological typing tools have been developed for GBS to investigate the association between genotype and disease and to assess genetic variations within genogroups. This study compared the semi-automated repetitive sequence-based PCR Diversilab® system (DL) with MLST and pulsed field gel electrophoresis (PFGE) for determining the relatedness of invasive GBS strains. We analysed 179 unrelated GBS strains isolated from adult (n = 108) and neonatal (n = 71) invasive infections. By MLST, strains were resolved into 6 clonal complexes (CCs) including 23 sequence-types (STs), and 4 unique STs, whereas DL differentiated these isolates into 12 rep-PCR clusters (rPCs) and 9 unique rep-PCR types. The discriminatory power of both methods was similar, with Simpson's diversity indexes of 71.9% and 70.6%, respectively. However, their clustering concordance was low with Wallace concordance coefficients inferior to 0.4. PFGE was performed on 31 isolates representative of the most relevant DLrPCs clustered within the 3 major MLST CCs (CC-17, CC-23 and CC-1). As already observed with MLST, the concordance of DL with PFGE was low for all three CCs (Wallace coefficient < 0.5), PFGE being more discriminative than rep-PCR. In summary, this work suggests that DL is less appropriate than MLST or PFGE to study GBS population genetic diversity.     

Ranking valid topologies of the secondary structure elements using a constraint graph

Electron cryo-microscopy is a fast advancing biophysical technique to derive three-dimensional structures of large protein complexes. Using this technique, many density maps have been generated at intermediate resolution such as 6-10 ? resolution. Although it is challenging to derive the backbone of the protein directly from such density maps, secondary structure elements such as helices and β-sheets can be computationally detected. Our work in this paper provides an approach to enumerate the top-ranked possible topologies instead of enumerating the entire population of the topologies. This approach is particularly practical for large proteins. We developed a directed weighted graph, the topology graph, to represent the secondary structure assignment problem. We prove that the problem of finding the valid topology with the minimum cost is NP hard. We developed an O(N(2)2(N)) dynamic programming algorithm to identify the topology with the minimum cost. The test of 15 proteins suggests that our dynamic programming approach is feasible to work with proteins of much larger size than we could before. The largest protein in the test contains 18 helical sticks detected from the density map out of 33 helices in the protein.     

Fishing pattern and management scenarios of Epinephelus gabriellae (Randall and Heemstra, 1991) fisheries in the Arabian Sea,Oman

Management of fish resources in the Western Indian Ocean is complicated due to the lack of data on the basic biology and landing statistics for exploited fish species. In this paper, a database including biological parameters, length frequency distributions and catches of Epinephelus gabriellae in Oman according to fleet components has been established to develop a management plan for its sustainable exploitation. Length cohort analyses and yield per recruit were examined by simulating changes in fishing effort in length at first capture and by introducing a seasonal ban for trawlers. The results showed a high sensitivity to the applied value of natural mortality (M). (i) With M = 0.40, a healthy status of the stock is observed; however, with M values of 0.20 and 0.15 the stock appears slightly overexploited, and actual F exceeds 10 and 30% of the F₀₁ level, respectively. (ii) A moderate increase of length at first capture would not significantly affect the long‐term yield or stock spawning biomass; however, a substantial length increase would in the long‐term lead to a decrease in yields for the artisanal fleet using traps. (iii) A seasonal ban regulation for trawlers would not have a significant effect on the sustainable yield, but if the fishing effort were to increase considerably, a significant long‐term gain in yield would be obtained with a closed season from April‐September.     

Effect of Acacia gum on blood pressure in rats with adenine-induced chronic renal failure

Chronic renal failure (CRF) occurring naturally in patients or induced by subtotal nephrectomy in rats induces several alterations in the cardiovascular system (CVS). However, the effect of chemically induced CRF in rats on the CVS is less well known. We induced CRF in rats by feeding adenine (0.75%, w/w, four weeks) and investigated the effect of the ensuing CRF on the systolic and diastolic blood pressure (BP) and heart rate (HR). Further, we investigated the effect of giving acacia gum (AG, 10%, w/v) in the drinking water concomitantly with adenine on the above parameters. AG has been previously shown to ameliorate the severity of CRF in humans and rats. We confirmed here that adenine-induced CRF significantly increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. Additionally, it significantly increased both systolic and diastolic BP, with no significant effect on HR. Both of these actions were significantly mitigated by AG treatment. The antihypertensive angiotenisn-converting enzyme inhibitor lisinopril (10 mg/kg) was given by gavage to rats concomitantly with adenine, significantly reduced the rise in blood pressure induced by adenine. In conclusion, adenine-induced CRF in rats significantly increased BP, and this was significantly mitigated by administration of AG. Possible mechanisms of these changes and the protective effect of AG will be investigated.     

Theranostic Gold Nanoparticles Modified for Durable Systemic Circulation Effectively and Safely Enhance the Radiation Therapy of Human Sarcoma Cells and Tumors

Radiation therapy (RT) is an integral component of the treatment of many sarcomas and relies on accurate targeting of tumor tissue. Despite conventional treatment planning and RT, local failure rates of 10% to 28% at 5 years have been reported for locally advanced, unresectable sarcomas, due in part to limitations in the cumulative RT dose that may be safely delivered. We describe studies of the potential usefulness of gold nanoparticles modified for durable systemic circulation (through polyethylene glycosylation; hereinafter “P-GNPs”) as adjuvants for RT of sarcomas. In studies of two human sarcoma-derived cell lines, P-GNP in conjunction with RT caused increased unrepaired DNA damage, reflected by approximately 1.61-fold increase in γ-H2AX (histone phosphorylated on Ser¹³⁹) foci density compared with RT alone. The combined RT and P-GNP also led to significantly reduced clonogenic survival of tumor cells, compared to RT alone, with dose-enhancement ratios of 1.08 to 1.16. In mice engrafted with human sarcoma tumor cells, the P-GNP selectively accumulated in the tumor and enabled durable imaging, potentially aiding radiosensitization as well as treatment planning. Mice pretreated with P-GNP before targeted RT of their tumors exhibited significantly improved tumor regression and overall survival, with long-term survival in one third of mice in this treatment group compared to none with RT only. Interestingly, prior RT of sarcoma tumors increased subsequent extravasation and in-tumor deposition of P-GNP. These results together suggest P-GNP may be integrated into the RT of sarcomas, potentially improving target imaging and radiosensitization of tumor while minimizing dose to normal tissues.     

The effect of turbidity on recognition and generalization of predators and non‐predators in aquatic ecosystems

Recent anthropogenic activities have caused a considerable change in the turbidity of freshwater and marine ecosystems. Concomitant with such perturbations are changes in community composition. Understanding the mechanisms through which species interactions are influenced by anthropogenic change has come to the forefront of many ecological disciplines. Here, we examine how a change in the availability of visual information influences the behavior of prey fish exposed to potential predators and non‐predators. When fathead minnows, Pimephales promelas, were conditioned to recognize predators and non‐predators in clear water, they showed a highly sophisticated ability to distinguish predators from non‐predators. However, when learning occurred under conditions of increased turbidity, the ability of the prey to learn and generalize recognition of predators and non‐predators was severely impaired. Our work highlights that changes at the community level associated with anthropogenic perturbations may be mediated through altered trophic interactions, and highlights the need to closely examine behavioral interactions to understand how species interactions change.