ALBERT

Description: When a wireless sensor network (WSN) is employed to monitor environmental data, efficient energy usage is demanded so that the WSN lifetime can be extended. In this context, we propose a distributed energy con...

Description: Macrophages’ phenotypic and functional diversity depends on differentiating programs related to local environmental factors. Recent interest was deserved to the signal transduction pathways acting in macrophage polarization, including the phosphoinositide (PI) system and related phospholipase C (PLC) family of enzymes. The expression panel of PLCs and the subcellular localization differs in quiescent cells compared to the pathological counterpart. We analyzed the expression of PLC enzymes in unpolarized (M0), as well as in M1 and M2 macrophages to list the expressed isoforms and their subcellular localization. Furthermore, we investigated whether inflammatory stimulation modified the basal panel of PLCs’ expression and subcellular localization. All PLC enzymes were detected within both M1 and M2 cells, but not in M0 cells. M0, as well as M1 and M2 cells own a specific panel of expression, different for both genes’ mRNA expression and intracellular localization of PLC enzymes. The panel of PLC genes’ expression and PLC proteins’ presence slightly changes after inflammatory stimulation. PLC enzymes might play a complex role in macrophages during inflammation and probably also during polarization.

Description: Objective Multi-component T2 relaxation allows for assessing the myelin water fraction in nervous tissue, providing a surrogate marker for demyelination. The assessment of the number and distribution of different T2 components for devising exact models of tissue relaxation has been limited by T2 sampling with conventional MR methods. Materials and methods A T2-prepared UTE sequence was used to assess multicomponent T2 relaxation at 9.4 T of fixed mouse and rat spinal cord samples and of mouse spinal cord in vivo. For in vivo scans, a cryogenically cooled probe allowed for 78-µm resolution in 1-mm slices. Voxel-wise non-negative least square analysis was used to assess the number of myelin water-associated T2 components. Results More than one myelin water-associated T2 component was detected in only 12 % of analyzed voxels in rat spinal cords and 6 % in mouse spinal cords, both in vivo and in vitro. However, myelin water-associated T2 values of individual voxels varied between 0.1 and 20 ms. While in fixed samples almost no components below 1 ms were identified, in vivo, these contributed 14 % of the T2 spectrum. No significant differences in MWF were observed in mouse spinal cord in vivo versus ex vivo measurements. Conclusion Voxel-wise analysis methods using relaxation models with one myelin water-associated T2 component are appropriate for assessing myelin content of nervous tissue.

Description: Stems cells of the colon crypt are the origin of colon mature cells. Colorectal cancer cells are also suggested to originate from crypt stem cells undergoing a series of epigenetic and genetic alterations. Aberrant methylation plays important roles in early carcinogenesis and lead to altered gene expression and regulation, resulting in accumulation of damages to cell function and ultimately, malignant transformation. Aberrances in hypermethylation and hypomethylation act in different mechanism through the regulation of various genes during CSC carcinogenesis, and both of them play crucial roles in stem cell differentiation towards cancer cells. A large majority of epigenetic and genetic abnormalities that work coordinately in colorectal carcinogenesis are related to cell growth and division, indicating that the intrinsic abnormalities of CRC lie in dysregulation of basic cellular processes. Detection of abnormal methylation can be used in cancer screening and early detection, while reversal of aberrant methylation using drugs may have potential in cancer therapy. This review will provide an overview on the roles of aberrant methylation and a summary of genes that are affected during CRC carcinogenesis.

Description: Purpose The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. Methods This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. Results Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage 〉7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan 〉7.5 mg and age ≥75 years. Conclusions A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.

Description: Recent years, information spreading under the environment of wireless communication has attracted increasing interest. Microblog platform on mobile terminals, as one product of wireless communication, facilita...

Description: Internet of Thing (IoT) or also referred to as IP-enabled wireless sensor network (IP-WSN) has become a rich area of research. This is due to the rapid growth in a wide spectrum of critical application domains...

Description: Background VAAM is an amino acid mixture that simulates the composition of Vespa larval saliva. VAAM enhanced physical endurance of mice and have been used by athletes as a supplementary drink before exercise. However, there is no information on the effect of VAAM on the physiology of freely moving animals. The purpose of this study was to obtain information about the VAAM-dependent regulation of liver and adipose tissue transcriptomes. Results Mice were orally fed a VAAM solution, an amino acid mixture mimicking casein hydrolysate (CAAM) or water under ad libitum feeding conditions for 5 days. Comparisons of the hepatic transcriptome between VAAM-, CAAM-, and water-treated groups revealed a VAAM-specific regulation of the metabolic pathway, i.e., the down-regulation of glycolysis and fatty acid oxidation and the up-regulation of polyunsaturated fatty acid synthesis and glucogenic amino acid utilization. Similar transcriptomic analyses of white and brown adipose tissues (WAT and BAT, respectively) indicated the up-regulation of phospholipid synthesis in WAT and the negative regulation of cellular processes in BAT. Because the coordinated regulation of tissue transcriptomes implied the presence of upstream signaling common to these tissues, we conducted an Ingenuity Pathways Analysis. This analysis showed that estrogenic and glucagon signals were activated in the liver and WAT and that beta-adrenergic signaling was activated in all three tissues. Conclusions We found that VAAM ingestion had an effect on multiple tissue transcriptomes of freely moving mice. Utilization of glycogenic amino acids may have been activated in the liver. Fatty acid conversion into phospholipid, not to triacylglycerol, may have been stimulated in adipocytes contrasting that a little effect was observed in BAT. Analysis of upstream factors revealed that multiple hormonal signals were activated in the liver, WAT, and BAT. Our data provide some clues to understanding the role of VAAM in metabolic regulation.

Description: Type II natural killer T cells (NKT) are a subset of the innate-like CD1d-restricted lymphocytes that are reactive to lipid antigens. Unlike the type I NKT cells, which express a semi-invariant TCR, type II NKT cells express a broader TCR repertoire. Additionally, other features, such as their predominance over type I cells in humans versus mice, the nature of their ligands, CD1d/lipid/TCR binding, and modulation of immune responses, distinguish type II NKT cells from type I NKT cells. Interestingly, it is the self-lipid-reactivity of type II NKT cells that has helped define their physiological role in health and in disease. The discovery of sulfatide as one of the major antigens for CD1d-restricted type II NKT cells in mice has been instrumental in the characterization of these cells, including the TCR repertoire, the crystal structure of the CD1d/lipid/TCR complex, and their function. Subsequently, several other glycolipids and phospholipids from both endogenous and microbial sources have been shown to activate type II NKT cells. The activation of a specific subset of type II NKT cells following administration with sulfatide or lysophosphatidylcholine (LPC) leads to engagement of a dominant immunoregulatory pathway associated with the inactivation of type I NKT cells, conventional dendritic cells, and inhibition of the proinflammatory Th1/Th17 cells. Thus, type II NKT cells have been shown to be immunosuppressive in autoimmune diseases, inflammatory liver diseases, and in cancer. Knowing their relatively higher prevalence in human than type I NKT cells, understanding their biology is imperative for health and disease.

Description: In this paper we address the safety analysis of chemical plants controlled by programmable logic controllers (PLCs). We consider a specification of the control program of the PLCs, extended with the specification of the dynamic plant behavior. The resulting hybrid models can be transformed to hybrid automata, for which advanced techniques for reachability analysis exist. However, the hybrid automata models are often too large to be analyzed. We propose two counterexample-guided abstraction refinement (CEGAR) approaches to keep the size of the hybrid models moderate.

Description: Nowadays, systems are growing in power and in access to more resources and services. This situation makes it necessary to provide user-centered systems that act as intelligent assistants. These systems should be able to interact in a natural way with human users and the environment and also be able to take into account user goals and environment information and changes. In this paper, we present an architecture for the design and development of a goal-oriented, self-adaptive, smart-home environment. With this architecture, users are able to interact with the system by expressing their goals which are translated into a set of agent actions in a way that is transparent to the user. This is especially appropriate for environments where ambient intelligence and automatic control are integrated for the user’s welfare. In order to validate this proposal, we designed a prototype based on the proposed architecture for smart-home scenarios. We also performed a set of experiments that shows how the proposed architecture for human-agent interaction increases the number and quality of user goals achieved.

Description: To meet the increasing demand of computational power, at present IT service providers’ should choose cloud based services for its flexibility, reliability and scalability. More and more datacenters are being b...

Description: Effects of benzoic acid (BA) on physicochemical properties and ecotoxicities of CuO nanoparticles (CuONPs) in model aqueous media were studied. The CuONPs had larger hydrodynamic sizes and higher surface zeta potentials during 96 h of settling in the presence of BA than when the BA were not present. BA interaction with CuONPs is shown to promote dissolved Cu release from CuONPs in a dose-dependent manner. The contribution of free Cu 2+ -ions to growth inhibition toxicity of the CuONP suspensions at a toxicologically relevant concentration for the green alga Scenedesmus obliquus was around 22 %, indicating that dissolved fraction was not the major source of toxicity of CuONPs. The toxicity of CuONPs increased as the BA concentration increased. BA significantly altered total antioxidant capacity of CuONPs-exposed algal cells. The mechanism of the BA effect on the CuONPs toxicity may be mainly associated with degree of agglomeration, dissolved Cu, and particle-induced oxidative stress.

Description: Mussel samples were collected monthly between October-2010 and October-2011 from four stations (Bosphorus, Bandırma, Gelibolu, Tekirdağ) in the Marmara Sea. Two consecutive months’ samples were homogenized and combined as a single group for analysis. Mussel samples were analyzed for Organochlorine pesticides (OCPs); (total-DDT, total-HCH, Endrin, α-Endosulfan, β-Endosulfan, Heptachlor) and Polychlorinated biphenyls (PCBs); (PCB 28, PCB 52, PCB 138, PCB 153, and PCB 180). All analyses were done according to Eurofins house method in ERGO Laboratory in Germany. Concentrations of α-endosulfan and heptachlor in mussel tissues were below method detection limits. The annual average OCPs concentrations among the stations ranged between 0.02 and 1.45 ng/g (wet weight), 1.9–99.75 ng/g (lipid weight) whereas the annual average PCBs concentrations among the stations ranged between 0.03 and 0.40 ng/g (wet weight), 1.71–26.48 ng/g (lipid weight), respectively. There was no relation between fat content of mussels and residues of the contaminants. PCB 138 and PCB 153 were the most predominant PCBs, while total-DDT and total-HCH were the most predominant OCPs in the mussels. Total-DDT concentrations were higher compared to total-HCH and PCBs isomers. Measured levels were below the national and international committees’ and institutions’ limits for human consumption and protection of aquatic biota.

Description: To monitor environmental pollutants in Faroese biota, samples from a top predator were analysed and put into a spatial and temporal context. Analysis of 20 Great Skua eggs sampled in 2012 from the Faroe Islands showed 〉70 % lower concentrations of legacy persistent organic pollutants (POPs) than in samples analysed in 1977. The 2012 Faroese eggs showed higher concentrations than for eggs in Shetland from about the same period (2008). Eggshells were analysed for sub-lethal effects but there were no detectable effects of legacy POP levels on eggshell colour or thickness. A temporal decline in legacy POPs would indicate a reduction in the general pollutant levels present in the environment as has been shown in other areas of the North Atlantic, but there are significant geographic differences in POPs levels likely due to differences in diet resulting in significantly different exposures on a relatively limited spatial scale.

Description: A natural experiment on a popular German Question & Answer community is used to find out whether the small-area hypothesis applies to user activation by means of a virtual reward in the form of badges. Koo and Fishbach’s small-area hypothesis posits that individuals in pursuit of a goal are more highly motivated when focusing on the smaller percentage of progress towards their goal, irrespective of whether this figure represents the actions already completed or those still remaining. Consistent with the authors’ theoretical predictions, the study finds empirical evidence for the small-area effect and its activating power, translated here into increased online user contributions. Besides contributing to the literature with an empirical study anchored in theory, the findings have direct practical implications for designers of online virtual reward systems by suggesting more effective (and motivating) ways of framing user progress towards virtual rewards.

Description: Autism spectrum disorder (ASD) is one of the most heritable neuropsychiatric conditions. The complex genetic landscape of the disorder includes both common and rare variants at hundreds of genetic loci. This marked heterogeneity has thus far hampered efforts to develop genetic diagnostic panels and targeted pharmacological therapies. Here, we give an overview of the current literature on the genetic basis of ASD, and review recent human brain transcriptome studies and their role in identifying convergent pathways downstream of the heterogeneous genetic variants. We also discuss emerging evidence on the involvement of non-coding genomic regions and non-coding RNAs in ASD.

Description: Energy consumption for datacenter has grown significantly and the trend is still growing due to the increasing popularity of cloud computing. Datacenter networks (DCNs), however, are starting to consume a grea...

Description: Hypoxia and hypoxia signalling through the transcription factor hypoxia inducible factor-1 (HIF-1), play an important role in normal tissue repair processes. Tissue injury generally produces at least the transient loss of normal vascular perfusion and the resulting hypoxia induces the expression of many genes that allow the tissue to adapt to hypoxia, to start the repair process and, in time, to re-establish oxygen delivery to the tissue. In most cases, transient hypoxia and the activation of the HIF-1 pathway are beneficial and promote the repair process, producing tissue that might not perfectly reform its original architecture but that has its function substantially restored. However, in some cases of chronic injury, chronic hypoxia and pathological repair, the hypoxia pathway might be responsible for driving the process of fibrosis and can lead to excessive scarring and compromised organ function.

Description: Ionic “vital dyes” are commonly used to assess cell viability based on the idea that their permeation is contingent on a loss of membrane integrity. However, the possibility that dye entry is conducted into live cells by endogenous membrane transporters must be recognized and controlled for. Several cation-selective plasma membrane-localized ion channels, including the adenosine 5ʹ-triphosphate (ATP)-gated P2X receptors, have been reported to conduct entry of the DNA-binding fluorescence dye, YO-PRO-1, into live cells. Extracellular ATP often becomes elevated as a result of release from dying cells, and so it is possible that activation of P2X channels on neighboring live cells could lead to exaggerated estimation of cytotoxicity. Here, we screened a number of fluorescent vital dyes for ion channel-mediated uptake in HEK293 cells expressing recombinant P2X2, P2X7, or TRPV1 channels. Our data shows that activation of all three channels caused substantial uptake and nuclear accumulation of YO-PRO-1, 4ʹ,6-diamidino-2-phenylindole (DAPI), and Hoechst 33258 into transfected cells and did so well within the time period usually used for incubation of cells with vital dyes. In contrast, channel activation in the presence of propidium iodide and SYTOX Green caused no measurable uptake and accumulation during a 20-min exposure, suggesting that these dyes are not likely to exhibit measurable uptake through these particular ion channels during a conventional cell viability assay. Caution is encouraged when choosing and employing cationic dyes for the purpose of cell viability assessment, particularly when there is a likelihood of cells expressing ion channels permeable to large ions.

Description: The smart power grid transforms into a distributed system of manifold stakeholders by integrating communication technology into the former static power grid. Distributed Energy Management (DEM) will play a vital role in future demand supply matching. An important and often overlooked factor in this concept is privacy. In this paper we present Priv-ADE, a privacy preserving algorithm for DEM. It utilises homomorphic encryption to privately gather aggregated data and perform energy management based on the max–min fairness principle. Simulations show that PrivADE achieves similar consumption results as two comparative approaches, while in contrast preserves privacy at all times. The computational and communicational complexity is analysed. Furthermore, the privacy concept is adopted to PowerMatcher.

Description: Smart Grids constitute massively distributed systems with many interconnected entities that require flexible and reliable machine-to-machine communication among each other. Providing such flexible and reliable communication enables the complex algorithms and control mechanisms that are necessary to ensure reliable grid operation and to trade energy generation and energy consumption to the mutual benefit of all involved entities. Messaging protocols such as the Extensible Messaging and Presence Protocol (XMPP) provide all the necessary mechanisms for implementing these tasks. Thus, they lend themselves to transmitting messages and data in Smart Grids by mapping Smart Grid protocols and data formats such as IEC 61850 and Common Information Model (CIM) to suitable messaging protocols. In this paper, we present an approach for mapping IEC 61850 and CIM to XMPP and elaborate on our experiences from implementing and evaluating this approach in a field trial conducted within the research project In2VPP.

Description: Serine proteases play an important role in inflammation via PARs. However, little is known of expression levels of PARs on monocytes of allergic patients, and influence of serine proteases and PARs on TNF-α secretion from monocytes. Using quantitative real-time PCR (qPCR) and flowcytometry techniques, we observed that the expression level of PAR-2 in monocytes of patients with allergic rhinitis and asthma was increased by 42.9 and 38.2 %. It was found that trypsin, thrombin, and tryptase induced up to 200, 320, and 310 % increase in TNF-α release from monocytes at 16 h, respectively. PAR-1 agonist peptide, SFLLR-NH 2 , and PAR-2 agonist peptide tc-LIGRLO-NH 2 provoked up to 210 and 240 % increase in release of TNF-α. Since SCH 79797, a PAR-1 antagonist, and PD98059, an inhibitor of ERK inhibited thrombin- and SFLLR-NH 2 -induced TNF-α release, the action of thrombin is most likely through a PAR-1- and ERK-mediated signaling mechanism. Similarly, because FSLLRN-NH 2 , an inhibitor of PAR-2 diminished tryptase- and tc-LIGRLO-NH 2 -induced TNF-α release, the action of tryptase appears PAR-2 dependent. Moreover, in vivo study showed that both recombinant cockroach major allergens Per a 1 and Per a 7 provoked upregulation of PAR-2 and PAR-1 expression on CD14+ cells in OVA-sensitized mouse peritoneum. In conclusion, increased expression of PAR-2 in monocytes of AR and asthma implicates that PAR-2 likely play a role in allergy. PAR-2- and PAR-1-mediated TNF-α release from monocytes suggests that these unique protease receptors are involved in the pathogenesis of inflammation.

Description: In the present study, the tube well water quality and the associated health risks, emphasizing on arsenic contamination, were investigated in rural and urban samples from Tehsil Mailsi located in Punjab, Pakistan. Arsenic concentrations (μg/L) were ranged from 12 to 448.5 and which exceeded the WHO recommended limit (10 μg/L) in all cases. The calculated average daily dose (3.3 × 10 −0.4 to 1.2 × 10 −0.2  mg/kg day) and hazard quotient (1.1–40) reflected the potential health risk to local population due to tube well water consumption as drinking purpose. Sodium percent (Na%), sodium absorption ratio, residual sodium carbonate, Kelly’s index and magnesium absorption ratio were also determined to assess the suitability of tube well water for irrigation purpose. The resulting piper plot revealed the Na–Ca–HCO 3 type water chemistry of the area and generally alkaline environment. The spatial distribution of arsenic in the tube well waters pinpoints the significant contribution of anthropogenic activities to arsenic pollution. Nevertheless, different statistical tools, including principal component analysis, hierarchical cluster analysis and correlation matrices, revealed the contribution of both natural and anthropogenic activities and alkaline type of aquifers toward the high level of arsenic contamination.

Description: While mining topics in a document collection, in order to capture the relationships between words and further improve the effectiveness of discovered topics, this paper proposed a feedback recurrent neural net...

Description: Throughput imbalances among contending flows are known to occur when any carrier sense multiple access (CSMA)-based protocol is employed in multi-hop wireless networks. These imbalances may vary from slight di...

Description: Purpose Chronic low-level systemic and adipose tissue inflammation has been identified as a major etiologic factor in many chronic diseases, including hypertension and cardiovascular diseases. Evidence from experimental studies suggests anti-inflammatory effects of dietary flavonols such as quercetin. Methods We investigated the effects of regular intake of quercetin on leptin, adiponectin, biomarkers of inflammation, glucose and insulin in overweight-to-obese patients with pre- and stage 1 hypertension. Another objective was to assess the safety of daily quercetin supplementation measured by parameters of liver and kidney function and of hematology. Subjects ( n  = 70) were randomized to receive a supra-nutritional dose of 162 mg/d quercetin or placebo in a double-blinded, placebo-controlled crossover trial with 6-week treatment periods separated by a 6-week washout period. Two subjects dropped out for personal reasons. Only data from the remaining 68 subjects were included in the analysis. Results Compared to placebo, quercetin did not significantly affect serum concentrations of leptin and adiponectin, HOMA-AD or the ratios of leptin/adiponectin and adiponectin/leptin. Neither quercetin nor placebo significantly changed serum C-reactive protein and plasma tumor necrosis factor alpha. Compared to placebo, quercetin did not significantly affect glucose, insulin, HOMA-IR, blood biomarkers of liver and renal function, hematology and serum electrolytes. Conclusion A supra-nutritional dose of 162 mg/d quercetin from onion skin extract for 6 weeks is safe but without significant effects on parameters of systemic and adipose tissue inflammation as well as glucose and insulin in overweight-to-obese subjects with (pre-)hypertension. This trial was registered at www.germanctr.de/ and http://apps.who.int/trialsearch/ as DRKS00000555.

Description: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the western world, with spectrum from simple steatosis to non-alcoholic steatohepatitis, which can progress to cirrhosis. NAFLD developments are known to be affected by host genetic background. Herein we emphasize the power of collaborative cross (CC) mouse for dissecting this complex trait and revealing quantitative trait loci (QTL) controlling hepatic fat accumulation in mice. 168 female and 338 male mice from 24 and 37 CC lines, respectively, of 18–20 weeks old, maintained on standard rodent diet, since weaning. Hepatic fat content was assessed, using dual DEXA scan in the liver. Using the available high-density genotype markers of the CC line, QTL mapping associated with percentage liver fat accumulation was performed. Our results revealed significant fatty liver accumulation QTL that were specifically, mapped in females. Two significant QTLs on chromosomes 17 and 18, with genomic intervals 3 and 2 Mb, respectively, were mapped. A third QTL, with a less significant P value, was mapped to chromosome 4, with genomic interval of 2 Mb. These QTLs were named Flal 1– Flal 3, referring to Fatty Liver Accumulation Locus 1–3, for the QTLs on chromosomes 17, 18, and 4, respectively. Unfortunately, no QTL was mapped with males. Searching the mouse genome database suggested several candidate genes involved in hepatic fat accumulation. Our results show that susceptibility to hepatic fat accumulations is a complex trait, controlled by multiple genetic factors in female mice, but not in male.

Description: Millions of poor people in the developing world still thrive on ragpicking. In the present study, we have examined whether ragpicking is associated with increased risk of cardiovascular disease. For this, we have enrolled 112 premenopausal female ragpickers (median age 30 years) and 98 age-matched housemaids as control from Kolkata, Eastern India. Venous blood was drawn for routine hematology; flow cytometry was used to measure generation of reactive oxygen species (ROS) by leukocytes, surface expression of CD62P (P-selectin) in platelets and CD11b in leukocytes. Collagen-induced platelet aggregation was evaluated by aggregometer, and erythrocytic superoxide dismutase (SOD) was measured by spectrophotometry. Soluble P-selectin (sP-sel) and CD40L (sCD40L), neutrophil-activating protein-2 (NAP-2), platelet and plasma serotonin, oxidized low-density lipoprotein (oxLDL), and anticardiolipin antibodies (aCL) in plasma were measured by ELISA. Compared with control, the ragpickers had significantly higher prevalence of hypertension and prehypertension, and hypertension was positively associated with ragpicking. The ragpickers also had higher levels of inflammation (elevated NAP-2), oxidative stress (elevated ROS generation with depleted SOD) with oxLDL, platelet activation and aggregability, soluble CD40 ligand, with altered serotonin level (rose in plasma but depleted in platelet). A greater percentage of ragpickers had elevated serum level of aCL of the IgG and IgM isotypes than the controls. The results suggest that the occupation of ragpicking increases the risk of cardiovascular diseases in premenopausal women of Eastern India via inflammation, oxidative stress, platelet hyperactivity, and hypertension.

Description: Thirty surface sediments and three sediment cores were collected from mangrove wetlands in the Pearl River Estuary of South China to investigate the spatial and vertical distribution of Dechlorane Plus (DP). DP concentrations in the mangrove surface sediments ranged from 0.0130 to 1.504 ng/g dry weight (dw). DP concentrations in sediments from Shenzhen were significantly greater than those from Guangzhou and Zhuhai. Anti -Cl 11 -DP, the dechlorinated product of anti -DP, was also detected in the mangrove sediments with concentrations ranged from not detected to 0.0198 ng/g dw. Significant positive relationship between anti -Cl 11 -DP and anti -DP levels was observed in the mangrove sediments, suggesting that photo and/or microbial degradation of anti -DP might occur in the sediments. The f anti values in the mangrove sediments were close to those in the technical DP products, suggesting that stereoselective enrichment of anti -DP may not exist in the mangrove sediments. DP concentrations in the mangrove sediment cores generally showed an increasing trend from the bottom to top layers. This is the first study to report the occurrence of DP and its degradation product in the mangrove wetlands.

Description: Commercially important bivalve Noah’s Ark shell ( Arca noae Linnaeus, 1758) represents a high-quality seafood product, but the data on levels of metal contaminants that could pose a human health risk and also on some essential elements that are important for health protection are lacking. This study examined the concentrations of Cd, Pb, Cr, Ni, Cu, Co, and Zn in the soft tissue of A. noae from harvesting area in the central Adriatic Sea, to survey whether heavy metals are within the acceptable limits for public health and whether tourism could have an impact on them. The concentrations of analysed metals varied for Cd: 0.15–0.74, Pb: 0.06–0.26, Cr: 0.11–0.34, Ni: 0.09–0.22, Cu: 0.65–1.95, Co: 0.04–0.09, and Zn: 18.3–74.7 mg/kg wet weight. These levels were lower than the permissible limits for safe consummation of seafood, and only for Cd, some precautions should be taken into account if older shellfish were consumed. Increase of Cd, Cr, and Cu in shell tissue was observed during the tourist season at the site closest to the marine traffic routes, indicating that metal levels in shellfish tissue should be monitored especially carefully during the peak tourist season to prevent eventual toxic effects due to increased intake of metals, specifically of Cd.

Description: Genomic instability drives cancer progression by promoting genetic abnormalities that allow for the multi-step clonal selection of cells with growth advantages. We previously reported that the IL-9-dependent TS1 cell line sequentially acquired activating substitutions in JAK1 and JAK3 upon successive selections for growth factor independent and JAK inhibitor-resistant cells, suggestive of a defect in mutation avoidance mechanisms. In the first part of this paper, we discovered that the gene encoding mutL homolog-1 (MLH1), a key component of the DNA mismatch repair system, is silenced by promoter methylation in TS1 cells. By means of stable ectopic expression and RNA interference methods, we showed that the high frequencies of growth factor-independent and inhibitor-resistant cells with activating JAK mutations can be attributed to the absence of MLH1 expression. In the second part of this paper, we confirm the clinical relevance of our findings by showing that chronic myeloid leukemia relapses upon ABL-targeted therapy correlated with a lower expression of MLH1 messenger RNA. Interestingly, the mutational profile observed in our TS1 model, characterized by a strong predominance of T:A〉C:G transitions, was identical to the one described in the literature for primitive cells derived from chronic myeloid leukemia patients. Taken together, our observations demonstrate for the first time a causal relationship between MLH1-deficiency and incidence of oncogenic point mutations in tyrosine kinases driving cell transformation and acquired resistance to kinase-targeted cancer therapies.

Description: Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.

Description: Atrazine is one of the most widely applied and persistent herbicides in the world. In view of limited information on the regional contamination of atrazine in soils in China, this study investigated the spatial distribution and environmental impacts of atrazine in agricultural soils collected from the Yangtze River Delta (YRD) as an illustrative analysis of rapidly developing regions in the country. The results showed that the concentrations of atrazine in the YRD agricultural soils ranged from 〈1.0 to 113 ng/g dry weight, with a mean of 5.7 ng/g, and a detection rate of 57.7 % in soils. Pesticide factory might be a major source for the elevated levels of atrazine in Zhejiang Province. The contamination of atrazine was closely associated with land use types. The concentrations and detection rates of atrazine were higher in corn fields and mulberry fields than in rice paddy fields. There was no significant difference in compositions of soil microbial phospholipids fatty acids among the areas with different atrazine levels. Positive relationship ( R  = 0.417, p  〈 0.05, n  = 30) was observed between atrazine and total microbial biomass. However, other factors, such as soil type and land management practice, might have stronger influences on soil microbial communities. Human health risks via exposure to atrazine in soils were estimated according to the methods recommended by the US EPA. Atrazine by itself in all the soil samples imposed very low carcinogenic risks (〈10 −6 ) and minimal non-cancer risks (hazard index 〈1) to adults and children.

Description: The widespread use of high-throughput genome sequencing methods is profoundly changing the way we understand, classify, and treat human cancers. To make sense of the deluge of sequencing data generated in the clinic, more effective and rapid assessments of the functional relevance of newly discovered cancer-associated mutations are urgently needed. In this review, we discuss how genome editing technologies are responding to this major challenge. Largely focusing on CRISPR-based methods, we will highlight their potential to accelerate discovery, discuss their current limitations, and speculate about future applications.

Description: Objective This work describes a phantom containing regions of controlled R 2* (1/ T 2*) values to provide a stable reference object for testing implementations of R 2* relaxometry commonly used for liver and heart iron assessments. Materials and methods A carrageenan-strengthened gadolinium DTPA doped agarose gel was used to enclose nine gels additionally doped with ultra-small superparamagnetic iron oxide. R 2* values were determined at 1.5 T using multi-echo GRE sequences and exponential regression of pixel values from a region of interest against echo time using non-linear regression algorithms. We measured R 2*, R 2 and R 1 values and the inter-scan and inter-operator reproducibility. Results The phantom reliably demonstrated R 2* values in seven steps between 22.4 s −1 (SE 1.98) and 441.9 s −1 (SE 6.76), with an R 2* relaxivity ( r 2*) of 792 (SE 5.6) mM −1  s −1 . The doped gels displayed a concentration-dependent R 2ʹ component of R 2* phantom, indicating superparamagnetic enhancement effects. We observed no significant change in relaxivity ( r 2*) over 12 months, and estimate a useful life of 3 years. Detailed descriptions of the production process and calculators are been provided as Online Resources. Conclusion The phantom provides a durable test object with controlled R 2* relaxation behaviour, useful for a range of R 2* relaxometry reference work.

Description: Primary cilium is a cellular antenna, signalling as a sensory organelle. Numerous pathological manifestation is associated with change of its length. Although the interaction between autophagy and primary cilia has been suggested, the role of autophagy in primary cilia length is largely unknown. In this study the primary cilia were immunostained and observed by using confocal fluorescence microscopy, and we found that silibinin, a natural flavonoid, shortened the length of primary cilia, meanwhile it also induced autophagy in 3T3-L1 cells. This study was designed to investigate the significance of silibinin-induced autophagy in primary ciliary structure in confluent mouse embryo fibroblast 3T3-L1 cells. Either blocking the autophagic flux with pre-treatment with the autophagy inhibitor, 3-methyladenine (3-MA), or transfection of siRNA targeting LC3 inhibited the reduction of cilia length caused by silibinin exposure. Autophagy induced by silibinin decreased expressions of the cilia-associated proteins, such as IFT88, KIF3a and Ac-tubulin, while 3-MA restored it, indicating that autophagy induced by silibinin led to a reduction of primary cilia length. Histone deacetylase 6 (HDAC6), which was suggested as a mediator of autophagy, was up-regulated by silibinin in a time-dependent manner. In addition, 3T3-L1 cells treated with siRNA against HDAC6 had a reduced autophagic level and were protected from silibinin-induced cilia shortening. Taken together, we conclude that the HDAC6-mediated autophagy negatively regulates primary cilia length during silibinin treatment and has the potential to serve as a therapeutic target for primary cilia-associated ciliopathies. These findings thus provide new information about the potential link between autophagy and primary cilia.

Description: Parkinson’s disease (PD) can degenerate dopaminergic (DA) neurons in midbrain, substantia-nigra pars compacta . Alleviation of its symptoms and protection of normal neurons against degeneration are the main aspects of researches to establish novel therapeutic strategies. PPARγ as a member of PPARs have shown neuroprotection in a number of neurodegenerative disorders such as Alzheimer’s disease and PD. Nuclear receptor related 1 protein (Nurr1) is, respectively, member of NR4A family and has received great attentions as potential target for development, maintenance, and survival of DA neurons. Based on neuroprotective effects of PPARγ and dual role of Nurr1 in anti-inflammatory pathways and development of DA neurons, we hypothesize that PPARγ and Nurr1 agonists alone and in combined form can be targets for neuroprotective therapeutic development for PD in vitro model. 1-Methyl-4-phenylpyridinium (MPP + ) induced neurotoxicity in PC12 cells as an in vitro model for PD studies. Treatment/cotreatment with PPARγ and Nurr1 agonists 24 h prior to MPP + induction enhanced the viability of PC12 cell. The viability of PC12 cells was determined by MTS test. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) were detected by flow cytometry. In addition, the relative expression of four genes including TH (the marker of DA neurons) , Ephrin A1, Nurr1, and Ferritin light chain were assessed by RT-qPCR. In the MPP + -pretreated PC12 cells, PPARγ and Nurr1 agonists and their combined form resulted in a decrease in the cell death rate. Moreover, production of intracellular ROS and MMP modulated by MPP + was decreased by PPARγ and Nurr1 agonists’ treatment alone and in the combined form.

Description: The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance along with obesity. 6,7-dimethylesculetin (DE) is an active component of Yin Zhi Huang which is a traditional Asian medicine used to treat neonatal jaundice via CAR. In this study, we examined whether DE could affect the expression of gluconeogenic and lipogenic genes via human CAR pathway using human HepG2 cells in vitro. We also studied whether DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in high-fat diet (HFD)-induced obese pregnant mice. Dimethylesculetin suppressed the mRNA expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and lipogenic genes, sterol regulatory element-binding protein 1 and stearoyl-CoA desaturase 1, and enhanced CAR-mediated transcription. Blocking the CAR-mediated pathway abolished the effect of DE in vitro. DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in HFD-induced obese pregnant mice in vivo. Our data indicate that DE might be a potential therapeutic agent for obese pregnant patients with insulin resistance through CAR to prevent the perinatal outcomes such as preeclampsia, gestational diabetes, and macrosomia. Further analysis of possible complications and side effects using animal models is required.

Description: Vascular dysfunction including vascular remodeling and endothelial dysfunction in hypertension often results in poor clinical outcomes and increased risk of vascular accidents. We investigate the effect of treatment with soluble receptor for advanced glycation end products (sRAGE) on vascular dysfunction in spontaneously hypertensive rats (SHR). Firstly, the aortic AGE/RAGE pathway was investigated in SHR. Secondly, SHR received intraperitoneal injections of sRAGE daily for 4 weeks. Effect of sRAGE against vascular dysfunction in SHR and underlying mechanism was investigated. SHR aortas exhibited enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE. Treatment of SHR with sRAGE had no significant effect on blood pressure, but alleviated aortic hypertrophy and endothelial dysfunction. In vitro, treatment with sRAGE reversed the effect of incubation with AGE on proliferation of smooth muscle cells and endothelial function. Treatment of SHR with sRAGE abated oxidative stress, suppressed inflammation and NF-κB activation, improved the balance between Ang II and Ang-(1-7) through reducing angiotensin-converting enzyme (ACE) activity and enhancing ACE2 expression, and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in aortas. In conclusion, treatment with sRAGE alleviated vascular adverse remodeling in SHR, possibly via suppression of oxidative stress and inflammation, improvement in RAS balance, and activation of PPAR-γ pathway.

Description: The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight ( P  〈 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy.

Description: Hydrogen peroxide is often required in sublethal, millimolar concentrations to show its oxidant effects on cells in culture as it is easily destroyed by cellular catalase. Previously, we had shown that diperoxovanadate, a physiologically stable peroxovanadium compound, can substitute H 2 O 2 effectively in peroxidation reactions. We report here that peroxovanadate when anchored to polyacrylic acid (PAPV) becomes a highly potent inhibitor of growth of lung carcinoma cells (A549). The early events associated with PAPV treatment included cytoskeletal modifications, increase in GTPase activity of Rac1, accumulation of the reactive oxygen species, and also increase in phosphorylation of H2AX (γH2AX), a marker of DNA damage. These effects persisted even at 24 h after removal of the compound and culminated in increased levels of p53 and p21 together with growth arrest. The PAPV-mediated growth arrest was significantly abrogated in cells pre-treated with the N-acetylcysteine, Rac1 knocked down by siRNA and DPI an inhibitor of NADPH oxidase. In conclusion, our results show that polyacrylate derivative of peroxovanadate efficiently arrests growth of A549 cancerous cells by activating the axis of Rac1-NADPH oxidase leading to oxidative stress and DNA damage. Graphical Abstract

Description: Demand side management is a promising approach towards the integration of renewable energy sources in the electric grid, which does not require massive infrastructural investments. In this paper, we report the analysis of the performance of a demand side management algorithm for the control of electric boilers, developed within the context of the GridSense project. GridSense is a multi-objective energy management system that aims at decreasing both the end user energy costs and the congestions on the local feeder. The latter objective is minimized exploiting the existent correlation between the voltage measured at the connection point to the grid and the power flow measured at the low voltage transformer. The algorithm behavior has been firstly investigated by means of simulation, using typical water consumption profiles and a simplified thermodynamic model of the electric boiler. The simulation results show that the algorithm can effectively shift the boiler’s electric consumption based on voltage and price profiles. In the second phase, we analyzed the results from a pilot project, in which the GridSense units were controlling the boilers of four households, located in the same low voltage grid.

Description: Fluid–structure interaction (FSI) phenomena are of interest in several engineering fields. It is highly desirable to develop computationally efficient models to predict the dynamics of FSI. The complexity of modeling lies in the highly non-linear response of both the fluid and structure. The current study proposes an overall model containing two blocks corresponding to a force model and a structural model. The force model consists of two submodels: one for the amplitude and one for the frequency, where the latter is composed of an input/output linear model and a non-linear corrector. The amplitude submodel and the non-linear corrector term in the frequency submodel are modeled using an Hammerstein–Wiener modeling technique in which the non-linear input and output functions are determined by training neural networks using a training dataset. The current model is tested on a well-known fluid–structure interaction problem: a suspended rigid cylinder immersed in a flow at a low Reynolds number regime that exhibits a non-linear behavior. First, a training dataset is generated for a given input profile using a high-fidelity numerical simulation and it is used to train the reduced-order model. Subsequently, the trained model is given a different input profile (i.e., a validation profile) to compare its predictive capability against the high-fidelity numerical simulation. The validation profile is significantly different from the one used for training. The predictive performance of the current reduced-order model is further compared with the results obtained from a reduced-order model that uses polynomial fitting. We demonstrate that the current model provides a superior performance for the validation profile, i.e., it results in a better prediction.

Description: Gabbroic rocks have intruded the sedimentary sequence at Ameta in Afikpo basin southeastern Nigeria. Petrographic and geochemical features of the rocks were studied in order to evaluate their genetic and geotectonic history. The petrographic results show that the rocks contain plagioclase, olivine, pyroxene, biotite, iron oxide, and traces of quartz in three samples. Major element characteristics show that the rocks are subalkaline. In addition, the rocks have geochemical characteristics similar to basaltic andesites. The trace elements results show inconsistent concentrations of high field strength elements (Zr, Nb, Th, Ta), moderate enrichment of large-ion lithophile elements (Rb, Sr, Ba) and low concentrations of Ni and Cr. Rare earth element results show that the rocks are characterized by enrichment of light rare earth elements, middle rare earth elements enrichment, and depletion of heavy rare earth elements with slight positive europium anomalies. Zinc concentrations are within the normal range in basaltic rocks. There are extremely high concentrations of Pb in three of the rock samples. The high Pb concentrations in some of these rocks could be as a result of last episodes of magmatic crystallization. The rocks intruded the Asu River Group; organic components in the sedimentary sequence probably contain Pb which has been assimilated into the magma at the evolutionary stage of the magma. Weathering of some rocks that contain galena could lead to an increase in the concentration of lead in the gabbroic rocks, especially when the migration and crystallization of magma take place in an aqueous environment. Nevertheless, high concentration of lead is hazardous to health and environment.

Description: Widespread potential dietary deficiencies of calcium (Ca), iron (Fe), iodine (I), selenium (Se) and zinc (Zn) have been identified in Malawi. Several deficiencies are likely to be compounded by high phytic acid (PA) consumption. Rice ( Oryza sativa ) is commonly consumed in some Malawian populations, and its mineral micronutrient content is important for food security. The considerable irrigation requirements and flooded conditions of paddy soils can also introduce or mobilise potentially toxic elements including arsenic (As), cadmium (Cd) and lead (Pb). The aim of this study was to determine the mineral composition of rice sampled from farmers’ fields and markets in Malawi. Rice was sampled from 18 extension planning areas across Malawi with 21 white (i.e. polished) and 33 brown samples collected. Elemental composition was determined by inductively coupled plasma-mass spectrometry (ICP-MS). Arsenic speciation was performed using high-performance liquid chromatography (HPLC)-ICP-MS. Concentration of PA was determined using a PA-total phosphorus assay. Median total concentrations (mg kg −1 , dry weight) of elements important for human nutrition in brown and white rice, respectively, were: Ca = 66.5 and 37.8; Cu = 3.65 and 2.49; Fe = 22.1 and 7.2; I = 0.006 and 〈0.005; Mg = 1130 and 265; Mn = 18.2 and 9.6; Se = 0.025 and 0.028; and Zn = 17.0 and 14.4. In brown and white rice samples, respectively, median PA concentrations were 5438 and 1906 mg kg −1 , and median PA:Zn molar ratios were 29 and 13. Concentrations of potentially toxic elements (mg kg −1 , dry weight) in brown and white rice samples, respectively, were: As = 0.030 and 0.006; Cd  ≤ 0.002 and 0.006; Pb = 0.008 and 0.008. Approximately 95 % of As was found to be inorganic As, where this could be quantified. Malawian rice, like the more widely consumed staple grain maize, contains inadequate Ca, I, Se or Zn to meet dietary requirements. Biofortification strategies could significantly increase Se and Zn concentrations and require further investigation. Concentrations of Fe in rice grain varied greatly, and this was likely due to contamination of rice samples with soil. Risk of As, Cd or Pb toxicity due to rice consumption in Malawi appears to be minimal.

Description: Purpose Up to 30–40 % of the major depressive disorder patients do not respond sufficiently to antidepressant treatment. Genetic variations in the serotonin transporter gene have been implicated in modulating treatment response to selective serotonin reuptake inhibitors, and this association is influenced by ethnicity. We investigated the influence of serotonin transporter gene variants 5-HTTLPR and rs25531 in Indian population on fluoxetine response. Methods One hundred and two major depressive disorder patients were started on fluoxetine treatment and after 6 weeks, classified as responders ( n  = 56) and non-responders ( n  = 46) using Hamilton depression rating scale and genotyped. Fisher’s exact test was used to compare genotype frequencies between responders and non-responders. One-way analysis of variance and student t test were used to compare the percentage reduction (week 0–6) in Hamilton depression rating scores between genotype and haplotype groups. Results We observed a significant association between LL genotype of 5-HTTLPR and fluoxetine treatment response ( p  = 0.0066, OR (95 %) = 4.0 (1.45–11.03)) but not with the functional groups of 5-HTTLPR –rs25531 . However, there was a significant difference in percentage reduction in HAM-D scores (week 0–6) between 5-HTTLPR genotypes (LL vs. LS + SS, p  = 0.0036; LL vs. LS, p  = 0.0109) as well as the functionally grouped haplotypes of 5-HTTLPR –rs25531 (L A L A carriers vs. non-carriers of L A L A , p  = 0.0118; L A L A vs. L A S+ L A L G , p  = 0.0419). Conclusion The LL genotype and L A L A haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in south Indian major depression patients.

Description: Aim To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. Methods Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity. Results The volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66 ± 1.65 vs. 9.25 ± 1.92, P  = 0.008 and 15.66 ± 1.65 vs. 8.21 ± 1.74, P  = 0.006, respectively). POR rs2868177 (6593 A 〉 G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13 ± 1.37 vs. 12.15 ± 2.97, P  = 0.005 and 8.13 ± 1.37 vs. 17.59 ± 3.25, P  = 0.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40 ± 2.01 vs. 12.40 ± 1.45, P  = 0.006 and 10.65 ± 1.47 vs. 6.54 ± 1.25, P  = 0.004, respectively). Meanwhile, a strong correlation between the genetic variations ( POR rs2868177 and CYP2B6*6 ) and AUC_hyd/ AUC_bup was found ( P  = 0.009 and P  = 0.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes ( P  〉 0.05) . Conclusion POR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.

Description: Purpose We systematically reviewed published observational studies and randomized controlled trials (RCT) reports of clinical trials on erythropoiesis-stimulating agents (ESA’s). Only studies evaluating the risk of developing anti-drug antibodies (ADA) of both original and biosimilar drugs were chosen. Methods Databases including PubMed, EMBASE and Cochrane Library were searched up to 17 March 2015. Two reviewers independently assessed the relevant studies for risk of bias. Results Twenty-one publications were included. The overall prevalence of ADA in the studies was about 0.2 to 0.5 %. Most studies were not designed to monitor the development of ADA and often the study duration was too short (less than 6 months) and the patient population too small. Moreover, in many studies, the assays used only determined the presence of ADA and did not measure therapy failure due to ADA. In one RCT, as many as 13 cases (4 %) of ADA were identified. Conclusion ADA development seems to be low in short-term studies with ESA. None of the efficacy and safety issues for ESA biosimilars were judged to be adequately addressed in the evaluated literature, with respect to ADA formation, due to the study design and the assay method used.

Description: Purpose To investigate the mechanistic effects of combined exposure to caffeine and catechins on lipid metabolism in mice. Methods Seventy mice were randomly assigned to seven groups and fed diets containing varying doses of caffeine and catechins for 24 weeks. Body weight gain, intraperitoneal adipose tissue (IPAT) weight, serum biochemical parameters, and enzymatic activities, mRNA and protein expression levels of lipid metabolism-related enzymes in the liver and IPAT were analyzed. Results Following administration of caffeine and catechins, body weight gain, IPAT weight, serum and liver concentrations of total cholesterol and triglyceride were markedly reduced. Lipase activities, including that of AMP-activated protein kinase (AMPK), acyl-CoA oxidase, carnitine acyltransferase, adipose triglyceride lipase, and hormone-sensitive lipase, were significantly upregulated; however, fatty acid synthase (FAS) activity in the liver was suppressed. Combined exposure to caffeine and catechins significantly upregulated mRNA and protein expression levels of lipases while downregulating FAS mRNA expression and protein expression of peroxisome proliferator-activated receptor γ2. Conclusions The combination of caffeine and catechins regulated the enzymatic activities, mRNA, and protein expression levels of lipid metabolism-related enzymes, resulting in suppression of body weight gain and IPAT weight in mice, potentially through activation of the AMPK signaling pathway. This study indicates that chronic intake of both caffeine and catechins can synergistically contribute to prevention of obesity and lifestyle-related diseases.

Description: Interval graphs are intersection graphs of closed intervals of the real-line. The well-known computational problem, called recognition , asks whether an input graph G can be represented by closed intervals, i.e., whether G is an interval graph. There are several linear-time algorithms known for recognizing interval graphs, the oldest one is by Booth and Lueker (J Comput Syst Sci 13:335–379, 1976 ) based on PQ-trees. In this paper, we study a generalization of recognition, called partial representation extension . The input of this problem consists of a graph G with a partial representation \({{{\mathcal {R}}}}'\) fixing the positions of some intervals. The problem asks whether it is possible to place the remaining interval and create an interval representation \({{{\mathcal {R}}}}\) of the entire graph G extending \({{{\mathcal {R}}}}'\) . We generalize the characterization of interval graphs by Fulkerson and Gross (Pac J Math 15:835–855, 1965 ) to extendible partial representations. Using it, we give a linear-time algorithm for partial representation extension based on a reordering problem of PQ-trees.

Description: Smart grid applications are going to reach the low voltage grid assets and households in order to efficiently use the resources in electrical distribution grids. A cost effective way to connect these devices is to utilize the existing network infrastructure or Power-Line Communication (PLC). In this work, we illustrate the impact of changing communication properties on a power balancing controller used to support frequency control in the setting of a microgrid. More specifically, we focus on PLC communication and show how time-varying delays can affect the control algorithm performance. Further, we propose and compare two different delay estimation techniques and demonstrate how the control algorithm can use this information to adapt its gains - yielding significantly better control performance, compared to the controller using static gains.

Description: The secretion of osteocalcin (OCN) is an excellent differentiation marker for the osteogenic differentiation. This study investigated the secretion of OCN during the osteogenic differentiation of DFCs. During the differentiation of DFCs the extracellular concentrations of OCN were higher in standard cell culture medium than in osteogenic differentiation medium. However, after 4 weeks in the osteogenic differentiation medium the extracellular OCN concentration decreased strongly, whereas the concentration remains high in the control medium. At this point in time DFCs formed connective tissue like structures with mineralized clusters and OCN. Real-time RT-PCR analyses and western-blot analyses proved that OCN was expressed in both cell culture media. However, the expression of the mRNA was inhibited in the osteogenic differentiation medium. These results suggest that DFCs secrete constitutively OCN into the cell culture medium and that the osteogenic differentiation medium suppresses the gene expression of OCN. Moreover, OCN imbeds into the extracellular matrix after the formation of connective tissue like structures, and the soluble OCN in the cell culture medium disappears. Hence, extracellular OCN in the cell culture medium is not a marker for the osteogenic differentiation of DFCs.

Description: There is no uniform approach in the literature for modelling sequential correlations in sequence classification problems. It is easy to find examples of unstructured models ( e.g.  logistic regression) where correlations are not taken into account at all, but there are also many examples where the correlations are explicitly incorporated into a—potentially computationally expensive—structured classification model ( e.g.  conditional random fields). In this paper we lay theoretical and empirical foundations for clarifying the types of problem which necessitate direct modelling of correlations in sequences, and the types of problem where unstructured models that capture sequential aspects solely through features are sufficient. The theoretical work in this paper shows that the rate of decay of auto-correlations within a sequence is related to the excess classification risk that is incurred by ignoring the structural aspect of the data. This is an intuitively appealing result, demonstrating the intimate link between the auto-correlations and excess classification risk. Drawing directly on this theory, we develop well-founded visual analytics tools that can be applied a priori on data sequences and we demonstrate how these tools can guide practitioners in specifying feature representations based on auto-correlation profiles. Empirical analysis is performed on three sequential datasets. With baseline feature templates, structured and unstructured models achieve similar performance, indicating no initial preference for either model. We then apply the visual analytics tools to the datasets, and show that classification performance in all cases is improved over baseline results when our tools are involved in defining feature representations.

Description: Polymorphic major histocompatibility complex (MHC) molecules play a central role in the vertebrate adaptive immune system. By presenting short peptides derived from pathogen-derived proteins, these “classical” MHC molecules can alert the T cell branch of the immune system of infected cells and clear the pathogen. There exist other “non-classical” MHC molecules, which while similar in structure to classical MHC proteins, are contrasted by their limited polymorphism. While the functions of many class Ib MHC molecules have still to be elucidated, the nature and diversity of antigens (if any) that some of them might present to the immune system is expected to be more restricted and might function as another approach to distinguish self from non-self. The MHC-related 1 (MR1) molecule is a member of this family of non-classical MHC proteins. It was recently shown to present unique antigens in the form of vitamin metabolites found in certain microbes. MR1 is strongly conserved genetically, structurally, and functionally through mammalian evolution, indicating its necessity in ensuring an effective immune system for members of this class. Although MR1 will be celebrating 21 years this year since its discovery, most of our understanding of how this molecule functions has only been uncovered in the past decade. Herein, we discuss where MR1 is expressed, how it selectively is able to bind to its appropriate antigens and how it, then, is able to specifically activate a distinct population of T cells.

Description: Business Process flexibility supports organizations in changing their everyday work activities to remain competitive. Since much research has been done on this topic a better awareness on the current state of knowledge is needed. This paper reports the results of a systematic literature review to develop a map on Business Process flexibility with a special focus on software systems related aspects. It covers a spectrum of the state of the art from academic point of view. It includes 164 research works from the main computer science digital libraries. After an introduction into the topic the applied methodology is described. The output of the paper is in the form of schemes and reflections. Starting from the needs for Business Process flexibility, its impact on Business Process life-cycle is introduced. Successively instruments used to express and to support Business Process flexibility are presented together with related validation scenarios. In this paper we also highlight possible future research lines needing further investigations. In particular we identified room for future works in the area of languages for modeling flexibility, on-the-fly verification solutions, adaptation of Business Process running instances, and techniques for evolution recognition.

Description: One of the biggest obstacles to software reuse is the cost involved in evaluating the suitability of possible reusable components. In recent years, code search engines have made significant progress in establishing the semantic suitability of components for new usage scenarios, but the problem of ranking components according to their non-functional suitability has largely been neglected. The main difficulty is that a component’s non-functional suitability for a specific reuse scenario is usually influenced by multiple, “soft” criteria, but the relative weighting of metrics for these criteria is rarely known quantitatively. What is required, therefore, is an effective and reliable strategy for ranking software components based on their non-functional properties without requiring users to provide quantitative weighting information. In this paper we present a novel approach for achieving this based on the non-dominated sorting of components driven by a specification of the relative importance of non-functional properties as a partial ordering. After describing the ranking algorithm and its implementation in a component search engine, we provide an explorative study of its properties on a sample set of components harvested from Maven Central.

Description: Government legislation and calls for greater levels of oversight and transparency are leading public bodies to publish their raw datasets online. Policy makers and elected officials anticipate that the accessibility of open data through online Government portals for citizens will enable public engagement in policy making through increased levels of fact based content elicited from open data. The usability and benefits of such open data are being argued as contributing positively towards public sector reforms, which are under extreme pressures driven by extended periods of austerity. However, there is very limited scholarly studies that have attempted to empirically evaluate the performance of government open data websites and the acceptance and use of these data from a citizen perspective. Given this research void, an adjusted diffusion of innovation model based on Rogers’ diffusion of innovations theory (DOI) is proposed and used in this paper to empirically determine the predictors influencing the use of public sector open data. A good understanding of these predictors affecting the acceptance and use of open data will likely assist policy makers and public administrations in determining the policy instruments that can increase the acceptance and use of open data through an active promotion campaign to engage-contribute-use .

Description: Purpose Recurrent ischemic events in Chinese patients with symptomatic extracranial or intracranial stenosis caused by aspirin or clopidogrel resistance are well known. We aimed to identify the contribution of genetic variants to the events. Methods Patients with symptomatic extracranial or intracranial stenosis receiving dual antiplatelet treatment for at least 5 days were enrolled in this study. The primary endpoint was a composite of ischemic events, including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality. Twenty-four single nucleotide polymorphisms (SNPs) were assessed and genotyped. The clinical characteristics of enrolled patients were collected from medical records. The influence of genetic polymorphisms on the recurrent ischemic events of the patients was examined. Results A total of 377 patients were included. During a 12-month follow-up, the composite primary endpoint was observed in 64 patients. The CYP2C19*3 (rs4986893) may increase the occurrence of the primary composite endpoint (OR = 2.56, 95 % CI = 1.29–5.10, P  = 0.007), and the mutation of CES1 rs8192950 was associated with the decreased recurrence of ischemic events (OR = 0.53, 95 % CI = 0.30–0.94, P  = 0.029). The other SNPs that were tested did not have statistically significant associations with the composite endpoint. Conclusions For Chinese patients with symptomatic extracranial or intracranial stenosis treated with clopidogrel, CYP2C19*3 mutation was associated with an increased risk of ischemic events, and the mutation of rs8192950 in CES1 is associated with a decreased risk of recurrent ischemic events. Testing these two SNPs could be of value in the identification of patients at risk for recurrent ischemic events.

Description: As the adoption of sensing and control networks rises to encompass the most diverse fields, the need for simple, efficient interconnection between many different devices will become ever more pressing. Though ...

Description: In real-time data-intensive multimedia processing applications, data transfer and storage significantly influence, if not dominate, all the major cost parameters of the design space—namely energy consumption, ...

Description: We survey genetic improvement (GI) of general purpose computing on graphics cards. We summarise several experiments which demonstrate four themes. Experiments with the gzip program show that genetic programming can automatically port sequential C code to parallel code. Experiments with the StereoCamera program show that GI can upgrade legacy parallel code for new hardware and software. Experiments with NiftyReg and BarraCUDA show that GI can make substantial improvements to current parallel CUDA applications. Finally, experiments with the pknotsRG program show that with semi-automated approaches, enormous speed ups can sometimes be had by growing and grafting new code with genetic programming in combination with human input.

Description: CD1 genes encode cell surface molecules that present lipid antigens to various kinds of T lymphocytes of the immune system. The structures of CD1 genes and molecules are like the major histocompatibility complex (MHC) class I system, the loading of antigen and the tissue distribution for CD1 molecules are like those in the class II system, and phylogenetic analyses place CD1 between class I and class II sequences, altogether leading to the notion that CD1 is a third ancient system of antigen presentation molecules. However, thus far, CD1 genes have only been described in mammals, birds and reptiles, leaving major questions as to their origin and evolution. In this review, we recount a little history of the field so far and then consider what has been learned about the structure and functional attributes of CD1 genes and molecules in marsupials, birds and reptiles. We describe the central conundrum of CD1 evolution, the genomic location of CD1 genes in the MHC and/or MHC paralogous regions in different animals, considering the three models of evolutionary history that have been proposed. We describe the natural killer (NK) receptors NKR-P1 and ligands, also found in different genomic locations for different animals. We discuss the consequence of these three models, one of which includes the repudiation of a guiding principle for the last 20 years, that two rounds of genome-wide duplication at the base of the vertebrates provided the extra MHC genes necessary for the emergence of adaptive immune system of jawed vertebrates.

Description: Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant αβ T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling. During infection, experimental evidence suggests that both TCR-driven and cytokine-driven mechanisms contribute to iNKT cell activation. While the relative contributions of these two signaling mechanisms can vary widely depending on the infectious context, both lipid antigens and PAMPs mediate reciprocal activation of iNKT cells and APCs, leading to downstream activation of multiple other immune cell types to promote pathogen clearance. In this review, we discuss the mechanisms involved in iNKT cell activation during infection, focusing on the central contributions of both lipid antigens and PAMP-induced inflammatory cytokines, and highlight in vivo examples of activation during bacterial, viral, and fungal infections.

Description: Purpose The effects of nonhormonal drugs on menopausal hot flashes are still not well quantified. We therefore did a model-based meta-analysis (MBMA) to quantitate and compare the efficacy features of nonhormonal drugs on menopausal hot flashes. Methods Literature was searched in the public databases to extract data of clinical trials on nonhormonal drugs, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), gabapentin, clonidine, and soy isoflavones. Pharmacodynamic models were used for the quantitative analysis of each drug. Results Thirty-nine studies were included in the analysis. The results revealed a classic pharmacodynamic maximal effect (E max ) model could describe the time course of hot-flash reduction by nonhormonal drugs. After deducting placebo effects, the E max of SSRIs/SNRIs, gabapentin, clonidine, and soy isoflavones was 13.9 %, 14.8 %, 18.5 %, and 25.0 %, respectively. The time to achieve half of the maximal effect (ET 50 ) of SSRIs/SNRIs, gabapentin, clonidine, and soy isoflavones was 0.18 weeks, 0 weeks, 0 weeks, and 11.6 weeks, respectively. The results showed that SSRIs/SNRIs, gabapentin, and clonidine had a rapid onset, which could reach the maximum effect immediately. However, the onset of soy isoflavones was very slow, and a duration of 16.6 weeks was needed to surpass the efficacy of paroxetine (a type of SSRIs). Conclusions The information provided in this study can be used as valuable supplementary information for treatment guidelines of nonhormonal drugs on menopausal hot flashes.

Description: Background Our previous study showed that fatty acids extract obtained from CLA-enriched egg yolks (EFA-CLA) suppressed the viability of MCF-7 cancer cell line more effectively than extract from non-enriched egg yolks (EFA). In this study, we analysed the effect of EFA-CLA and EFA on transcriptome profile of MCF-7 cells by applying the whole Human Genome Microarray technology. Results We found that EFA-CLA and EFA treated cells differentially regulated genes involved in cancer development and progression. EFA-CLA, compared to EFA, positively increased the mRNA expression of TSC2 and PTEN tumor suppressors as well as decreased the expression of NOTCH1 , AGPS , GNA12 , STAT3 , UCP2 , HIGD2A , HIF1A , PPKAR1A oncogenes. Conclusions We show for the first time that EFA-CLA can regulate genes engaged in AKT/mTOR pathway and inhibiting cell cycle progression. The observed results are most likely achieved by the combined effect of both: incorporated CLA isomers and other fatty acids in eggs organically modified through hens’ diet. Our results suggest that CLA-enriched eggs could be easily available food products with a potential of a cancer chemopreventive agent.

Description: The moment of MR1 discovery is described. The MR1 gene is the first and the last reported human MHC-related gene intentionally isolated from the human genome composed of three billion base pairs. Evolutionary considerations formed the basis of its isolation. Some details surrounding the moment and some retrospective descriptions with various kinds of encounters are also included.

Description: In this paper, we present a new method for adaptive all-quadrilateral mesh generation for two-dimensional domains, including domains modeled by constraints with complex geometry or with varying scales. The method subdivides the domain’s bounding box using a new extended quadtree scheme. In this subdivision process, the quadtree node corners are moved onto the geometrical constraints using local deformation criteria during the tree refinement steps. We define new subdivision patterns as part of our extended quadtree to add flexibility in the adaptation and guarantee that geometrical constraints are entirely modeled by tree edges. During the process, we ensure grid alignment with constraint accuracy and element quality at every scale. Our proposal converts the tree structure into a mesh with only quadrilateral elements. Results showed that our method generates elements of reasonable quality even for complex geometries and varying scales. The small number of parameters controlling the process is intuitive and makes our method efficient and user friendly.

Description: Large scale social events that involve violence may have dramatic political, economic and social consequences. These events may result in higher crime rates, spreading of infectious diseases, economic crises, ...

Description: Online social systems are multiplex in nature as multiple links may exist between the same two users across different social media. In this work, we study the geo-social properties of multiplex links, spanning...

Description: Purpose Depression is a major public health issue because it is a common cause of disability worldwide. It has been suggested that an optimal vitamin D status may be related to fewer depressive symptoms, but findings are inconsistent. We aimed to investigate the association between plasma vitamin D at midlife and recurrent depressive symptoms and to test for a modulating effect by overall dietary quality. Methods The relationship between plasma 25-hydroxyvitamin D (25(OH)D) and recurrent depressive symptoms was evaluated among 1196 participants of the Supplémentation en Vitamines et Minéraux Antioxydants cohort with available data on the Center for Epidemiologic Studies-Depression Scale (CES-D) at baseline (1996–1997) and follow-up (2007–2009). Recurrent depressive symptoms were defined as a CES-D score ≥16 at baseline and follow-up. Prevalence ratios (PR) and 95 % confidence intervals (95 %-CI) were estimated using extensively adjusted Poisson regression models. Dietary quality was estimated using an index measuring adherence to the French national recommendations. Results Having 25(OH)D concentrations above 10 ng/mL was related to a lower probability of recurrent depressive symptoms: PR (95 %-CI) = 0.48 (0.33; 0.69); P  〈 0.0001). When comparing individuals with concentrations 〈 versus ≥20 or 〈 versus ≥30 ng/mL, no significant results were obtained. In contrast, among individuals with low dietary quality, a better vitamin D status was related to a lower probability of recurrent depressive symptoms independently of the applied cutoff. Conclusions Plasma vitamin D might have a preventive role against recurrent depressive symptoms, notably among individuals with poor dietary quality. Our findings are relevant for the development of depression prevention programs.

Description: This paper proposes a new method to build boundary layer meshes over an immersed complex geometry. It allows to generate an anisotropic semi-structured mesh with a smooth gradation of mesh size from a geometry immersed into an arbitrary coarse domain, while capturing and keeping the interface. The idea is to generate an a priori mesh fitting the geometry boundary layer which is ready for simulations. The mesh size distribution is driven by a levelset distance function and is determined using physical parameters available before the simulation, based on the boundary layer theory. The aspect ratio is then determined knowing the shape of the geometry, and all is applied in a metric tensor field using a gradation thanks to the new multi-levelset method. Then, the mesh generator adapt the initial mesh on the given metric field to create the desired boundary layer mesh.

Description: Purpose The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have both implemented procedures in order to shorten review time for marketing authorizations with potential therapeutic added value, called priority review and accelerated assessment procedure, respectively. The aim of this study is to compare the new molecular entities (NME) assessed in shorter review time by both agencies and to investigate whether granting a shorter review time status subsequently predicts its therapeutic value attributed by a health technology assessment agency, the French Haute Autorité de Santé (HAS). Methods All NME approved by the EMA and the FDA with a therapeutic added value between 2007 and June 30, 2015 were extracted. We assessed the sensibility, the positive predictive value, and the EMA review time. Results One hundred seventy-eight NME were approved by the FDA and the EMA and a therapeutic value was available for 160 NME. Eighty-eight (55.0 %) NME were on FDA priority review, 24 (15.0 %) on EMA accelerated procedure and 43 (26.9 %) were considered of high clinical added value. The sensibility was 86.0 % for the FDA and 30.2 % for the EMA. The positive predictive value was, respectively, 42.0 and 54.2 %. Twenty-five NME on FDA priority review and of high therapeutic added value were not on EMA accelerated assessment procedure, leading to a supplementary mean EMA review time of 146 days. Conclusion The EMA was restrictive to grant a shorten review time status for products with therapeutic interest during the study period.

Description: The P/Q-type voltage-dependent calcium channel (Cav2.1) in the presynaptic membranes of motor nerve terminals plays an important role in regulating Ca 2+ transport, resulting in transmitter release within the nervous system. The recovery of Ca 2+ -dependent signal transduction on motor end plates (MEPs) and innervated muscle may directly reflect nerve regeneration following peripheral nerve injury. Although the functional significance of calcium channels and the levels of Ca 2+ signalling in nerve regeneration are well documented, little is known about calcium channel expression and its relation with the dynamic Ca 2+ ion distribution at regenerating MEPs. In the present study, end-to-side neurorrhaphy (ESN) was performed as an in vivo model of peripheral nerve injury. The distribution of Ca 2+ at regenerating MEPs following ESN was first detected by time-of-flight secondary ion mass spectrometry, and the specific localization and expression of Cav2.1 channels were examined by confocal microscopy and western blotting. Compared with other fundamental ions, such as Na + and K + , dramatic changes in the Ca 2+ distribution were detected along with the progression of MEP regeneration. The re-establishment of Ca 2+ distribution and intensity were correlated with the functional recovery of muscle in ESN rats. Furthermore, the re-clustering of Cav2.1 channels after ESN at the nerve terminals corresponded with changes in the Ca 2+ distribution. These results indicated that renewal of the Cav2.1 distribution within the presynaptic nerve terminals may be necessary for initiating a proper Ca 2+ influx and shortening the latency of muscle contraction during nerve regeneration.

Description: Pigs share numerous physiological and phenotypic similarities with human and thus have been considered as a good model in nonrodent mammals for the study of genetic basis of human obesity. Researches on candidate genes for obesity traits have successfully identified some common genes between humans and pigs. However, few studies have assessed how many similarities exist between the genetic architecture of obesity in pigs and humans by large-scale comparative genomics. Here, we performed a genome-wide association study (GWAS) using the porcine 60 K SNP Beadchip for BMI and other four conformation traits at three different ages in a Chinese Laiwu pig population, which shows a large variability in fat deposition. In total, 35 SNPs were found to be significant at Bonferroni-corrected 5 % chromosome-wise level ( P  = 2.13 × 10 −5 ) and 88 SNPs had suggestive ( P  〈 10 −4 ) association with the conformation traits. Some SNPs showed age-dependent association. Intriguingly, out of 32 regions associated with BMI in pigs, 18 were homologous with the loci for BMI in humans. Furthermore, five closest genes to GWAS peaks including HIF1AN , SMYD3 , COX10 , SLMAP , and GBE1 have been already associated with BMI in humans, which makes them very promising candidates for these QTLs. The result of GO analysis provided strong support to the fact that mitochondria and synapse play important roles in obesity susceptibility, which is consistent with previous findings on human obesity, and it also implicated new gene sets related to chromatin modification and Ig-like C2-type 5 domain. Therefore, these results not only provide new insights into the genetic architecture of BMI in pigs but also highlight that humans and pigs share the significant overlap of obesity-related genes.

Description: In this paper, we investigate the coexistence of two technologies that have been put forward for the fifth generation (5G) of cellular networks, namely, network-assisted device-to-device (D2D) communications a...

Description: Purpose Zinc is essential for normal growth and metabolism. We aimed to characterise the total and bioavailable dietary zinc intake and plasma zinc concentrations in healthy children, longitudinally, and to examine the association between plasma zinc concentrations, dietary zinc intake and cardiometabolic markers in the same cohort. Methods A secondary data analysis of a prospective cohort study, the Nepean Longitudinal Study, which followed an Australian birth cohort at ages 8 ( n  = 436) and 15 years ( n  = 290) collecting dietary, anthropometry and biochemistry data (plasma zinc, fasting glucose, insulin and lipid profile). Diet was assessed by a 3-day food record and a food frequency questionnaire at 8 and 15 years, respectively. Zinc bioavailability was determined by the phytate/zinc molar ratio. Results At 8 years, the median zinc intake was 7.84 mg (interquartile range 6.57–9.35) for boys and 7.06 mg (5.98–8.30) for girls. Three of 345 children reported inadequate absorbable zinc intake, and none reported inadequate total zinc intake. At 15 years, median zinc intake was 11.8 mg (9.41–14.8) for boys and 8.54 mg (6.76–10.7) for girls. The prevalence of inadequate intakes of absorbable zinc and total zinc was 19 and 29 %, respectively. Plasma zinc concentration was not correlated with dietary zinc intake, adiposity nor lipids at either time point, but it was inversely correlated with fasting glucose at 8 year and with insulin at 15 years. Conclusions Australian children had an overall adequate zinc status. However, adolescents who reported suboptimal dietary zinc intakes were more likely to have raised insulin concentrations.

Description: Cognitive radio networks (CRN), in their quest to become the preferred next-generation wireless communication paradigm, will depend heavily on their ability to efficiently manage the limited resources at their...

Description: Improving energy efficiency and reducing energy wastage is an important topic of our time. But it is quite difficult to figure out how much of our total electricity bill can be mapped to which device or at wha...

Description: The role-based access control (RBAC) has significantly simplified the management of users and permissions in information systems. In dynamic environments, systems are constantly undergoing changes, and accordingly, the associated configurations need to be updated in order to reflect the systems’ security evolutions. However, such updating process is generally complicated as the resulting system state is expected to meet necessary constraints. This paper presents an approach for assisting administrators to make a desirable update, in light of changes in RBAC systems. We propose a formalization of the update approach, investigate its properties, and develop an updating algorithm based on model checking techniques. Our experimental results demonstrate the effectiveness of the proposed approach.

Description: Temporally uncertain data widely exist in many real-world applications. Temporal uncertainty can be caused by various reasons such as conflicting or missing event timestamps, network latency, granularity mismatch, synchronization problems, device precision limitations, data aggregation. In this paper, we propose an efficient algorithm to mine sequential patterns from data with temporal uncertainty. We propose an uncertain model in which timestamps are modeled by random variables and then design a new approach to manage temporal uncertainty. We integrate it into the pattern-growth sequential pattern mining algorithm to discover probabilistic frequent sequential patterns. Extensive experiments on both synthetic and real datasets prove that the proposed algorithm is both efficient and scalable.

Description: Coal-burning power plants supply approximately 37 % of the electricity in the United States. However, incomplete combustion produces ash wastes enriched with toxic trace elements that have historically been disposed of in aquatic basins. Organisms inhabiting such habitats may accumulate these trace elements; however, studies investigating the effects on biota have been primarily restricted to shorter-lived, lower-trophic organisms. The American alligator ( Alligator mississippiensis ), a long-lived, top-trophic carnivore, has been observed inhabiting these basins, yet the health or immune effects of chronic exposure and possible accumulation remains unknown. In this study, we investigated how chronic dietary ingestion of prey contaminated with coal combustion wastes (CCWs) for 25 months, and subsequent accumulation of trace elements present in CCWs, affected juvenile alligator immune function and health. Alligators were assigned to one of four dietary-treatment groups including controls and those fed prey contaminated with CCWs for one, two, or three times a week. However, no effect of Dietary Treatment ( p  〉 0.05) was observed on any immune parameter or hematological or plasma analyte we tested. Our results suggest that neither exposure to nor accumulation of low doses of CCWs had a negative effect on certain aspects of the immune and hematological system. However, future studies are required to elucidate this further.

Description: The aim of this study was to determine the levels of different inorganic elements (lead [Pb], mercury [Hg], and arsenic [As]) and persistent chlorinated pollutants (including polychlorinated biphenyls [PCBs] and organochlorine pesticides [OCPs]) in blood and plasma of White stork ( Ciconia ciconia ) nestlings from northwest (NW) Spain. The concentrations of PCBs were lower than the limit of detection in all samples. The OCPs γ-HCH, 4,4′-DDE, HCB, and endosulfan were detected most frequently in plasma from White stork nestlings. These OCPs were detected in 98, 54, 39, and 37 % of all samples, respectively. However, the concentrations of organic pollutants were lower than the risk thresholds for birds. The mean levels of the inorganic elements Pb, Hg, and As were found to be 36.92 ± 33.48, 16.48 ± 12.87, and 9.813 ± 13.84 µg/L, respectively. These levels were also lower than the risk thresholds for birds. This study not only provides a snapshot of the levels of both inorganic and organic contaminants in wild White storks in NW Spain, it also provides a useful baseline for biomonitoring levels of the measured contaminants in this area.

Description: This study is the first to investigate the pharmaceutical burden from point sources affecting the UNESCO Biosphere Reserve Kristianstads Vattenrike, Sweden. The investigated Biosphere Reserve is a 〉1000 km 2 wetland system with inflows from lakes, rivers, leachate from landfill, and wastewater-treatment plants (WWTPs). We analysed influent and treated wastewater, leachate water, lake, river, and wetland water alongside sediment for six model pharmaceuticals. The two WWTPs investigated released pharmaceutical residues at levels close to those previously observed in Swedish monitoring exercises. Compound-dependent WWTP removal efficiencies ranging from 12 to 100 % for bendroflumethiazide, oxazepam, atenolol, carbamazepine, and diclofenac were observed. Surface-water concentrations in the most affected lake were ≥100 ng/L for the various pharmaceuticals with atenolol showing the highest levels (〉300 ng/L). A small risk assessment showed that adverse single-substance toxicity on aquatic organisms within the UNESCO Biosphere Reserve is unlikely. However, the effects of combinations of a large number of known and unknown pharmaceuticals, metals, and nutrients are still unknown.

Description: The proliferation and apoptosis of cells in the placenta play a critical role in preeclampsia (PE) in which estrogen has been implicated via estrogen receptors (ERs). A novel ER, G-protein-coupled receptor 30 (GPR30), has recently been shown to be involved in PE. We investigated the basic levels of proliferation and apoptosis in normal placentae and placentae with PE and compared GPR30 expression levels between the two groups. We demonstrated that low GPR30 expression levels, more apoptosis, and less proliferation were associated with PE. Moreover, our in vitro study showed that both the selective GPR30 agonist G1 and the general ER agonist 17-β-estradiol were able to protect the placenta from hypoxia-reoxygenation injuries, resulting in decreased apoptosis and increased proliferation. Furthermore, this protective effect was abolished by the addition of the selective GPR30 inhibitor G15. These results provide evidence that (1) GPR30 is involved in regulating cell proliferation and apoptosis; (2) pharmacologic upregulation of GPR30 is beneficial for PE management; (3) GPR30 may therefore be an interventional target for pregnancies complicated by PE.

Description: Depression is a significant public health concern all over the world, especially in modern communities. This study aims to assess the efficacy of musk in alleviating the behavioral, biochemical and histopathological changes induced by chronic unpredictable mild stress (CUMS) in an animal model of depression and to explore the underlying mechanism of this effect. Male Swiss albino mice were divided into four groups ( n  = 10): control, CUMS, CUMS+fluoxetine and CUMS+musk. At the end of the experiment, behavioral tests were administered and serum corticosterone and testosterone levels were assessed. Surface markers, proteins and gene expressions of brain-derived neurotropic factor (BDNF) and glucocorticoid receptors (GRs) in the hippocampus were assessed. The immunoexpression of glial fibrillary acidic protein, Ki67 and caspase-3 was also assessed. Data were analyzed using the Statistical Package for the Social Sciences and a P value of less than 0.05 was considered significant. Musk alleviated the behavioral changes caused by CUMS and reduced elevated corticosterone levels. It reduced CUMS-induced neuronal atrophy in the CA3 and dentate gyrus of the hippocampus and restored astrocytes. Musk reduced the neuro- and glial apoptosis observed in stressed mice in a manner comparable to that of fluoxetine. Musk induced these effects through up-regulating both BDNF and GR gene and protein expressions. Musk has an antidepressant-like effect in an animal model of depression, so it is advisable to assess its efficacy in people continually exposed to stressors.

Description: Three-dimensional (3D) cell culture is a powerful in vitro technique to study the stratification and differentiation of keratinocytes. However, culture conditions, including culture media, supplements, and scaffolds (e.g., collagen gels with or without fibroblasts), can vary considerably. Here, we evaluated the roles of calcium, l -ascorbic acid phosphate magnesium salt n -hydrate (APM), and keratinocyte growth factor (KGF) in a chemically defined medium, EpiLife, in 3D cultures of primary human epidermal keratinocytes directly plated on polycarbonate filter inserts under airlifted or submerged conditions. Eight culture media containing various combinations of these three supplements were examined. Calcium was necessary for the stratification and differentiation of keratinocytes based on the localization of keratins and involucrin. However, the localization patterns of keratins and integrin β4 were partially disrupted and Ki67-positive basal cells almost disappeared 3 weeks after airlift. The addition of KGF, but not APM, prevented these changes. Further addition of APM markedly improved the tissue architecture, including basal cell morphology and the appearance of keratohyalin granules and localized involucrin in the upper suprabasal cells, even after 1 week. Although the submerged culture also formed cornified epithelium-like multilayers, involucrin was localized in the cornified layer, where nuclei were often found. Based on these results, it is most effective to culture keratinocytes at the air–liquid interface in EpiLife medium supplemented with calcium, APM, and KGF to form well-organized and orthokeratinized multilayers as skin analogues.

Description: In this review, we provide a description of the recent methods used for immunohistochemical staining of the human inner ear using formalin-fixed frozen, paraffin and celloidin-embedded sections. We also show the application of these immunohistochemical methods in auditory and vestibular endorgans microdissected from the human temporal bone. We compare the advantages and disadvantages of immunohistochemistry (IHC) in the different types of embedding media. IHC in frozen and paraffin-embedded sections yields a robust immunoreactive signal. Both frozen and paraffin sections would be the best alternative in the case where celloidin-embedding technique is not available. IHC in whole endorgans yields excellent results and can be used when desiring to detect regional variations of protein expression in the sensory epithelia. One advantage of microdissection is that the tissue is processed immediately and IHC can be made within 1 week of temporal bone collection. A second advantage of microdissection is the excellent preservation of both morphology and antigenicity. Using celloidin-embedded inner ear sections, we were able to detect several antigens by IHC and immunofluorescence using antigen retrieval methods. These techniques, previously applied only in animal models, allow for the study of numerous important proteins expressed in the human temporal bone potentially opening up a new field for future human inner ear research.