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1.  Wikidata as a semantic framework for the Gene Wiki initiative 
Open biological data are distributed over many resources making them challenging to integrate, to update and to disseminate quickly. Wikidata is a growing, open community database which can serve this purpose and also provides tight integration with Wikipedia. In order to improve the state of biological data, facilitate data management and dissemination, we imported all human and mouse genes, and all human and mouse proteins into Wikidata. In total, 59 721 human genes and 73 355 mouse genes have been imported from NCBI and 27 306 human proteins and 16 728 mouse proteins have been imported from the Swissprot subset of UniProt. As Wikidata is open and can be edited by anybody, our corpus of imported data serves as the starting point for integration of further data by scientists, the Wikidata community and citizen scientists alike. The first use case for these data is to populate Wikipedia Gene Wiki infoboxes directly from Wikidata with the data integrated above. This enables immediate updates of the Gene Wiki infoboxes as soon as the data in Wikidata are modified. Although Gene Wiki pages are currently only on the English language version of Wikipedia, the multilingual nature of Wikidata allows for usage of the data we imported in all 280 different language Wikipedias. Apart from the Gene Wiki infobox use case, a SPARQL endpoint and exporting functionality to several standard formats (e.g. JSON, XML) enable use of the data by scientists.
In summary, we created a fully open and extensible data resource for human and mouse molecular biology and biochemistry data. This resource enriches all the Wikipedias with structured information and serves as a new linking hub for the biological semantic web.
Database URL: https://www.wikidata.org/
doi:10.1093/database/baw015
PMCID: PMC4795929  PMID: 26989148
2.  The Prevalence of Job Stress and its Relationship with Burnout Syndrome among the Academic Members of Lorestan University of Medical Sciences  
Journal of Caring Sciences  2016;5(1):75-84.
Introduction: Burnout syndrome is one of the consequences and the results of occupational or job stress emerged in the form of emotional exhaustion feeling, depersonalization and decrement personal accomplishment. The aim of this study was to determine the occupational stress and its relationship with burnout syndrome in the academic members of Lorestan University of Medical Sciences.
Methods: This descriptive cross-sectional survey was conducted on 111 of the faculty members via multistage sampling. Data were collected by the questionnaire of Maslach Burnout Inventory (MBI), and Osipow Occupational Stress Inventory (OSI- R). Data were analyzed by using descriptive statistics as well as analytical statistics such as chi square, Kruskal-Wallis, Mann Whitney tests and Pearson correlation coefficient.
Results: The results showed that the most of the participants had a low level of burnout three dimensions including emotional burnout (72.1%), depersonalization (81.1%), and the decrement of personal accomplishment (56.8%). Moreover 79.3% of samples had a low occupational stress, but there was a meaningful relationship between occupational stress and dimensions of burnout syndrome with an exception for the intensity of decrement of personal accomplishment.
Conclusion: Academic members were in an appropriate condition concerning burnout syndrome and occupational stress. However by applying some strategies to decrease stress and determining stress resources, we can improve their psychological health of academic members.
doi:10.15171/jcs.2016.008
PMCID: PMC4794547  PMID: 26989668
Workplace; Professional burnout; Faculty; Stress; Psychological
3.  Wasp sting-induced acute kidney injury 
Clinical Kidney Journal  2016;9(2):201-204.
Background
Wasp stings are a common form of envenomation in tropical countries, especially in farmers. The aim of this study was to document the clinical presentation, treatment and outcomes of patients with acute kidney injury (AKI) due to multiple wasp stings in a tertiary care hospital.
Methods
We conducted a retrospective observational study of patients with multiple wasp stings and AKI at the Department of Nephrology between July 2011 and August 2015. The clinical features, laboratory data, treatment details and outcomes were noted.
Results
A total of 11 patients were included. All were from rural areas. All of them were males with age ranging from 21 to 70 years, mean age 45 ± 23 years. Six had oliguria and two had hypotension. All 11 patients had evidence of rhabdomyolysis and three also had hemolysis. Ten patients required hemodialysis with a mean number of hemodialysis sessions of 8.7 ± 2.8. Renal biopsy carried out on four patients, showed acute interstitial nephritis (AIN) in one patient, acute tubular necrosis (ATN) in two patients, and one patient had both AIN and ATN. The two patients with AIN were given steroids, while all other patients were managed with supportive measures. One patient died within 48 h of presentation due to shock. At a mean follow-up of 24 months, one had progressed to chronic kidney disease and the remaining nine had normal renal function.
Conclusions
Wasp sting is an occupational hazard. AKI was most commonly due to rhabdomyolysis. Early renal biopsy is indicated in those patients who do not respond to supportive measures. Timely dialysis and steroid in the case of AIN improves renal survival.
doi:10.1093/ckj/sfw004
PMCID: PMC4792632  PMID: 26985369
acute kidney injury; hemodialysis; rhabdomyolysis; steroids; wasp stings
4.  Challenges for opioid receptor nomenclature: IUPHAR Review 9 
British Journal of Pharmacology  2014;172(2):317-323.
Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
doi:10.1111/bph.12612
PMCID: PMC4292949  PMID: 24528283
5.  Bioengineering thermodynamics of biological cells 
Background
Cells are open complex thermodynamic systems. They can be also regarded as complex engines that execute a series of chemical reactions. Energy transformations, thermo-electro-chemical processes and transports phenomena can occur across the cells membranes. Moreover, cells can also actively modify their behaviours in relation to changes in their environment.
Methods
Different thermo-electro-biochemical behaviours occur between health and disease states. But, all the living systems waste heat, which is no more than the result of their internal irreversibility. This heat is dissipated into the environment. But, this wasted heat represent also a sort of information, which outflows from the cell toward its environment, completely accessible to any observer.
Results
The analysis of irreversibility related to this wasted heat can represent a new approach to study the behaviour of the cells themselves and to control their behaviours. So, this approach allows us to consider the living systems as black boxes and analyze only the inflows and outflows and their changes in relation to the modification of the environment. Therefore, information on the systems can be obtained by analyzing the changes in the cell heat wasted in relation to external perturbations.
Conclusions
The bioengineering thermodynamics bases are summarized and used to analyse possible controls of the calls behaviours based on the control of the ions fluxes across the cells membranes.
doi:10.1186/s12976-015-0024-z
PMCID: PMC4666120  PMID: 26620568
Entropy generation; Exergy; Irreversibility; Living systems; Medicine and biochemistry thermodynamics; Membrane transport
6.  Natural hybrid of Leishmania infantum/L. donovani: development in Phlebotomus tobbi, P. perniciosus and Lutzomyia longipalpis and comparison with non-hybrid strains differing in tissue tropism 
Parasites & Vectors  2015;8:605.
Background
Infection caused by parasites from L. donovani complex can manifest as a serious visceral disease or a self-healing milder cutaneous form. The different tropism and pathology in humans is caused by the interaction between parasites, host and vector determinants but the mechanisms are not well understood. In Cukurova region in Turkey we previously identified a major focus of cutaneous leishmaniasis caused by L. donovani/infantum hybrids (CUK strain) and isolated this parasite from the locally abundant sand fly, Phlebotomus tobbi. Here, we present the first experimental study with P. tobbi. We tested the susceptibility of this species to various Leishmania under laboratory conditions, characterized glycoproteins in the P. tobbi midgut putatively involved in parasite-vector interaction and compared the development of the CUK strain in the sand fly with one other dermotropic and three viscerotropic strains belonging to the L. donovani complex.
Methods
Females of laboratory reared P. tobbi, P. perniciosus and Lutzomyia longipalpis were infected using membrane feeding on rabbit blood containing promastigotes of various Leishmania species with different tropisms. The individual guts were checked microscopically for presence and localization of Leishmania parasites; the number of parasites was assessed more precisely by qPCR. In addition, glycosylation of midgut proteins of P. tobbi was studied by lectin blotting of midgut lysate with lectins specific for terminal sugars of N-type and O-type glycans.
Results
High infection rates, heavy parasite loads and late-stage infection with colonization of the stomodeal valve were observed in P. tobbi infected by Leishmania major or L. infantum CUK hybrid. In parallel, lectin blotting revealed the presence of O-glycosylated proteins in the P. tobbi midgut. In P. perniciosus and L. longipalpis all five Leishmania strains tested developed well. In both vectors, significantly higher parasite numbers were detected by qPCR for dermotropic L. donovani from Cyprus, however, in all other parameters studied, including localization of infection and colonization of stomodeal valve, dermotropic and viscerotropic strains were not significantly different.
Conclusions
We showed high susceptibility of P. tobbi to various Leishmania spp. This, together with the presence of O-glycosylated midgut proteins in their midguts demonstrate that P. tobbi is a permissive vector. Two dermotropic and three viscerotropic strains from the L. donovani complex developed late-stage infections in natural L. infantum vectors, P. perniciosus and L. longipalpis and none of the parameters studied seem to be linked with different tropism of parasites in the vertebrate host.
doi:10.1186/s13071-015-1217-3
PMCID: PMC4660806  PMID: 26608249
Phlebotomus tobbi; Vector competence; Leishmania development; Tropism
7.  DFGmodel: Predicting Protein Kinase Structures in Inactive States for Structure-Based Discovery of Type-II Inhibitors 
ACS Chemical Biology  2014;10(1):269-278.
Protein kinases exist in equilibrium of active and inactive states, in which the aspartate-phenylalanine-glycine motif in the catalytic domain undergoes conformational changes that are required for function. Drugs targeting protein kinases typically bind the primary ATP-binding site of an active state (type-I inhibitors) or utilize an allosteric pocket adjacent to the ATP-binding site in the inactive state (type-II inhibitors). Limited crystallographic data of protein kinases in the inactive state hampers the application of rational drug discovery methods for developing type-II inhibitors. Here, we present a computational approach to generate structural models of protein kinases in the inactive conformation. We first perform a comprehensive analysis of all protein kinase structures deposited in the Protein Data Bank. We then develop DFGmodel, a method that takes either a known structure of a kinase in the active conformation or a sequence of a kinase without a structure, to generate kinase models in the inactive conformation. Evaluation of DFGmodel’s performance using various measures indicates that the inactive kinase models are accurate, exhibiting RMSD of 1.5 Å or lower. The kinase models also accurately distinguish type-II kinase inhibitors from likely nonbinders (AUC > 0.70), suggesting that they are useful for virtual screening. Finally, we demonstrate the applicability of our approach with three case studies. For example, the models are able to capture inhibitors with unintended off-target activity. Our computational approach provides a structural framework for chemical biologists to characterize kinases in the inactive state and to explore new chemical spaces with structure-based drug design.
doi:10.1021/cb500696t
PMCID: PMC4301084  PMID: 25420233
8.  Plasmon-Enhanced Light Absorption in GaAs Nanowire Array Solar Cells 
In this paper, we propose a plasmon-enhanced solar cell structure based on a GaAs nanowire array decorated with metal nanoparticles. The results show that by engineering the metallic nanoparticles, localized surface plasmon could be excited, which can concentrate the incident light and propagate the energy to nanowires. The surface plasmon can dramatically enhance the absorbance of near-bandgap light, and the enhancement is influenced by the size and material of nanoparticles. By optimizing the particle parameters, a large absorbance enhancement of 50 % at 760 nm and a high conversion efficiency of 14.5 % can be obtained at a low diameter and period ratio (D/P ratio) of 0.3. The structure is promising for low-cost high-performance nanoscale solar cells.
doi:10.1186/s11671-015-1110-1
PMCID: PMC4636537  PMID: 26546326
Solar cells; Surface plasmon; Nanowire arrays; Nanoparticle; Semiconductors
9.  Enhanced Recyclable Magnetized Palm Shell Waste-Based Powdered Activated Carbon for the Removal of Ibuprofen: Insights for Kinetics and Mechanisms 
PLoS ONE  2015;10(10):e0141013.
A novel preparation method of magnetized palm shell waste-based powdered activated carbon (MPPAC, avg. size 112 μm) was developed. The prepared MPPAC was assessed by several physicochemical analyses, and batch tests were performed for ibuprofen (IBP) removal. Field emission scanning electron microscopy (FESEM) and N2 gas isotherms revealed that magnetite and maghemite were homogeneous and deposited mostly on the surface of PPAC without a significant clogging effect on the micropores. Isotherm results showed that 3.8% Fe (w/w) impregnated PPAC [MPPAC-Fe(3.8%)] had about 2.2-fold higher maximum sorption capacity (157.3 mg g-1) and a 2.5-fold higher sorption density (0.23 mg m-2) than pristine PPAC. Both Fourier-transform infrared spectroscopy (FTIR) and isotherm data indicated that the high sorption capacity and density of IBP by MPPAC was primarily attributable to donor-acceptor complexes with the C = O group and dispersive π-π interactions with the carbon surface. Based on kinetic and repeated adsorption tests, pore diffusion was the rate-limiting step, and MPPAC-Fe(3.8%) had about 1.9~2.8- and 9.1~15.8-fold higher rate constants than MPPAC-Fe(8.6%) and palm shell-waste granular activated carbon (PGAC, avg. size 621 μm), respectively. MPPAC showed almost eight fold greater re-adsorption capacity than PPAC due to a thermal catalytic effect of magnetite/maghemite.
doi:10.1371/journal.pone.0141013
PMCID: PMC4619863  PMID: 26496196
10.  Evaluating the Diagnostic Accuracy of Xpert MTB/RIF Assay in Pulmonary Tuberculosis 
PLoS ONE  2015;10(10):e0141011.
Pulmonary tuberculosis still remains a major communicable disease worldwide. In 2013, 9 million people developed TB and 1.5 million people died from the disease. India constitutes 24% of the total TB burden. Early detection of TB cases is the key to successful treatment and reduction of disease transmission. Xpert MTB/RIF, an automated cartridge-based molecular technique detects Mycobacterium tuberculosis and rifampicin resistance within two hours has been endorsed by WHO for rapid diagnosis of TB. Our study is the first study from India with a large sample size to evaluate the performance of Xpert MTB/RIF assay in PTB samples. The test showed an overall sensitivity and specificity of 95.7% (430/449) and 99.3% (984/990) respectively. In smear negative-culture positive cases, the test had a sensitivity of 77.7%. The sensitivity and specificity for detecting rifampicin resistance was 94.5% and 97.7% respectively with respect to culture as reference standard. However, after resolving the discrepant samples with gene sequencing, the sensitivity and specificity rose to 99.0% and 99.3% respectively. Hence, while solid culture still forms the foundation of TB diagnosis, Xpert MTB/RIF proposes to be a strong first line diagnostic tool for pulmonary TB cases.
doi:10.1371/journal.pone.0141011
PMCID: PMC4619889  PMID: 26496123
11.  Urinary Biomarkers Improve the Diagnosis of Intrinsic Acute Kidney Injury in Coronary Care Units 
Medicine  2015;94(40):e1703.
Supplemental Digital Content is available in the text
Abstract
Acute kidney injury (AKI) is associated with increased morbidity and mortality and is frequently encountered in coronary care units (CCUs). Its clinical presentation differs considerably from that of prerenal or intrinsic AKI. We used the biomarkers calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) and compared their utility in predicting and differentiating intrinsic AKI.
This was a prospective observational study conducted in a CCU of a tertiary care university hospital. Patients who exhibited any comorbidity and a kidney stressor were enrolled. Urinary samples of the enrolled patients collected between September 2012 and August 2013 were tested for calprotectin and NGAL. The definition of AKI was based on Kidney Disease Improving Global Outcomes classification. All prospective demographic, clinical, and laboratory data were evaluated as predictors of AKI.
A total of 147 adult patients with a mean age of 67 years were investigated. AKI was diagnosed in 71 (50.3%) patients, whereas intrinsic AKI was diagnosed in 43 (60.5%) of them. Multivariate logistic regression analysis revealed urinary calprotectin and serum albumin as independent risk factors for intrinsic AKI. For predicting intrinsic AKI, both urinary NGAL and calprotectin displayed excellent areas under the receiver operating characteristic curve (AUROC) (0.918 and 0.946, respectively). A combination of these markers revealed an AUROC of 0.946.
Our result revealed that calprotectin and NGAL had considerable discriminative powers for predicting intrinsic AKI in CCU patients. Accordingly, careful inspection for medication, choice of therapy, and early intervention in patients exhibiting increased biomarker levels might improve the outcomes of kidney injury.
doi:10.1097/MD.0000000000001703
PMCID: PMC4616771  PMID: 26448023
13.  ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort 
Neurology  2014;83(14):1271-1276.
Objective:
To assess the relationships among ABO group, factor VIII (FVIII), and incident cognitive impairment in a large, prospective cohort study of black and white adults in the United States using a nested case-control design.
Methods:
Incident cognitive impairment was defined using cognitive domain tests over a mean follow-up of 3.4 years. ABO blood group was measured by genotyping in a nested case-control sample of 495 cases with cognitive impairment and 587 controls.
Results:
Those with blood group AB and those with higher FVIII had an increased risk of cognitive impairment, adjusting for age, race, region, and sex (respective odds ratios 1.82, 95% confidence interval [CI] 1.15–2.90; and 1.24, 95% CI 1.10–1.38 for 40 IU/dL higher FVIII). Mean FVIII was higher in those with blood type AB (142 IU/dL; 95% CI 119–165) compared with O (104 IU/dL; 95% CI 101–107), and FVIII mediated 18% of the association between AB group and incident cognitive impairment (95% CI for mediation −30% to 68%).
Conclusions:
Blood group AB and higher FVIII were associated with increased incidence of cognitive impairment in this prospective study. The association of blood group AB with incident cognitive impairment was not significantly mediated by FVIII levels.
doi:10.1212/WNL.0000000000000844
PMCID: PMC4180487  PMID: 25209581
14.  SNAREs Interact with Retinal Degeneration Slow and Rod Outer Segment Membrane Protein-1 during Conventional and Unconventional Outer Segment Targeting 
PLoS ONE  2015;10(9):e0138508.
Mutations in the photoreceptor protein peripherin-2 (also known as RDS) cause severe retinal degeneration. RDS and its homolog ROM-1 (rod outer segment protein 1) are synthesized in the inner segment and then trafficked into the outer segment where they function in tetramers and covalently linked larger complexes. Our goal is to identify binding partners of RDS and ROM-1 that may be involved in their biosynthetic pathway or in their function in the photoreceptor outer segment (OS). Here we utilize several methods including mass spectrometry after affinity purification, in vitro co-expression followed by pull-down, in vivo pull-down from mouse retinas, and proximity ligation assay to identify and confirm the SNARE proteins Syntaxin 3B and SNAP-25 as novel binding partners of RDS and ROM-1. We show that both covalently linked and non-covalently linked RDS complexes interact with Syntaxin 3B. RDS in the mouse is trafficked from the inner segment to the outer segment by both conventional (i.e., Golgi dependent) and unconventional secretory pathways, and RDS from both pathways interacts with Syntaxin3B. Syntaxin 3B and SNAP-25 are enriched in the inner segment (compared to the outer segment) suggesting that the interaction with RDS/ROM-1 occurs in the inner segment. Syntaxin 3B and SNAP-25 are involved in mediating fusion of vesicles carrying other outer segment proteins during outer segment targeting, so could be involved in the trafficking of RDS/ROM-1.
doi:10.1371/journal.pone.0138508
PMCID: PMC4583372  PMID: 26406599
15.  H-rev107 Regulates Cytochrome P450 Reductase Activity and Increases Lipid Accumulation 
PLoS ONE  2015;10(9):e0138586.
H-rev107 is a member of the HREV107 type II tumor suppressor gene family and acts as a phospholipase to catalyze the release of fatty acids from glycerophospholipid. H-rev107 has been shown to play an important role in fat metabolism in adipocytes through the PGE2/cAMP pathway, but the detailed molecular mechanism underlying H-rev107-mediated lipid degradation has not been studied. In this study, the interaction between H-rev107 and cytochrome P450 reductase (POR), which is involved in hepatic lipid content regulation, was determined by yeast two-hybrid screen and confirmed by using in vitro pull down assays and immunofluorescent staining. The expression of POR in H-rev107-expressing cells enhanced the H-rev107-mediated release of arachidonic acid. However, H-rev107 inhibited POR activity and relieved POR-mediated decreased triglyceride content in HtTA and HeLa cervical cells. The inhibitory effect of H-rev107 will be abolished when POR-expressing cells transfected with PLA2-lacking pH-rev107 or treated with PLA2 inhibitor. Silencing of H-rev107 using siRNA resulted in increased glycerol production and reversion of free fatty acid-mediated growth suppression in Huh7 hepatic cells. In summary, our results revealed that H-rev107 is also involved in lipid accumulation in liver cells through the POR pathway via its PLA2 activity.
doi:10.1371/journal.pone.0138586
PMCID: PMC4575093  PMID: 26381418
16.  Objectively measured physical activity and sedentary time in youth: the International children’s accelerometry database (ICAD) 
Background
Physical activity and sedentary behaviour in youth have been reported to vary by sex, age, weight status and country. However, supporting data are often self-reported and/or do not encompass a wide range of ages or geographical locations. This study aimed to describe objectively-measured physical activity and sedentary time patterns in youth.
Methods
The International Children’s Accelerometry Database (ICAD) consists of ActiGraph accelerometer data from 20 studies in ten countries, processed using common data reduction procedures. Analyses were conducted on 27,637 participants (2.8–18.4 years) who provided at least three days of valid accelerometer data. Linear regression was used to examine associations between age, sex, weight status, country and physical activity outcomes.
Results
Boys were less sedentary and more active than girls at all ages. After 5 years of age there was an average cross-sectional decrease of 4.2 % in total physical activity with each additional year of age, due mainly to lower levels of light-intensity physical activity and greater time spent sedentary. Physical activity did not differ by weight status in the youngest children, but from age seven onwards, overweight/obese participants were less active than their normal weight counterparts. Physical activity varied between samples from different countries, with a 15–20 % difference between the highest and lowest countries at age 9–10 and a 26–28 % difference at age 12–13.
Conclusions
Physical activity differed between samples from different countries, but the associations between demographic characteristics and physical activity were consistently observed. Further research is needed to explore environmental and sociocultural explanations for these differences.
Electronic supplementary material
The online version of this article (doi:10.1186/s12966-015-0274-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12966-015-0274-5
PMCID: PMC4574095  PMID: 26377803
Accelerometer; Physical activity; Sedentary; Children; Adolescents
17.  Risk of Congenital Heart Disease in Relatives of Probands with Conotruncal Cardiac Defects: An Evaluation of 1620 Families 
Current recurrence risk counseling for conotruncal cardiac defects (CTD) is based on empiric estimates from multiple studies. We examined the risk of congenital heart disease (CHD) in relatives of probands with CTDs to assist in counseling practices in the current era. 1,620 probands with CTDs and no reported chromosomal or genetic abnormalities were recruited sequentially. A three-generation pedigree was obtained for each proband by a genetic counselor detailing the presence and type of CHD in each family member. Risks and 95% confidence intervals (CI) were calculated for subgroups of relatives based on degree of relationship for all probands and by individual lesion of the proband. For pairs of affected relatives, concordance rates were calculated. Severity of CHD in the affected relative was assessed. The risk of CHD was higher in siblings (4.4%, 95% CI 3.4–5.4) than in parents (1.5%, 95% CI 1.1–1.9). Risk varied by the cardiac lesion of the proband with the highest risk in first-degree relatives of probands with tetralogy of Fallot and the lowest in D- transposition of the great arteries. 39% of affected parents and 69% of affected siblings had a concordant lesion (i.e. CTD). Most affected siblings of probands with severe CTDs had complex defects (58%), whereas very few affected parents had complex defects (20%). These data suggest that recurrence risk varies by lesion and relationship, with substantial concordance observed by cardiac lesion and complexity of disease, particularly among siblings. These findings contribute to risk counseling in the current era.
doi:10.1002/ajmg.a.36500
PMCID: PMC4571453  PMID: 24677430
Congenital heart defects; Conotruncal cardiac defects; Recurrence risk; Genetic counseling
18.  Modular design of metabolic network for robust production of n-butanol from galactose–glucose mixtures 
Background
Refactoring microorganisms for efficient production of advanced biofuel such as n-butanol from a mixture of sugars in the cheap feedstock is a prerequisite to achieve economic feasibility in biorefinery. However, production of biofuel from inedible and cheap feedstock is highly challenging due to the slower utilization of biomass-driven sugars, arising from complex assimilation pathway, difficulties in amplification of biosynthetic pathways for heterologous metabolite, and redox imbalance caused by consuming intracellular reducing power to produce quite reduced biofuel. Even with these problems, the microorganisms should show robust production of biofuel to obtain industrial feasibility. Thus, refactoring microorganisms for efficient conversion is highly desirable in biofuel production.
Results
In this study, we engineered robust Escherichia coli to accomplish high production of n-butanol from galactose–glucose mixtures via the design of modular pathway, an efficient and systematic way, to reconstruct the entire metabolic pathway with many target genes. Three modular pathways designed using the predictable genetic elements were assembled for efficient galactose utilization, n-butanol production, and redox re-balancing to robustly produce n-butanol from a sugar mixture of galactose and glucose. Specifically, the engineered strain showed dramatically increased n-butanol production (3.3-fold increased to 6.2 g/L after 48-h fermentation) compared to the parental strain (1.9 g/L) in galactose-supplemented medium. Moreover, fermentation with mixtures of galactose and glucose at various ratios from 2:1 to 1:2 confirmed that our engineered strain was able to robustly produce n-butanol regardless of sugar composition with simultaneous utilization of galactose and glucose.
Conclusions
Collectively, modular pathway engineering of metabolic network can be an effective approach in strain development for optimal biofuel production with cost-effective fermentable sugars. To the best of our knowledge, this study demonstrated the first and highest n-butanol production from galactose in E. coli. Moreover, robust production of n-butanol with sugar mixtures with variable composition would facilitate the economic feasibility of the microbial process using a mixture of sugars from cheap biomass in the near future.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-015-0327-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-015-0327-7
PMCID: PMC4559943  PMID: 26347006
Metabolic engineering; Synthetic biology; Galactose; Redox balance; Butanol
19.  Use of the life table to compare mortality in ethnic groups in Amsterdam, the Netherlands 
BMC Public Health  2015;15:825.
Background
The life table is a valid and frequently used instrument to compare the mortality of migrant groups. Most analyses are limited to an overview and give only life expectancy; however, further analysis of the life table can give more insight into differences in patterns of mortality between groups.
Methods
A thorough life table analysis was applied to the mortality data of seven ethnic groups by age and gender.
Results
Life expectancy is systematically higher in migrants compared with the Dutch citizens of Amsterdam. However, between birth and the age of 40 the probability of death is higher among non-western migrants compared with citizens of western origin. The number of deaths is small among the young. This results in very small differences in survival between the groups; from birth up to the age of 40 the survival rate is 98.7 % for citizens of western origin and 98.3 % for citizens of non-western origin. In all seven ethnic groups over 90.7 % of babies, male and female, survive up to the age of 60. In all female groups the survival is better than in male groups. Males and females aged 0 to 40 from Antillean origin are the only exception.
Conclusion
Life expectancy is generally higher in non-western than in western groups. Differences in survival between ethnic groups are small up to middle age.
doi:10.1186/s12889-015-2170-y
PMCID: PMC4549834  PMID: 26310865
20.  Security Enhancement Using Cache Based Reauthentication in WiMAX Based E-Learning System 
The Scientific World Journal  2015;2015:878327.
WiMAX networks are the most suitable for E-Learning through their Broadcast and Multicast Services at rural areas. Authentication of users is carried out by AAA server in WiMAX. In E-Learning systems the users must be forced to perform reauthentication to overcome the session hijacking problem. The reauthentication of users introduces frequent delay in the data access which is crucial in delaying sensitive applications such as E-Learning. In order to perform fast reauthentication caching mechanism known as Key Caching Based Authentication scheme is introduced in this paper. Even though the cache mechanism requires extra storage to keep the user credentials, this type of mechanism reduces the 50% of the delay occurring during reauthentication.
doi:10.1155/2015/878327
PMCID: PMC4553329  PMID: 26351658
21.  Macrodiolide Formation by the Thioesterase of a Modular Polyketide Synthase** 
Elaiophylin is an unusual C2-symmetric antibiotic macrodiolide produced on a bacterial modular polyketide synthase assembly line. To probe the mechanism and selectivity of diolide formation, we sought to reconstitute ring formation in vitro by using a non-natural substrate. Incubation of recombinant elaiophylin thioesterase/cyclase with a synthetic pentaketide analogue of the presumed monomeric polyketide precursor of elaiophylin, specifically its N-acetylcysteamine thioester, produced a novel 16-membered C2-symmetric macrodiolide. A linear dimeric thioester is an intermediate in ring formation, which indicates iterative use of the thioesterase active site in ligation and subsequent cyclization. Furthermore, the elaiophylin thioesterase acts on a mixture of pentaketide and tetraketide thioesters to give both the symmetric decaketide diolide and the novel asymmetric hybrid nonaketide diolide. Such thioesterases have potential as tools for the in vitro construction of novel diolides.
doi:10.1002/ange.201500401
PMCID: PMC4535664  PMID: 26300568
Biosynthese; Diolide; Elaiophylin; Polyketid-Synthase; Thioesterase
22.  Development of a greenhouse-based inoculation protocol for the fungus Colletotrichum cereale pathogenic to annual bluegrass (Poa annua) 
PeerJ  2015;3:e1153.
The fungus Colletotrichum cereale incites anthracnose disease on Poa annua (annual bluegrass) turfgrass. Anthracnose disease is geographically widespread throughout the world and highly destructive to cool-season turfgrasses, with infections by C. cereale resulting in extensive turf loss. Comprehensive research aimed at controlling turfgrass anthracnose has been performed in the field, but knowledge of the causal organism and its basic biology is still needed. In particular, the lack of a reliable greenhouse-based inoculation protocol performed under controlled environmental conditions is an obstacle to the study of C. cereale and anthracnose disease. Our objective was to develop a consistent and reproducible inoculation protocol for the two major genetic lineages of C. cereale. By adapting previously successful field-based protocols and combining with components of existing inoculation procedures, the method we developed consistently produced C. cereale infection on two susceptible P. annua biotypes. Approximately 7 to 10 days post-inoculation, plants exhibited chlorosis and thinning consistent with anthracnose disease symptomology. Morphological inspection of inoculated plants revealed visual signs of the fungus (appressoria and acervuli), although acervuli were not always present. After stringent surface sterilization of inoculated host tissue, C. cereale was consistently re-isolated from symptomatic tissue. Real-time PCR detection analysis based on the Apn2 marker confirmed the presence of the pathogen in host tissue, with both lineages of C. cereale detected from all inoculated plants. When a humidifier was not used, no infection developed for any biotypes or fungal isolates tested. The inoculation protocol described here marks significant progress for in planta studies of C. cereale, and will enable scientifically reproducible investigations of the biology, infectivity and lifestyle of this important grass pathogen.
doi:10.7717/peerj.1153
PMCID: PMC4558069  PMID: 26339538
Anthracnose; Infectivity; Putting greens; Turfgrass; Poaceae
23.  “If I Were Nick”: Men’s Responses to an Interactive Video Drama Series to Support Smoking Cessation 
Background
Men continue to smoke in greater numbers than women; however, few interventions have been developed and tested to support men’s cessation. Men tend to rely on quitting strategies associated with stereotypical manliness, such as willpower, stoicism, and independence, but they may lack the self-efficacy skills required to sustain a quit. In this paper, we describe the development of and reception to an interactive video drama (IVD) series, composed of 7 brief scenarios, to support and strengthen men’s smoking cessation efforts. The value of IVD in health promotion is predicated on the evidence that viewers engage with the material when they are presented characters with whom they can personally identify. The video dramatizes the challenges unfolding in the life of the main character, Nick, on the first day of his quit and models the skills necessary to embark upon a sustainable quit.
Objective
The objective was to describe men’s responses to the If I were Nick IVD series as part of a study of QuitNow Men, an innovative smoking cessation website designed for men. Specific objectives were to explore the resonance of the main character of the IVD series with end-users and explore men’s perceptions of the effectiveness of the IVD series for supporting their quit self-management.
Methods
Seven brief IVD scenarios were developed, filmed with a professional actor, and uploaded to a new online smoking cessation website, QuitNow Men. A sample of 117 men who smoked were recruited into the study and provided baseline data prior to access to the QuitNow Men website for a 6-month period. During this time, 47 men chose to view the IVDs. Their responses to questions about the IVDs were collected in online surveys at 3-month and 6-month time points and analyzed using descriptive statistics.
Results
The majority of participants indicated they related to the main character, Nick. Participants who “strongly agreed” they could relate to Nick perceived significantly higher levels of support from the IVDs than the “neutral” and “disagree” groups (P<.001, d=2.0, P<.001, d=3.1). The “agree” and “neutral” groups were significantly higher on rated support from the videos than the “disagree” (P<.001, d=2.2, P=.01, d=1.5). Participants’ perception of the main character was independent of participant age, education attainment, or previous quit attempts.
Conclusions
The findings suggest that IVD interventions may be an important addition to men’s smoking cessation programs. Given that the use of IVD scenarios in health promotion is in its infancy, the positive outcomes from this study signal the potential for IVD and warrant ongoing evaluation in smoking cessation and, more generally, men’s health promotion.
doi:10.2196/jmir.4491
PMCID: PMC4705026  PMID: 26265410
smoking cessation; tobacco use; technology; interactive video drama; self-efficacy
24.  Increased inflammation but similar physical composition and function in older-aged, HIV-1 infected subjects 
BMC Immunology  2015;16:43.
Background
Systemic immune activation (inflammation) and immunosenescence develop in some people with advancing age. This process, known as “inflamm-aging,” is associated with physical frailty and sarcopenia. Meanwhile, successful antiretroviral therapy has led to a growing number of older HIV-1-infected individuals who face both age-related and HIV-1-related inflammation, which may synergistically promote physical decline, including frailty and sarcopenia. The purpose of our study was to determine if inflammation during treated HIV-1 infection worsens physical impairment in older individuals.
Methods
We determined the severity of HIV-associated inflammation and physical performance (strength and endurance) in 21 older HIV-infected individuals (54–69 years) receiving suppressive antiretroviral therapy, balanced for confounding variables including age, anthropometrics, and co-morbidities with 10 uninfected control individuals. Biomarkers for microbial translocation (lipopolysaccharide [LPS]), inflammation (soluble CD14 [sCD14], osteopontin, C-reactive protein [CRP], interleukin-6 [IL-6], soluble ICAM-1 [sICAM-1] and soluble VCAM-1 [sVCAM-1]), and coagulopathy (D-dimer) were assayed in plasma. Activation phenotypes of CD4+T cells, CD8+ T cells and monocytes were measured by flow cytometry. Physical performance was measured by 400 m walking speed, a short physical performance battery [SPPB], and lower extremity muscle strength and fatigue.
Results
Overall physical function was similar in the uninfected and HIV-infected groups. Compared to uninfected individuals, the HIV-infected group had elevated levels of sCD14 (P < 0.001), CRP (P < 0.001) and IL-6 (P = 0.003) and an increased frequency of CD4+ and CD8+ T cells with an immunosenescent CD57+ phenotype (P = 0.004 and P = 0.043, respectively). Neither plasma inflammatory biomarkers nor CD57+ T cells correlated with CD4+ T cell counts. Furthermore, none of the elevated inflammatory biomarkers in the HIV-infected subjects were associated with any of the physical performance results.
Conclusions
When age-related co-morbidities were carefully balanced between the uninfected and HIV-infected groups, no evidence of inflammation-associated physical impairment was detected. Despite careful balancing for age, BMI, medications and co-morbidities, the HIV-infected group still displayed evidence of significant chronic inflammation, including elevated sCD14, CRP, IL-6 and CD57+ T cells, although the magnitude of this inflammation was unrelated to physical impairment.
doi:10.1186/s12865-015-0106-z
PMCID: PMC4513956  PMID: 26204934
25.  MicroRNA-203 represses selection and expansion of oncogenic Hras transformed tumor initiating cells 
eLife  null;4:e07004.
In many mouse models of skin cancer, only a few tumors typically form even though many cells competent for tumorigenesis receive the same oncogenic stimuli. These observations suggest an active selection process for tumor-initiating cells. Here, we use quantitative mRNA- and miR-Seq to determine the impact of HrasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HrasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 using an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for Hras-initiated tumorigenesis. These targets include critical regulators of the Ras pathway and essential genes required for cell division. This study establishes a role for the loss of microRNA-203 in promoting selection and expansion of Hras mutated cells and identifies a mechanism through which microRNA-203 antagonizes Hras-mediated tumorigenesis.
DOI: http://dx.doi.org/10.7554/eLife.07004.001
eLife digest
DNA mutations occur and accumulate during an individual's lifetime. Often these changes are harmless. But some mutations—called driver mutations—can trigger the formation of tumors. This is often because these mutations allow the cells to grow faster than normal cells. Mutations in genes in the Ras gene family are among the most common driver mutations found in human cancers. These common mutations lead to the uncontrolled activation of genes that are normally tightly controlled, which in turn allows the cells to divide more and live for longer: these are two key features of cancer cells.
So, how are Ras genes and the genes that they control regulated to prevent such dangerous over activation? One mechanism rests on binding sites in their messenger RNA sequence that are recognized by smaller RNA molecules called microRNAs. RNA molecules are created when genes are transcribed. Some RNAs, called messenger RNAs, are then decoded to create proteins. Many other RNAs, including microRNAs, do not code for proteins, but instead bind to many messenger RNA targets, and repress their ability to be decoded into proteins. Three genes, called Hras, Kras, and Nras, are regulated in this way by numerous microRNAs, which together act to dampen the normal activities of these genes.
Riemondy et al. investigate how a cancer-promoting mutation in the Hras gene affects the activities of microRNAs in mouse skin cells in culture. By measuring RNA levels, the experiments reveal that skin cells carrying this mutation produce significantly lower levels of what is normally the most highly produced microRNA in the skin. This microRNA, called microRNA-203, acts to limit the proliferation of skin cells when these cells are dividing rapidly. When the gene encoding microRNA-203 was deleted in mice, the skin cells proliferated more. These mice also developed more skin tumors than normal mice when they were exposed to cancer-causing chemicals. When the gene for microRNA-203 was added into skin cells carrying the Hras mutation and then activated, the cells both divided less and, as a results, grew less. This indicates that microRNA-203 could prevent cancerous cells from expanding in number, a key event in the initiation of tumors.
Riemondy et al. also used a variety of approaches to identify the molecules targeted by microRNA-203 in the skin, and reveal that it targets multiple signaling pathways, including components of the Ras pathway, to suppress cell proliferation. Together, these findings highlight microRNA-203 as a potential source of new treatments to prevent or slow tumor growth in humans.
DOI: http://dx.doi.org/10.7554/eLife.07004.002
doi:10.7554/eLife.07004
PMCID: PMC4536367  PMID: 26203562
microRNA; tumor suppressor; Hras; skin cancer; mouse

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