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Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Recent studies suggest that Spirulina may have great therapeutic benefits due to its antioxidant and anti-inflammatory properties. The primary objective of this study was to evaluate the chemopreventive properties of the Spirulina microalgae (Spi) on the regression and survival of tumor, histopathological features of glioblastoma, and detection of the molecular mechanism of Spi. Tumor viability versus Spi was determined using the MTT assay. In vivo antitumor activity of Spi was studied using the glioblastoma model. After tumor induction, the animals were euthanized, and their brains were removed. Histological evaluation was performed for tumor size and manifestation. The mechanisms of the anticancer effects of Spi were investigated by evaluating the microRNAs and their targets. The results demonstrated that Spi inhibited C6 and U87 cell proliferation and induced cell death. Histopathologic results showed that the administration of Spi could delay the development of tumors and prolonged the survival of tumor-bearing animals. Furthermore, Spi significantly upregulated miR-34a and miR-125b that have a key role in the progression of PI3K/AKT/mTOR pathway. This is the first in vivo report on the chemo-preventive effect of Spi against glioblastoma, suggesting its potential use in the chemoprevention of this cancer and the antiglioma molecular mechanism of Spi.

Motivation Multiple independently associated SNPs within a linkage disequilibrium region are a common phenomenon. Conditional analysis has been successful in identifying secondary signals. While conditional association tests are limited to specific genomic regions, they are benchmarked with genome-wide scale criterion, a conservative strategy. Within the weighted hypothesis testing framework, we developed a ‘quasi-adaptive’ method that uses the pairwise correlation (r2) and physical distance (d) from the index association to construct priority functions G =G(r2, d), which assign an SNP-specific α-threshold to each SNP. Family-wise error rate (FWER) and power of the approach were evaluated via simulations based on real GWAS data. We compared a series of different G-functions. Results Simulations under the null hypothesis on 1,100 primary SNPs confirmed appropriate empirical FWER for all G-functions. A G-function with optimal r2 = 0.3 between index and secondary SNP which down-weighted SNPs at higher distance step-wise-strong and gave more emphasis on d than on r2 had overall best power. It also gave the best results in application to the real datasets. As a proof of concept, ‘quasi-adaptive’ method was applied to GWAS on free thyroxine (FT4), inflammatory bowel disease (IBD) and human height. Application of the algorithm revealed 5 secondary signals in our example GWAS on FT4, 5 secondary signals in case of the IBD and 19 secondary signals on human height, that would have gone undetected with the established genome-wide threshold (α=5×10−8). Availability and implementation https://github.com/sghasemi64/Secondary-Signal. Supplementary information Supplementary data are available at Bioinformatics online.

A super lightweight deck can enhance load rating and functionality of a bridge, especially those identified as structurally deficient. This study was aimed to develop and experimentally validate a novel bridge deck as an ultra-lightweight low-profile waffle slab of ultra-high-performance concrete (UHPC) with either carbon fiber reinforced polymer (CFRP) or high strength steel (HSS) reinforcement. The proposed system lends itself to accelerated bridge construction, rapid deck replacement in bridges with load restrictions, and bridge widening applications without the need to replace girders. Performance and failure modes of the proposed deck were initially assessed through extensive lab experiments and finite element analysis, which together confirmed that the proposed deck panel meets the AASHTO LRFD requirements. The proposed deck system is not susceptible to punching shear of its thin slab and fails in a rather ductile manner. To evaluate its long-term performance, the system was further tested under the dynamic impact of wheel load at the Accelerated Pavement Testing (APT) facility of the Florida Department of Transportation using a Heavy Vehicle Simulator (HVS).

BackgroundThe function of CD73, an enzyme that is involved in adenosine (ADO) generation, in glioblastoma development has been demonstrated however the details of its molecular mechanisms are not realized nevertheless. MethodsDue to the significance of angiogenesis in cancer progression, invasion, and metastasis, we intended to evaluate the impact of CD73 inhibition by adenosine 5′-(α, β-methylene) diphosphate (APCP) on the angiogenesis process of experimental orthotopic glioblastoma at mRNAs, microRNAs, and proteins levels. ResultsAccording to the real time-PCR findings, CD73 inhibition decreased glioblastoma angiogenesis by reducing vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) expression. Also, immunohistochemical staining showed that this treatment protocol attenuated the expression of VEGF and CD31. Moreover, APCP treatment in the glioblastoma model rats significantly increased miR-16 expression, although there is not observed significant change in expression in miR-29A. Treatment did not induce systemic damage or significant body weight loss.Conclusion In conclusion, our findings indicate that CD73 inhibition can diminish tumor new vessel generation by inhibiting the molecules involved in this process, thereby CD73 may be a practical target and provide novel opportunities for improving the treatment of malignant brain tumors.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Recent studies suggest that Spirulina may have great therapeutic benefits due to its antioxidant and anti-inflammatory properties. The primary objective of this study was to evaluate the chemopreventive properties of the Spirulina microalgae (Spi) on the regression and survival of tumor, histopathological features of glioblastoma, and detection of the molecular mechanism of Spi. Tumor viability versus Spi was determined using the MTT assay. In vivo antitumor activity of Spi was studied using the glioblastoma model. After tumor induction, the animals were euthanized, and their brains were removed. Histological evaluation was performed for tumor size and manifestation. The mechanisms of the anticancer effects of Spi were investigated by evaluating the microRNAs and their targets. The results demonstrated that Spi inhibited C6 and U87 cell proliferation and induced cell death. Histopathologic results showed that the administration of Spi could delay the development of tumors and prolonged the survival of tumor-bearing animals. Furthermore, Spi significantly upregulated miR-34a and miR-125b that have a key role in the progression of PI3K/AKT/mTOR pathway. This is the first in vivo report on the chemo-preventive effect of Spi against glioblastoma, suggesting its potential use in the chemoprevention of this cancer and the antiglioma molecular mechanism of Spi.

© 2019 Farjadian et al. Background: Smart materials capable of responding to external stimuli are noteworthy candidates in designing drug delivery systems. In many of the recent research, temperature and pH have been recognized as the main stimulating factors in designing systems for anticancer drugs delivery systems. Purpose: In this study, thermo and pH-responsive character of a nano-carrier drug delivery platform based on lysine modified poly (vinylcaprolactam) hydrogel conjugated with doxorubicin was assessed. Methods: Poly (vinylcaprolactam) cross-linked with poly (ethyleneglycol) diacrylate was prepared via RAFT polymerization, and the prepared structure was linked with lysine through ring-opening. The anti-cancer drug doxorubicin, was linked to lysine moiety of the prepared structure via Schiff-base reaction. The prepared platform was characterized by 1HNMR and FTIR, while molecular weight characterization was performed by size exclusion chromatography. The temperature-responsive activity was evaluated using differential scanning calorimetry and dynamic light scattering. In vitro release pattern in simulated physiologic pH at 37°C was compared with acidic pH attributed to tumor site and elevated temperature. The anticancer efficiency of the drug-conjugated structure was evaluated in breast cancer cell line MCF-7 in 24 and 48 h, and cell uptake assay was performed on the same cell line. Conclusion: According to the results, well-structure defined smart pH and temperature responsive nano-hydrogel was prepared. The enhanced release rates are observed at acidic pH and elevated temperature. We have concluded that the doxorubicin-conjugated nanoparticle results in higher cellular uptakes and more cytotoxicity.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort was comprised of 4,915 CKD patients and three independent validation cohorts were comprised of a total of 3,063. Patients were followed-up for approximately five years. NEW PREDICTORS & ESTABLISHED PREDICTORS: 22 demographic, anthropometric and laboratory variables commonly assessed in CKD patients. OUTCOMES: Progression to ESKD requiring KRT. ANALYTICAL APPROACH: A Least Absolute Shrinkage and Selection Operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for ESKD. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation. Both used a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable (Z6) risk score included serum creatinine, albumin, cystatin C and urea, as well as hemoglobin and the urine albumin-to-creatinine ratio. Based on the resampling approach, Z6 achieved a median C value of 0.909 (95% CI, 0.868-0.937) at two years after the baseline visit, whereas the T4 achieved a median C value of 0.855 (95% CI, 0.799-0.915). In the three independent validation cohorts, Z6 C values were 0.894, 0.921, and 0.891, whereas the T4 C values were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation, based on six routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to ESKD.

Molecular imprinting technology (MIT) was employed to fabricate polysulfone (PSf) membranes with specific nano-cavities for selective separation and enrichment of paclitaxel from a neat solution and also from yew tree extract. Polymer/template ratio, feed concentration, and the template extractor solvent were optimized. In accordance with the paclitaxel molecular dimension, the specific nano-cavities size was predicted to be 2.18 × 1.16 nm. The membranes were characterized in terms of pure water flux, molecular weight cut-off (MWCO), adsorption and diffusion, porosity, contact angle, and fouling. The results revealed that water flux through the molecularly imprinted membrane (MiM) is slightly less than that for the non-imprinted membrane (NiM), although the other properties relatively enhanced. For an in-depth understanding of the separation performance, the optimized membrane was analyzed by Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), and diffuse reflectance spectroscopy (DRS). ATR-FTIR spectra and SEM images showed no significant difference between the imprinted and non-imprinted membranes, while DRS spectra revealed a spatial orientation in the polymer chain. At the optimum condition (paclitaxel concentration in the dope solution =0.5 wt%, feed initial concentration = 20 ppm, and ethanol/water ratio = 50:50 v/v) the MiM exhibited relatively high ability to recognize and separate paclitaxel with imprinting factor of 2.28. The reuse of the MiM up to 3 repeated cycles showed no obvious deterioration in the performance. Furthermore, in a single pass MiM could enrich paclitaxel from a crude yew tree extract, a real or complex solution, up to 48%, which could be quite encouraging from industrial and pharmaceutical points of view.

Barley (Hordeum vulgare L.) is an important crop in many areas of the world. Drought and scarce resource of irrigation water are serious concerns in agricultural production in Iran and other arid and semi-arid regions. The objective of this study is to investigate the interaction effects of partial root drying (PRD) irrigation, planting method and different nitrogen application rates on yield, water and nitrogen use efficiencies and economical nitrogen and water use for barley in 2011–2012 cropping season. The experiment was designed as split–split plot that arranged in randomized complete blocks with irrigation strategy as the main plot, planting method as the subplot and nitrogen levels as the sub-subplot in three replications. The irrigation strategies consisted of ordinary furrow irrigation (OFI) and variable alternate furrow irrigation (VAFI) as a PRD technique. The planting methods included of on-ridge planting (ORP) and in-furrow planting (IFP) methods. The nitrogen levels were 0 (N0), 90 (N1) and 180 (N2) kg N ha−1 as urea. The results indicated that using VAFI method, 25% reduction in irrigation water depth was occurred compared with OFI, with no significant yield reduction. Furthermore, in IFP method, yield increased 13% compared with ORP. The maximum profits, water economic productivity, water use efficiency and water productivity were obtained in VAFI with IFP and nitrogen application rate of 180 kg/ha. Nitrogen use efficiency in VAFI compared with OFI was increased due to higher nitrogen absorption by plant. Thus, it is indicated that in areas with water limiting, it is preferable to recommend VAFI, IFP and 180 kg N ha−1 as best management practice for barley farm in the study region.

The aim of this work was the preparation of molecularly imprinted membrane (MiM) using polysulfone (PSf) polymer for targeted removal of polycyclic aromatic hydrocarbons from petrochemical wastewater. Naphthalene was opted as a model pollutant, and the imprinted membrane was fabricated by phase inversion technique. Nonimprinted membrane (NiM) was also prepared in the absence of naphthalene and used as a reference. The polymers (MiM/NiM) were systematically characterized using different characterization techniques. The selectivity property of the membranes was evaluated by their ability in separation of naphthalene through filtration tests. Results showed that in comparison with NiM, the imprinted membrane exhibits higher affinity toward naphthalene molecules. It was found that the selectively of MiM is 2.27-fold more than that of the corresponding NiM. This finding can be encouraging from industrial applications points of view.

Composite membranes are known to be promising platform for treatment of water and wastewaters. The aim of this work was to produce an effective and versatile hazardous material separation platform, polysulfone/graphene oxide (PSf/GO) nanocomposite membranes with different ratios of GO. The nanocomposite membranes were prepared through phase inversion technique and characterized by Fourier transform infrared, Raman spectroscopy, X-ray diffraction, and scanning electron microscope. The results from the GO and PSf/GO analyses confirmed the formation of exfoliated GO nanosheets and relatively the homogeneous dispersion of GO in the PSf nanocomposite membranes. Addition of GO to the membrane matrix led to about 10 degrees decrease in the contact angle, which nearly remained constant for all the composite membranes. The prepared membranes (i.e., PSf/GO and blank PSf membranes) were used for the separation of methylene blue from aqueous solution. In comparison with PSf membrane, PSf/GO membrane exhibited a remarkable adsorption/separation behavior.

Objectives: In recent years despite medical advances the Cesarean Section (CS) rate and its associated complications remain very high in Iran. This is while the CS carries serious risks for mother and child. Materials and Methods: This semi-experimental study was carried out on a sample 0f 87 primigravida women who referred to obstetrics and gynecology clinics affiliated to Shiraz University of Medical Sciences for receiving prenatal care in winter 2014. After a pre-test by using a valid and reliable questionnaire in both groups educational intervention was provided for the intervention group. The post-test was conducted after one month of the intervention. Then the data were analyzed by the Statistical Package for the Social Sciences (SPSS) version 20. Results: The findings showed a significant statistical differences between two groups’ behavioral beliefs outcome evaluation attitude control beliefs perceived power and perceived behavioral control scores after intervention (P

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

Background Smart materials capable of responding to external stimuli are noteworthy candidates in designing drug delivery systems. In many of the recent research, temperature and pH have been recognized as the main stimulating factors in designing systems for anti-cancer drugs delivery systems. Purpose In this study, thermo and pH-responsive character of a nano-carrier drug delivery platform based on lysine modified poly (vinylcaprolactam) hydrogel conjugated with doxorubicin was assessed. Methods Poly (vinylcaprolactam) cross-linked with poly (ethyleneglycol) diacrylate was prepared via RAFT polymerization, and the prepared structure was linked with lysine through ring-opening. The anti-cancer drug doxorubicin, was linked to lysine moiety of the prepared structure via Schiff-base reaction. The prepared platform was characterized by 1HNMR and FT-IR, while molecular weight characterization was performed by size exclusion chromatography. The temperature-responsive activity was evaluated using differential scanning calorimetry and dynamic light scattering. In vitro release pattern in simulated physiologic pH at 37°C was compared with acidic pH attributed to tumor site and elevated temperature. The anticancer efficiency of the drug-conjugated structure was evaluated in breast cancer cell line MCF-7 in 24 and 48 h, and cell uptake assay was performed on the same cell line. Conclusion According to the results, well-structure defined smart pH and temperature responsive nano-hydrogel was prepared. The enhanced release rates are observed at acidic pH and elevated temperature. We have concluded that the doxorubicin-conjugated nanoparticle results in higher cellular uptakes and more cytotoxicity.

Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10−56) and SLC2A9 (p = 4.5 × 10−7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10−3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout., Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico.

In this study, bovine serum albumin (BSA) hollow-nano-spheres (HNS) were synthesized as nano-carriers for paclitaxel (PTX) as model drug. Hierarchically, first, the exterior surface of silica nanoparticles was modified with (3-aminopropyl)triethoxysilane (APTES) and then with glutaraldehyde (GA). Then, BSA at alkaline pH was adsorbed on the surface of the modified nanoparticles and further crosslinked with GA. Finally, the core was acid washed to obtain HNS. The results indicated that the HNS is successfully formed with a spherical structure and an average shell thickness of 8 nm and a diameter of 28 nm. Subsequently, different ratios of PTX-HNS were used for in vitro release study of PTX. The opted amount of PTX-HNS was 10% and the release data were more compatible with the Gallagher-Corrigan model. The in vitro cytotoxicity activity of the PTX-loaded HNS was assessed using lung cancer cell lines. According to the MTT assay for 24 and 48 h period, the cell survival rate reduction of the incubated cells with the PTX-HNS of 0.1, 1, and 10 μg mL−1 doses after 48 h was remarkably higher than that of the pure drug. The present study could represent a further step towards a rational colloidal hollow-nanocarrier design, preparation, and usage.

In this work, novel hydroxyl-modified magnetite nanocarriers are introduced as efficient host for methotrexate conjugation. The modification was based on the Micheal type addition reaction between tris(hydroxymethyl) aminomethane and acrylamidopropyl functionalized, silica-coated magnetite nanoparticle. The chemical structure characterization was carried out by FT-IR and the organic content was determined by CHN analysis. The topography was studied by SEM, TEM, AFM. DLS was performed to show particles' mean diameter. Furthermore, the magnetite properties of modified particles were evaluated by VSM and the crystallinity was proved by XRD. To illustrate the efficiency of the modified particles, the anti-cancer drug methotrexate was conjugated to hydroxyl groups through estric bond formation. The controlled release activity of established nanoparticles was evaluated in simulated cellular fluid. Later, the anti-cancer behavior of drug conjugated nanoparticles was evaluated in vitro in MCF-7 cell line which showed enhanced toxicity after 48 h. Conclusively, the modified nanoparticles have remarked as powerful carrier to be applied as an anti-cancer agent.

Movable bridges often include open grid steel deck for its light weight and ease of installation. These decks, however, suffer from poor rideability and high maintenance costs. In search for a new generation of lightweight solid decks that address these issues, a novel system was recently developed using ultra-high performance concrete (UHPC) in the form of a low-profile asymmetric waffle slab reinforced with high-strength steel (HSS) rebars. The deck was shown as a structurally viable alternative, yet its overall weight including haunches and connections exceeded the weight limits for deck replacement on some existing movable bridges. The purpose of this study was to optimize the design of proposed UHPC–HSS deck system to meet the weight limits for existing movable bridges. The size and reinforcement of the proposed deck were modified in two phases, and five specimens with single or multiple ribs were tested in simple or two-span configurations. Test results have shown that the optimized section with an overall depth of 102 mm and the main longitudinal reinforcement of No. 16 M (16 mm) can suitably meet the load demand, ductility and serviceability requirements, while staying within the weight limits of 1.0 kN/m 2 for a movable bridge with a stringer spacing of 1.2 m.

Though a joyful event for most women, pregnancy is often a stressful period both physically and mentally, and pregnant women need social support from husband, family, friends, health professionals, and other important people in order to facilitate, adapt with, and obtain mental balance. Therefore, the present study aimed to determine the relationship between perceived social supports and some demographic characteristics in Primigravida women. This analytical, cross-sectional study was conducted on the Primigravida women referred to obstetrics and gynecology clinics of Shahid Ayatollah Motahari and Hafez hospitals affiliated to Shiraz University of Medical Sciences for receiving prenatal care in 2014. The data were gathered by demographic characteristics questionnaire and multidimensional scale of perceived social support (MSPSS). Then, the data were analyzed by the statistical package for the social sciences (SPSS), version 20 using Pearson’s correlation coefficient and multivariate linear regression analysis. The results showed that the highest and lowest mean scores were related to perceived social support from husband and perceived social support from friends, respectively. Besides, the majority of the participants had high levels of perceived social support. However, no significant correlation was found between perceived social support from husband and total perceived social support and husband’s age, pregnant woman’s age, age at marriage, and gestational age. Moreover, the results showed that husband’s education level, husband’s occupation, pregnant woman’s education level, pregnant woman’s occupation, and socioeconomic class could not predict perceived social support from husband and total perceived social support. The results of the present study revealed no significant association between demographic variables and perceived social support. This might be attributed to the fact that perceived social support is more a subjective phenomenon, and depends on an individual’s level of perception but not to the amount received. Key words: Pregnancy, primiparity, social support, perception.

Methyl-tert-butyl ether (MTBE) is widely used as an antiknock additive for increasing octane number of gasoline. Recently, the in vivo studies demonstrated that MTBE has genotoxic potential and able to form adducts with DNA. In the work, the interactions of MTBE with calf thymus DNA (ct-DNA) and the Na+ form of G-quadruplex DNA (wtTel22) were studied by using of head space-solid phase microextraction technique coupled to gas chromatography. The binding equilibrium constants were measured through the equilibriums of a four phase system. In addition, the MTBE Henry's law constants for two different buffers in the temperature range of 283–303 K were measured. Thermodynamic studies revealed that the complexation of MTBE to both DNAs is enthalpy favored and entropy disfavored. The thermodynamic results revealed that MTBE may have interaction with ct-DNA via the minor groove of DNA. Also, MTBE may be complexed into the basket of G-quadruplex structure. In addition, the low difference in the binding constants of MTBE for both different DNA targets may confirm that MTBE is poorly selective for different conformations of DNA.