Comprehensive evaluation of apolipoprotein H gene (APOH) variation identifies novel associations with measures of lipid metabolism in GENOA

Apolipoprotein H (apoH, also named beta-2 glycoprotein I) is found on several classes of lipoproteins, and is involved in the activation of lipoprotein lipase in lipid metabolism. We have comprehensively investigated the association of variation in the apoH gene (APOH) with lipid traits in hepatic cholesterol transport, dietary cholesterol transport (DCT), and reverse cholesterol transport (RCT). Our study population consisted of families from the Genetic Epidemiology Network of Arteriopathy multicenter study that include African Americans, Mexican Americans, and European Americans. We individually tested 36 single-nucleotide polymorphisms (SNPs) that span the APOH locus, including nonsynonymous variants that result in known apoH charge isoforms. In addition, we constructed haplotypes from SNPs in the 5' promoter region that comprise cis-acting regulatory elements, as well as haplotypes for multiple amino acid substitutions. We found point-wise significant associations of APOH variants with various lipid measures in the three racial groups. The strongest associations were found for DCT traits (triglyceride and apoE levels) in Mexican Americans with a nonsynonymous variant (SNP 14917, Cys306Gly) that may alter apoH protein folding in a region involved in phospholipid binding. In conclusion, family-based analyses of APOH variants have identified associations with measures of lipid metabolism in three American racial groups.     

Application of discrete choice experiments to enhance stakeholder engagement as a strategy for advancing implementation: a systematic review

Background

One of the key strategies to successful implementation of effective health-related interventions is targeting improvements in stakeholder engagement. The discrete choice experiment (DCE) is a stated preference technique for eliciting individual preferences over hypothetical alternative scenarios that is increasingly being used in health-related applications. DCEs are a dynamic approach to systematically measure health preferences which can be applied in enhancing stakeholder engagement. However, a knowledge gap exists in characterizing the extent to which DCEs are used in implementation science.

Methods

We conducted a systematic literature search (up to December 2016) of the English literature to identify and describe the use of DCEs in engaging stakeholders as an implementation strategy. We searched the following electronic databases: MEDLINE, Econlit, PsychINFO, and the CINAHL using mesh terms. Studies were categorized according to application type, stakeholder(s), healthcare setting, and implementation outcome.

Results

Seventy-five publications were selected for analysis in this systematic review. Studies were categorized by application type: (1) characterizing demand for therapies and treatment technologies (n?=?32), (2) comparing implementation strategies (n?=?22), (3) incentivizing workforce participation (n?=?11), and (4) prioritizing interventions (n?=?10). Stakeholders included providers (n?=?27), patients (n?=?25), caregivers (n?=?5), and administrators (n?=?2). The remaining studies (n?=?16) engaged multiple stakeholders (i.e., combination of patients, caregivers, providers, and/or administrators). The following implementation outcomes were discussed: acceptability (n?=?75), appropriateness (n?=?34), adoption (n?=?19), feasibility (n?=?16), and fidelity (n?=?3).

Conclusions

The number of DCE studies engaging stakeholders as an implementation strategy has been increasing over the past decade. As DCEs are more widely used as a healthcare assessment tool, there is a wide range of applications for them in stakeholder engagement. The DCE approach could serve as a tool for engaging stakeholders in implementation science.

     

Multivariate models for human genetic analysis: aggregation, coaggregation, and tracking of systolic blood pressure and weight.

A multivariate path model parameterizing the sources of familial aggregation and coaggregation of systolic blood pressure and weight, as well as their tracking across time, is applied to longitudinal data collected in Muscatine, Iowa. Genetic, common household, and individual environmental effects, pleiotropy, and a direct regression effect of blood pressure on weight are parameterized. The sample consisted of 998 individuals distributed in 261 families of whom 601 were measured on four successive occasions. The data were divided with times 1 and 2 forming group 1, and times 3 and 4, group 2. Model fitting and estimation was performed using group 1, followed by testing the model and estimates using the data in group 2. Heritability estimates for systolic blood pressure and weight were .15 and .54, respectively. The genetic correlation between these traits was nonsignificant, but there was a significant direct regression effect. The results indicate that 30% of the full-sib correlation for systolic blood pressure is attributable to the aggregation of weight. In terms of tracking, 59% and 60% of the predicted systolic blood pressure and weight correlations, respectively, were attributable to genetic effects. Testing the model from group 1 in group 2 indicates that the qualitative relationships between blood pressure and weight are stable with time.     

Cultivation of the first mesophilic representative ("mesotoga") within the order Thermotogales

Cultivated members of the order Thermotogales comprise only thermophilic to hyperthermophilic anaerobic microorganisms. However, based on molecular studies, the existence of mesophilic members (“mesotoga”) within this order has been postulated but has not been demonstrated by cultural approaches so far. A “mesotoga” (strain PhosAc3) that belonged to an uncultivated lineage distantly related to the thermophilic Kosmotoga genus has now been cultivated in axenic culture. It grew between 30 °C and 50 °C (optimum 40 °C) and oxidized lactate using elemental sulphur as a terminal electron acceptor. Further genomic and physiological characterization of strain PhosAc3 will be important not only for understanding bacterial adaptation to high and moderate temperatures at small evolutionary scales, but also because “mesotoga” might play a crucial ecological role in ecosystems polluted by aromatic compounds.     

Facile synthesis and stereochemical investigation of Mannich base derivatives: evaluation of antioxidant property and antituberculostic potency

A mini-library of diversely substituted 2,4-diaryl-3-azabicyco[3.3.1]nonan-9-one O-methyloximes and their N-methyl analogs were synthesized by a non-laborious, modified and an optimized Mannich condensation in good yields. Both the ring N-methylation and oxime O-methylation were employed by various methods; of them, the usage of ^tBuOK was found to be the superior in terms of good yield in short time. Stereochemistry of all the synthesized compounds was unambiguously established by their NMR spectral (¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C one and multiple bond COSY and NOESY) as well as single-crystal XRD studies. Irrespective of the nature and position of the substituents, all the synthesized oxime ethers of the bicyclic Mannich bases as well as their N-methyl analogs adopted the twin-chair conformation with equatorial orientations of all the substituents. All the synthesized oxime ethers were evaluated for their antioxidant property by DPPH radical scavenging method. According to the structure-activity correlations, compound 4y was found to be a lead molecule with the IC₅₀ of 0.187 mg/mL. Thus, the present study exploits the scope of finding more active analogs by further optimization with the incorporation of more electron enriched alkoxy/amino and/or phenolic groups on the heterocycle as well as oxime ether pharmacophore. Most of the synthesized molecules were screened for their antituberculostic potency against Mycobacterium tuberculosis H₃₇Rv by zone of inhibition method. Of them, 4w/5d and 4x showed very promising inhibition zones of 21 and 23 mm, respectively, which leads to the optimization of 4x by introducing various substituents on the O-benzyl moiety to enhance the antituberculostic potency.     

Bacterial diversity and composition of an alkaline uranium mine tailings-water interface

The microbial diversity and biogeochemical potential associated with a northern Saskatchewan uranium mine water-tailings interface was examined using culture-dependent and -independent techniques. Morphologically-distinct colonies from uranium mine water-tailings and a reference lake (MC) obtained using selective and non-selective media were selected for 16S rRNA gene sequencing and identification, revealing that culturable organisms from the uranium tailings interface were dominated by Firmicutes and Betaproteobacteria; whereas, MC organisms mainly consisted of Bacteroidetes and Gammaproteobacteria. Ion Torrent (IT) 16S rRNA metagenomic analysis carried out on extracted DNA from tailings and MC interfaces demonstrated the dominance of Firmicutes in both of the systems. Overall, the tailings-water interface environment harbored a distinct bacterial community relative to the MC, reflective of the ambient conditions (i.e., total dissolved solids, pH, salinity, conductivity, heavy metals) dominating the uranium tailings system. Significant correlations among the physicochemical data and the major bacterial groups present in the tailings and MC were also observed. Presence of sulfate reducing bacteria demonstrated by culture-dependent analyses and the dominance of Desulfosporosinus spp. indicated by Ion Torrent analyses within the tailings-water interface suggests the existence of anaerobic microenvironments along with the potential for reductive metabolic processes.     

The genetic constitutions of complementary genes Pp and Pb determine the purple color variation in pericarps with cyanidin-3-O-glucoside depositions in black rice

The purple pericarp color in rice was controlled by two dominant complementary genes, Pb and Pp. Crossing black rice ‘Heugnambyeo’ variants with three varieties of white pericarp rice gave a segregation ratio of 9 purple: 3 brown: 4 white. The Pp genes were segregated by homozygous PpPp alleles for the dark purple pericarps, heterozygous Pppp alleles for the medium and mixed purple pericarps, and homozygous pppp alleles for either brown or white pericarps with a 1 PpPp: 2 Pppp: 1 pppp segregation ratio, indicating that the Pp allele in rice is incompletely dominant to the recessive pp allele. Among the purple seeds, the amount of cyanidin-3-O-glucoside was higher in the dark purple seeds (Pb_PpPp) than in the medium purple seeds (Pb_Pppp). Moreover, no cyanidin-3-glucoside was detected in brown (Pb_pppp) or white pericarp seeds (pbpbpppp). These findings indicated that the level of cyanidin-3-glucoside was determined by the copy number of the Pp allele. Further genotype investigation of the F₃ progeny demonstrated that the dominant Pb allele was present in either purple or brown pericarp. A 2-bp (GT) deletion from the DNA sequences of the dominant and functional Pb was found in the same DNA sequences of the recessive and non-functional pb allele. These findings suggested that the presence of at least a dominant Pb allele was an essential factor for color development in rice pericarps. In conclusion, the Pp allele in rice is incompletely dominant to the recessive pp allele; thus, the number of dominant Pp alleles determines the concentration of cyanidin-3-O-glucoside in black rice.     

Anti-RAGE (Receptor Advanced Glycation End products) Antibody Improves Diabetic Retinopathy in Rats via Hypoglycemic and Anti-inflammatory Mechanism

Background:Receptor advanced glycation end products (RAGE) activation plays an essential role in diabetic retinopathy (DR) progression. This study was aimed to explore the role of anti-RAGE antibodies (RAGE antagonists) in inhibiting DR progression through their hypoglycemic and anti-inflammatory mechanism in diabetic retinopathy induced rats.Methods:A total of 30 male Wistar rats were randomly divided into five group. The group was consisted of normal control group, DR group without treatment, DR group with anti-RAGE 1 ηg/kg BW, 10 ηg/kg BW, and 100 ηg/kg BW. To assess the diabetic retinopathy, fundus photographs were taken every week using a camera with 16x magnification placed in front of the rat''s eyes. Blood glucose was checked by the glucose oxidase-peroxidase method. Retinal TNF-α levels and VEGF were examined using an enzyme-linked immunosorbent assay (ELISA) kit.Results:The finding of this study showed that anti-RAGE treatment at dose of 10 and 100 ηg/kg BW, HbA1c levels were significantly higher (p< 0.05) compared to the normal control group but significantly lower (p< 0.05) than in the diabetes group. The mean blood vessel diameter in the DR+anti-RAGE 10 and 100 ηg/kg BW groups was significantly lower than in the diabetic retinopathy group (p< 0.05). The administration of anti-RAGE 10 and 100 ηg/kg BW showed the ability to significantly reduce VEGF levels compared to the DR group (p< 0.05).DiscussionThis study revealed at doses of 10 and 100 ηg/kg BW, anti-RAGE antibodies improved diabetic retinopathy in Wistar rats through hypoglycemic effects and anti-inflammatory mechanisms.Key Words: Anti-RAGE (Receptor Advanced Glycation End products), Diabetic Retinopathy, Glycated Hemoglobin A, Hypoglycemic Agents, Peroxidases, Vascular Endothelial Growth Factor A