KofamKOALA: KEGG ortholog assignment based on profile HMM and adaptive score threshold

Summary: KofamKOALA is a web server to assign KEGG Orthologs (KOs) to protein sequences by homology search against a database of profile hidden Markov models (KOfam) with pre-computed adaptive score thresholds. KofamKOALA is faster than existing KO assignment tools with its accuracy being comparable to the best performing tools. Function annotation by KofamKOALA helps linking genes to KEGG resources such as the KEGG pathway maps and facilitates molecular network reconstruction. Availability and implementation: KofamKOALA, KofamScan and KOfam are freely available from GenomeNet (https://www.genome.jp/tools/kofamkoala/). Supplementary information: Supplementary data are available at Bioinformatics online

Effects of a high-fat diet on the electrical properties of porcine atria

AbstractBackgroundBecause obesity is an important risk factor for atrial fibrillation (AF), we conducted an animal study to examine the effect of a high-fat diet (HFD) on atrial properties and AF inducibility.MethodsTen 8-week-old pigs (weight, 18–23kg) were divided into two groups. For 18 weeks, five pigs were fed a HFD (HFD group) and five were fed a normal diet (control group). Maps of atrial activation and voltages during sinus rhythm were created for all pigs using the EnSite NavX system. Effective refractory period (ERP) and AF inducibility were also determined. When AF was induced, complex fractionated atrial electrogram (CFAE) mapping was performed. At 18 weeks, hearts were removed for comparing the results of histological analysis between the two groups. Body weight, lipid levels, hemodynamics, cardiac structures, and electrophysiological properties were also compared.ResultsTotal cholesterol levels were significantly higher (347 [191–434] vs. 81 [67–88]mg/dL, P=0.0088), and left atrium pressure was higher (34.5 [25.6–39.5] vs. 24.5 [21.3–27.8]mmHg, P=0.0833) in the HFD group than in the control group, although body weight only increased marginally (89 [78–101] vs. 70 [66–91]kg, P=0.3472). ERPs of the pulmonary vein (PV) were shorter (P<0.05) and AF lasted longer in the HFD group than in the control group (80 [45–1350] vs. 22 [3–30]s, P=0.0212). Neither CFAE site distribution nor histopathological characteristics differed between the two groups.ConclusionsThe shorter ERPs for the PV observed in response to the HFD increased vulnerability to AF, and these electrophysiological characteristics may underlie obesity-related AF

Synthesis and biological activity of artificial mRNA prepared with novel phosphorylating reagents

Though medicines that target mRNA are under active investigation, there has been little or no effort to develop mRNA itself as a medicine. Here, we report the synthesis of a 130-nt mRNA sequence encoding a 33-amino-acid peptide that includes the sequence of glucagon-like peptide-1, a peptide that stimulates glucose-dependent insulin secretion from the pancreas. The synthesis method used, which had previously been developed in our laboratory, was based on the use of 2-cyanoethoxymethyl as the 2′-hydroxy protecting group. We also developed novel, highly reactive phosphotriester pyrophosphorylating reagents to pyrophosphorylate the 5′-end of the 130-mer RNA in preparation for capping. We completed the synthesis of the artificial mRNA by the enzymatic addition of a 5′-cap and a 3′-poly(A) tail to the pyrophosphorylated 130-mer and showed that the resulting mRNA supported protein synthesis in a cell-free system and in whole cells. As far as we know, this is the first time that mRNA has been prepared from a chemically synthesized RNA sequence. As well as providing a research tool for the intracellular expression of peptides, the technology described here may be used for the production of mRNA for medical applications

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

IMPORTANCE ‐ Early identification of individuals at elevated risk of developing chronic kidney disease  could improve clinical care through enhanced surveillance and better management of underlying health  conditions.  OBJECTIVE – To develop assessment tools to identify individuals at increased risk of chronic kidney  disease, defined by reduced estimated glomerular filtration rate (eGFR).  DESIGN, SETTING, AND PARTICIPANTS – Individual level data analysis of 34 multinational cohorts from  the CKD Prognosis Consortium including 5,222,711 individuals from 28 countries. Data were collected  from April, 1970 through January, 2017. A two‐stage analysis was performed, with each study first  analyzed individually and summarized overall using a weighted average. Since clinical variables were  often differentially available by diabetes status, models were developed separately within participants  with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external  cohorts (N=2,253,540). EXPOSURE Demographic and clinical factors.  MAIN OUTCOMES AND MEASURES – Incident eGFR <60 ml/min/1.73 m2.  RESULTS – In 4,441,084 participants without diabetes (mean age, 54 years, 38% female), there were  660,856 incident cases of reduced eGFR during a mean follow‐up of 4.2 years. In 781,627 participants  with diabetes (mean age, 62 years, 13% female), there were 313,646 incident cases during a mean follow‐up of 3.9 years. Equations for the 5‐year risk of reduced eGFR included age, sex, ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, BMI, and albuminuria. For participants  with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction  between the two. The risk equations had a median C statistic for the 5‐year predicted probability of  0.845 (25th – 75th percentile, 0.789‐0.890) in the cohorts without diabetes and 0.801 (25th – 75th percentile, 0.750‐0.819) in the cohorts with diabetes. Calibration analysis showed that 9 out of 13 (69%) study populations had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was  similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 out of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. CONCLUSIONS AND RELEVANCE – Equations for predicting risk of incident chronic kidney disease developed in over 5 million people from 34 multinational cohorts demonstrated high discrimination and  variable calibration in diverse populations

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity