EFIN: predicting the functional impact of nonsynonymous single nucleotide polymorphisms in human genome

Background Predicting the functional impact of amino acid substitutions (AAS) caused by nonsynonymous single nucleotide polymorphisms (nsSNPs) is becoming increasingly important as more and more novel variants are being discovered. Bioinformatics analysis is essential to predict potentially causal or contributing AAS to human diseases for further analysis, as for each genome, thousands of rare or private AAS exist and only a very small number of which are related to an underlying disease. Existing algorithms in this field still have high false prediction rate and novel development is needed to take full advantage of vast amount of genomic data. Results Here we report a novel algorithm that features two innovative changes: 1. making better use of sequence conservation information by grouping the homologous protein sequences into six blocks according to evolutionary distances to human and evaluating sequence conservation in each block independently, and 2. including as many such homologous sequences as possible in analyses. Random forests are used to evaluate sequence conservation in each block and to predict potential impact of an AAS on protein function. Testing of this algorithm on a comprehensive dataset showed significant improvement on prediction accuracy upon currently widely-used programs. The algorithm and a web-based application tool implementing it, EFIN (Evaluation of Functional Impact of Nonsynonymous SNPs) were made freely available (http://paed.hku.hk/efin/) to the public. Conclusions Grouping homologous sequences into different blocks according to evolutionary distance of the species to human and evaluating sequence conservation in each group independently significantly improved prediction accuracy. This approach may help us better understand the roles of genetic variants in human disease and health.published_or_final_versio

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases

A Randomized Trial of Insulin Glargine plus Oral Hypoglycemic Agents versus Continuous Subcutaneous Insulin Infusion to Treat Newly Diagnosed Type 2 Diabetes

Aims. Basal insulin plus oral hypoglycemic agents (OHAs) has not been investigated for early intensive antihyperglycemic treatment in people with newly diagnosed type 2 diabetes. This study is aimed at comparing the short-term (over a period of 12 days) effects of basal insulin glargine plus OHAs and continuous subcutaneous insulin infusion (CSII) on glycemic control and beta-cell function in this setting. Methods. An open-label parallel-group study. Newly diagnosed hospitalized patients with type 2 diabetes and fasting plasma glucose (FPG) ≥11.1 mmol/L or glycated hemoglobin (HbA1c) ≥9% (75 mmol/mol) were randomized to CSII or insulin glargine in combination with metformin and gliclazide. The primary outcome measure was the mean amplitude of glycemic excursions (MAGE), and secondary endpoints included time to reach glycemic control target (FPG < 7 mmol/L and 2-hour postprandial plasma glucose < 10 mmol/L), markers of β-cell function, and hypoglycemia. Results. Subjects in the CSII (n=35) and basal insulin plus OHA (n=33) groups had a similar significant reduction from baseline to end of treatment in glycated albumin (−6.44 ± 3.23% and− 6.42 ± 3.56%, P=0.970). Groups A and B have comparable time to glycemic control (3.6 ± 1.2 days and 4.0 ± 1.4 days), MAGE (3.40 ± 1.40 mmol/L vs. 3.16 ± 1.38 mmol/L; p=0.484), and 24-hour mean blood glucose (7.49 ± 0.96 mmol/L vs. 7.02 ± 1.03 mmol/L). Changes in the C-peptide reactivity index, the secretory unit of islet in transplantation index, and insulin secretion-sensitivity index-2 indicated a greater β-cell function improvement with basal insulin plus OHAs versus CSII. Conclusions. Short-term insulin glargine plus OHAs may be an alternative to CSII for initial intensive therapy in people with newly diagnosed type 2 diabetes

Supplemental Material - Relationship between dust allergen sensitization and cardiac autonomic function in patients with chronic obstructive pulmonary disease

Supplemental Material for Relationship between dust allergen sensitization and cardiac autonomic function in patients with chronic obstructive pulmonary disease by Meie Zeng, Shuifen Ye, Wanling Huang, Weiwei Deng, Simin Zou, Chunmei Huang and Hanzhong Qiu in Chronic Respiratory Disease</p

Analysis of factors influencing parents’ willingness to accept the quadrivalent influenza vaccine for school-aged children in the Nanhai District, China

Recently, China has attached great importance to promoting immunization, prompting the media, scholars, and public to focus on its coverage and efficacy. This study aimed to understand the factors influencing parental willingness to have their school-aged children vaccinated with quadrivalent influenza vaccines (QIVs). A cross-sectional study through face-to-face interviews was conducted between September and December 2018. Forty-four kindergartens and primary and junior high schools were randomly selected via stratified three-stage cluster sampling. Of 4,430 participants, 24.6% reported having heard of QIV and 24.2% reported having previously received information on QIV. Of these, 42.8% expressed willingness to obtain the QIV for their children. A junior college degree (adjusted odds ratio [aOR] = 1.447; 95% confidence interval [95% CI]: 1.202–1.742), higher influenza knowledge level (medium level, aOR = 1.150, 95% CI, 1.006–1.314; high level, aOR = 1.332, 95% CI, 1.045–1.697), and previous influenza information (aOR = 2.241; 95% CI, 1.604–3.130) were positively correlated with vaccination willingness. In contrast, no previous QIV-related information (aOR = 0.490; 95% CI, 0.418–0.575), no perceived susceptibility of children to influenza (aOR = 0.576; 95% CI, 0.489–0.680), fear of side effects (aOR = 0.599; 95% CI, 0.488–0.735), concern that vaccines need to be carefully administered (aOR = 0.728; 95% CI, 0.593–0.894), and mistrust of new vaccines (aOR = 0.730; 95% CI, 0.628–0.849) were pivotal barriers hindering parents from having their children vaccinated. This study provides baseline information for future immunization programs and delivery, with the ultimate goal of increasing vaccine uptake and minimizing school-wide influenza outbreaks

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRABACh (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors