Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene

Abstract The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases (TALENs) technology to generate Leptin receptor (Lepr) knockout rats on the Sprague Dawley (SD) genetic background. Through direct injection of in vitro transcribed mRNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models.</jats:p

Safety and Effectiveness of Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

Recent clinical trials have shown that while bivalirudin exhibits similar efficacy with heparin, it offers several advantages over heparin, such as a better safety profile. We aimed to evaluate the efficacy and safety of bivalirudin use during Percutaneous Coronary Intervention (PCI) in the treatment of angina and acute coronary syndrome (ACS). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, EMBASE, and Science Direct from January 1980 to January 2016. Randomized controlled trials (RCTs) comparing bivalirudin to heparin during the course of PCI in patients with angina or ACS were included. Outcome measures included all-cause mortality, myocardial infarction, revascularisation, stent thrombosis, stroke, and major bleeding. The selection, quality assessment, and data extraction of the included trials were done independently by four authors, and disagreements were resolved by consensus. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated. A total of 12 RCTs involving 44,088 subjects were included. Bivalirudin appeared to be non-superior compared to heparin in reducing all-cause mortality, myocardial infarction, revascularisation, and stroke. Bivalirudin appeared to be related to a higher risk of stent thrombosis when compared to heparin plus provisional use of a glycoprotein IIb/IIIa inhibitor (GPI) at day 30 (RR 1.94 [1.16, 3.24] p &lt; 0.01). Overall, bivalirudin-based regimens present a lesser risk of major bleeding (RR 0.56 [0.44–0.71] p &lt; 0.001), and Thrombolysis In Myocardial Infarction (TIMI) major bleeding (RR 0.56 [0.43–0.73]) compared with heparin-based regimens either with provisional or routine use of a GPI. However, the magnitude of TIMI major bleeding effect varied greatly (p &lt; 0.001), depending on whether a GPI was provisionally used (RR 0.42 [0.34–0.52] p &lt; 0.001) or routinely used (RR 0.60 [0.43 –0.83] p &lt; 0.001), in the heparin arm. This meta-analysis demonstrated that bivalirudin is associated with a lower risk of major bleeding, but a higher risk of stent thrombosis compared to heparin

Transcription-driven genome organization::A model for chromosome structure and the regulation of gene expression tested through simulations

Current models for the folding of the human genome see a hierarchy stretching down from chromosome territories, through A/B compartments and topologically-associating domains (TADs), to contact domains stabilized by cohesin and CTCF. However, molecular mechanisms underlying this folding, and the way folding affects transcriptional activity, remain obscure. Here we review physical principles driving proteins bound to long polymers into clusters surrounded by loops, and present a parsimonious yet comprehensive model for the way the organization determines function. We argue that clusters of active RNA polymerases and their transcription factors are major architectural features; then, contact domains, TADs and compartments just reflect one or more loops and clusters. We suggest tethering a gene close to a cluster containing appropriate factors—a transcription factory—increases the firing frequency, and offer solutions to many current puzzles concerning the actions of enhancers, super-enhancers, boundaries and eQTLs (expression quantitative trait loci). As a result, the activity of any gene is directly influenced by the activity of other transcription units around it in 3D space, and this is supported by Brownian-dynamics simulations of transcription factors binding to cognate sites on long polymers

A Speech Enhancement Algorithm for Speech Reconstruction Based on Laser Speckle Images

In the optical system for reconstructing speech signals based on laser speckle images, the resonance between the sound source and nearby objects leads to frequency response problem, which seriously affects the accuracy of reconstructed speech. In this paper, we propose a speech enhancement algorithm to reduce the frequency response. The results show that after using the speech enhancement algorithm, the frequency spectrum correlation coefficient between the reconstructed sinusoidal signal and the original sinusoidal signal is improved by up to 82.45%, and the real speech signal is improved by up to 56.40%. This proves that the speech enhancement algorithm is a valuable tool for solving the frequency response problem and improving the accuracy of reconstructed speech

An algorithm for cognitive fusion targeted tumor puncture based on 3-D mathematical modelling

Background: Percutaneous puncture is an important means of tumor diagnosis and treatment. At present, most puncture operations are still based on imaging location and clinical experience, and quantitative and accurate targeted puncture cannot be achieved. How to improve the accuracy of percutaneous tumor puncture, avoid errors to the greatest extent, reduce the occurrence of complications, and improve the overall clinical diagnosis and treatment quality and curative effect, are scientific problems worthy of further study. Method: In the present study, mathematical modeling was first used to construct the tumor puncture path, determine the needle entry angle, and define the relevant limited parameters and the substitution formula. Secondly, relevant parameters were extracted from CT and other imaging data and substituted into formulas, the deviation angle and puncture path were determined, and the personalized tumor puncture scheme was carried out. Third, targeted puncture was precisely implemented under the guidance of B-ultrasound. Compared with the traditional empirical puncture, our model improved the accuracy, decreased the puncture time, and reduced the pain of diagnosis and treatment for patients. Results: A tumor-targeted puncture model was established based on mathematical theory and imaging data. By extracting clinical data, such as tumor radius, projection distance of tumor center and projection distance from puncture point to body surface, the optimal puncture deviation angle was modeled and calculated and a personalized puncture scheme was established. Compared with the conventional method, our model markedly increased the puncture accuracy rate by ∼30%. The puncture number was decreased by ∼50% using our model. Furthermore, our model shortened the operation time by 20% to ease pain of patients and guarantee greater security for patients. Doctor satisfaction and patient discomfort scores were examined. Our model improved doctor satisfaction by ∼20% and reduced subjective discomfort of patients by ∼25%. These data revealed that the model could markedly improve the accuracy and efficiency of puncture, clinical efficacy and accuracy of tumor diagnosis. Additionally, the confidence of doctors in the operation was greatly enhanced and patient discomfort was greatly reduced. Conclusion: The present study analyzed in detail how to find the best puncture path using a mathematical model. Based on the mathematical model of cognitive fusion puncture, combined with clinical personalized data and mathematical calculation analysis, accurate puncture was effectively realized. It not only greatly improved the effectiveness of puncture, but also ensured the safety of clinical patients and reduced injury, which means it may be worthy of clinical application

Safety and Effectiveness of Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

Recent clinical trials have shown that while bivalirudin exhibits similar efficacy with heparin, it offers several advantages over heparin, such as a better safety profile. We aimed to evaluate the efficacy and safety of bivalirudin use during Percutaneous Coronary Intervention (PCI) in the treatment of angina and acute coronary syndrome (ACS). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, EMBASE, and Science Direct from January 1980 to January 2016. Randomized controlled trials (RCTs) comparing bivalirudin to heparin during the course of PCI in patients with angina or ACS were included. Outcome measures included all-cause mortality, myocardial infarction, revascularisation, stent thrombosis, stroke, and major bleeding. The selection, quality assessment, and data extraction of the included trials were done independently by four authors, and disagreements were resolved by consensus. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated. A total of 12 RCTs involving 44,088 subjects were included. Bivalirudin appeared to be non-superior compared to heparin in reducing all-cause mortality, myocardial infarction, revascularisation, and stroke. Bivalirudin appeared to be related to a higher risk of stent thrombosis when compared to heparin plus provisional use of a glycoprotein IIb/IIIa inhibitor (GPI) at day 30 (RR 1.94 [1.16, 3.24] p < 0.01). Overall, bivalirudin-based regimens present a lesser risk of major bleeding (RR 0.56 [0.44-0.71] p < 0.001), and Thrombolysis In Myocardial Infarction (TIMI) major bleeding (RR 0.56 [0.43-0.73]) compared with heparin-based regimens either with provisional or routine use of a GPI. However, the magnitude of TIMI major bleeding effect varied greatly (p < 0.001), depending on whether a GPI was provisionally used (RR 0.42 [0.34-0.52] p < 0.001) or routinely used (RR 0.60 [0.43 -0.83] p < 0.001), in the heparin arm. This meta-analysis demonstrated that bivalirudin is associated with a lower risk of major bleeding, but a higher risk of stent thrombosis compared to heparin

Genome-Wide Association Study Reveals Novel QTLs and Candidate Genes for Grain Number in Rice

Grain number per panicle (GNPP), determined mainly by panicle branching, is vital for rice yield. The dissection of the genetic basis underlying GNPP could help to improve rice yield. However, genetic resources, including quantitative trait loci (QTL) or genes for breeders to enhance rice GNPP, are still limited. Here, we conducted the genome-wide association study (GWAS) on the GNPP, primary branch number (PBN), and secondary branch number (SBN) of 468 rice accessions. We detected a total of 18 QTLs, including six for GNPP, six for PBN, and six for SBN, in the whole panel and the indica and japonica subpanels of 468 accessions. More importantly, qPSG1 was a common QTL for GNPP, PBN, and SBN and was demonstrated by chromosome segment substitution lines (CSSLs). Considering gene annotation, expression, and haplotype analysis, seven novel and strong GNPP-related candidate genes were mined from qPSG1. Our results provide clues to elucidate the molecular regulatory network of GNPP. The identified QTLs and candidate genes will contribute to the improvement of GNPP and rice yield via molecular marker-assisted selection (MAS) breeding and genetic engineering techniques