Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

Reactive Infection Control Strategy for Control of New Delhi Metallo-β-Lactamase (NDM)-Producing Enterobacteriaceae Analyzed Using Whole-Genome Sequencing: Hits and Misses.

Genetically distinct isolates of New Delhi metallo-β-lactamase (NDM)-producing Enterobacteriaceae were identified from the clinical cultures of 6 patients. Screening of shared-ward contacts identified 2 additional NDM-positive patients. Phylogenetic analysis proved that 1 contact was a direct transmission while the other was unrelated to the index, suggesting hidden routes of transmission.

Simplified laparoscopic cervical cerclage after failure of vaginal suture: technique and results of a consecutive series of 100 cases.

Objective: To evaluate the efficacy of simplified laparoscopic cervical cerclage (SLCC) in the prevention of miscarriage and preterm delivery in women with cervical incompetence who failed to have a live birth following a vaginal cervical cerclage in a previous pregnancy.

Study Design: From Dec 2010 to January 2015, a consecutive cases of 100 subjects with cervical incompetence but who failed to have a live birth following a vaginal cervical cerclage in a previous pregnancy underwent SLCC. Surgical outcome parameters (estimated total blood loss, operation time, complications) were recorded, the outcome of any subsequent pregnancy was evaluated.

Transcriptome Analysis Identifies Candidate Genes Related to Triacylglycerol and Pigment Biosynthesis and Photoperiodic Flowering in the Ornamental and Oil-Producing Plant, Camellia reticulata (Theaceae).

Camellia reticulata, which is native to Southwest China, is famous for its ornamental flowers and high-quality seed oil. However, the lack of genomic information for this species has largely hampered our understanding of its key pathways related to oil production, photoperiodic flowering process and pigment biosynthesis. Here, we first sequenced and characterized the transcriptome of a diploid C.

The Combination of Grazoprevir, a Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, and Elbasvir, an HCV NS5A Inhibitor, Demonstrates a High Genetic Barrier to Resistance in HCV Genotype 1a Replicons.

The selection of resistance-associated variants (RAVs) against single agents administered to patients chronically infected with hepatitis C virus (HCV) necessitates that direct-acting antiviral agents (DAAs) targeting multiple viral proteins be developed to overcome failure resulting from emergence of resistance. The combination of grazoprevir (formerly MK-5172), an NS3/4A protease inhibitor, and elbasvir (formerly MK-8742), an NS5A inhibitor, was therefore studied in genotype 1a (GT1a) replicon cells. Both compounds were independently highly potent in GT1a wild-type replicon cells, with 90% effective concentration (EC90) values of 0.

Gene editing: A new step and a new direction toward finding a cure for Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disease affecting one out of 3500 male births. Patients usually succumb to the disease by age 25. It has been shown that skipping exons of the gene that contain disease-causing mutations from the pre-mRNA can result in a shortened, but functional, dystrophin protein that could bring clinical benefits to patients.

SpoTyping: fast and accurate in silico Mycobacterium spoligotyping from sequence reads.

SpoTyping is a fast and accurate program for in silico spoligotyping of Mycobacterium tuberculosis isolates from next-generation sequencing reads. This novel method achieves high accuracy for reads of both uniform and varying lengths, and is about 20 to 40 times faster than SpolPred. SpoTyping also integrates the function of producing a report summarizing associated epidemiological data from a global database of all isolates having the same spoligotype.

Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.

CandiSSR: An Efficient Pipeline used for Identifying Candidate Polymorphic SSRs Based on Multiple Assembled Sequences.

Simple sequence repeats (SSRs), also known as microsatellites, are ubiquitous short tandem duplications commonly found in genomes and/or transcriptomes of diverse organisms. They represent one of the most powerful molecular markers for genetic analysis and breeding programs because of their high mutation rate and neutral evolution. However, traditionally experimental screening of the SSR polymorphic status and their subsequent applicability to genetic studies are extremely labor-intensive and time-consuming.

The Structure-Activity Relationship of the Antioxidant Peptides from Natural Proteins.

Peptides derived from dietary proteins, have been reported to display significant antioxidant activity, which may exert notably beneficial effects in promoting human health and in food processing. Recently, much research has focused on the generation, separation, purification and identification of novel peptides from various protein sources. Some researchers have tried to discover the structural characteristics of antioxidant peptides in order to lessen or avoid the tedious and aimless work involving the ongoing generated peptide preparation schemes.

Autotetraploid rice methylome analysis reveals methylation variation of transposable elements and their effects on gene expression.

Polyploidy, or whole-genome duplication (WGD), serves as a key innovation in plant evolution and is an important genomic feature for all eukaryotes. Neopolyploids have to overcome difficulties in meiosis, genomic alterations, changes of gene expression, and epigenomic reorganization. However, the underlying mechanisms for these processes are poorly understood.

Major Chemical Constituents of Bamboo Shoots (Phyllostachys pubescens): Qualitative and Quantitative Research.

Bamboo shoots are a delicacy in Asia. Two novel compounds, adenine-(1'R,2'R,3'R)-cyclic butanetetraol carbonate (16) and (-)-(7R,8S)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-D-[6-O-4-hydroxy-3-methoxybenzoyl])-glucopyranoside (20), together with 12 known nucleosides (1-12), 3 amino acids (13-15), β-carboline (17), and 2 megastigmane glycosides (18, 19) were isolated from bamboo shoots (Phyllostachys pubescens). Their structures and absolute configurations were rigorously determined by detailed spectroscopic analysis, and the composition of carbohydrates in bamboo shoots was qualitatively detected and quantitatively analyzed with ion chromatography.

Selective small-molecule inhibition of an RNA structural element.

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors.

Management of false passage created during hysteroscopic adhesiolysis for Asherman's syndrome.

False passage in the uterus, if unrecognised, will almost certainly lead to perforation of the uterus and associated complications. We present our experience of the management of a false passage encountered during hysteroscopic surgery for the treatment of severe Asherman's syndrome. Five women with severe Asherman's syndrome resulting in complete obliteration of the uterine cavity and a false passage created during hysteroscopy were included in our study.

Lung gene therapy-How to capture illumination from the light already present in the tunnel.

Gene therapy has been considered as the most ideal medical intervention for genetic diseases because it is intended to target the cause of diseases instead of disease symptoms. Availability of techniques for identification of genetic mutations and for manipulation of genes makes it practical and attractive. After the initial hype in 1990s and later disappointments in clinical trials for more than a decade, light has finally come into the tunnel in recent years, especially in the field of eye gene therapy where it has taken big strides.

De novo transcriptome assembly of the wild relative of tea tree (Camellia taliensis) and comparative analysis with tea transcriptome identified putative genes associated with tea quality and stress response.

Background: Camellia taliensis is one of the most important wild relatives of cultivated tea tree, C. sinensis. The species extensively occupies mountainous habitats representing a wide-range abiotic tolerance and biotic resistance and thus harbors valuable gene resources that may greatly benefit genetic improvement of cultivated tea tree.

Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes.

Causative mutations and variants associated with cardiac diseases have been found in genes encoding cardiac ion channels, accessory proteins, cytoskeletal components, junctional proteins, and signaling molecules. In most cases the functional evaluation of the genetic alteration has been carried out by expressing the mutated proteins in in-vitro heterologous systems. While these studies have provided a wealth of functional details that have greatly enhanced the understanding of the pathological mechanisms, it has always been clear that heterologous expression of the mutant protein bears the intrinsic limitation of the lack of a proper intracellular environment and the lack of pathological remodeling.

Genome-wide identification and comparative expression analysis reveal a rapid expansion and functional divergence of duplicated genes in the WRKY gene family of cabbage, Brassica oleracea var. capitata.

WRKY transcription factors (TFs), one of the ten largest TF families in higher plants, play important roles in regulating plant development and resistance. To date, little is known about the WRKY TF family in Brassica oleracea. Recently, the completed genome sequence of cabbage (B.

Rapid diversification of five Oryza AA genomes associated with rice adaptation.

Comparative genomic analyses among closely related species can greatly enhance our understanding of plant gene and genome evolution. We report de novo-assembled AA-genome sequences for Oryza nivara, Oryza glaberrima, Oryza barthii, Oryza glumaepatula, and Oryza meridionalis. Our analyses reveal massive levels of genomic structural variation, including segmental duplication and rapid gene family turnover, with particularly high instability in defense-related genes.

Transcriptome analysis of the oil-rich tea plant, Camellia oleifera, reveals candidate genes related to lipid metabolism.

Background: Rapidly driven by the need for developing sustainable sources of nutritionally important fatty acids and the rising concerns about environmental impacts after using fossil oil, oil-plants have received increasing awareness nowadays. As an important oil-rich plant in China, Camellia oleifera has played a vital role in providing nutritional applications, biofuel productions and chemical feedstocks. However, the lack of C.

A matched cohort study comparing the outcome of intrauterine adhesiolysis for Asherman's syndrome after uterine artery embolization or surgical trauma.

Study Objective: To compare the outcome of hysteroscopic adhesiolysis in women who had Asherman's syndrome after uterine artery embolization (UAE) with those who had Asherman's syndrome caused by surgical trauma.

Design: A retrospective cohort study matched for age and intrauterine adhesion score (Canadian Task Force classification II-2).

Setting: A tertiary hysteroscopic center in a teaching hospital.

Identification and characterization of transcript polymorphisms in soybean lines varying in oil composition and content.

Background: Variation in seed oil composition and content among soybean varieties is largely attributed to differences in transcript sequences and/or transcript accumulation of oil production related genes in seeds. Discovery and analysis of sequence and expression variations in these genes will accelerate soybean oil quality improvement.

Results: In an effort to identify these variations, we sequenced the transcriptomes of soybean seeds from nine lines varying in oil composition and/or total oil content.

Ultrasound-assisted extraction of Mangiferin from Mango (Mangifera indica L.) leaves using response surface methodology.

Mangiferin is a xanthone widely distributed in higher plants showing antioxidative, antiviral, anticancer, antidiabetic, immunomodulatory, hepatoprotective and analgesic effects. In the present study, an ultrasonic-assisted extraction method was developed for the effective extraction of mangiferin from mango leaves. Some parameters such as ethanol concentration, liquid-to-solid ratio, extraction temperature, and extraction time were optimized by single-factor experiment and response surface methodology.

The expression of cyclooxygenase-2 and vascular endothelial growth factor in the endometrium during the peri-implantation period in women with and without polyps.

Objective: This prospective study was designed to determine whether the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in the endometrial tissue obtained from the peri-implantation period of women with endometrial polyp (EP) differs from that of control subjects without a polyp.

Methods: Endometrial samples were collected from 30 patients with EP and 30 control subjects without EP, in the mid-secretory phase. The expression of COX-2 and VEGF in the endometrium was examined with the use of immunohistochemistry.