Difluoromethylation-Carboxylation and -Deuteration of Alkenes Triggered by Electroreduction of Difluoromethyltriphenylphosphonium Bromide.

It is significant to develop novel difluoromethylation methods because of the important roles of difluoromethyl groups in the medicinal chemistry and material industries. Here, we developed a novel difluoromethylation-carboxylation and difluoromethylation-deuteration method triggered by a difluoromethyl radical generated by electroreduction of stable and easily available difluoromethyltriphenylphosphonium bromide. Various molecules containing difluoromethyl and carboxyl or deuterium groups can be synthesized through this method. The establishment of this method will provide an alternative to radical difluoromethylation reactions.

Photocatalytic Synthesis of Diarylmethyl Silanes via 1,6-Conjugate Addition of Silyl Radicals to p-Quinone Methides.

A novel photocatalytic method for the preparation of diarylmethyl silanes was reported through silyl radicals addition strategy to p-QMs (p-quinone methides). This protocol could tolerate a variety of functional groups affording the corresponding silylation products with moderate to excellent yields. The resulting silylation products could be easily converted into a series of bioactive GPR40 agonists and useful p-QMs precursors for the synthesis of compounds possessing both quaternary carbon centers and silicon substituents through simple operation. A plausible mechanism of silyl radicals to p-QMs was proposed on the basis of experimental results and previous literature.

Liver Fibrosis in the Natural Course of Chronic Hepatitis B Viral Infection: A Systematic Review with Meta-Analysis.

BACKGROUND: Quantitative data are limited on the natural course of liver fibrosis in patients with chronic HBV infection (CHB). AIMS: To estimate the prevalence of fibrosis status including non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis throughout the natural course of CHB. METHODS: We searched Cochrane library, EMBASE, PubMed, SCOPUS, Web of Science, and ScienceDirect from January 1993 to November 2019 for studies with histologic data on liver fibrosis in CHB natural course. CHB course was defined based on current criteria for identifying infection phases as recommended by international clinical practice guidelines, including the HBeAg-positive immune-tolerant, HBeAg-positive immune-active, HBeAg-negative immune-inactive, HBeAg-negative immune-reactive, and HBsAg-negative phases. Pooled prevalence rate of fibrosis status at each phase was obtained from random-effect meta-analyses. RESULTS: Thirty-three studies with 9,377 adult participants (23.8-49.0 age years; 45.5-88.6% males) were eligible and finally included. The estimated prevalence of non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis was, for HBeAg-positive immune-tolerant phase: 31.2% (95%CI 15.6-46.7), 16.9% (95%CI 7.8-26.1), 5.4% (95%CI 0.0-11.2), and 0.0% (95%CI 0.0-1.5); HBeAg-positive immune-active phase: 6.9% (95%CI 3.6-10.2), 50.6% (95%CI 39.2-61.9), 32.1% (95%CI 24.2-40.0), and 12.8% (95%CI 8.6-17.0); HBeAg-negative immune-inactive phase: 32.4% (95%CI 0.0-100.0), 24.8% (95%CI 4.5-45.1), 3.0% (95%CI 0.0-8.3), and 0.0% (95%CI 0.0-1.0); and HBeAg-negative immune-reactive phase: 6.3% (95%CI 3.5-9.2), 50.3% (95%CI 38.9-61.7), 30.3% (95%CI 20.9-39.6), and 10.0% (95%CI 6.6-13.5), respectively. There was only one study for HBsAg-negative phase, thus not allowing further meta-analyses. CONCLUSIONS: Fibrosis risk persists through CHB natural course. These data can support risk estimation in clinical practice and provide reference for noninvasive investigation.

Re-emergence of a genotype VIII virulent Newcastle disease virus isolated from Chinese game fowl after 13 years.

Circulation of dominant genotypes VI and VII of Newcastle disease virus (NDV) is causing significant economic losses to the poultry industry in China. However, reports of Newcastle disease (ND) outbreaks caused by genotype VIII strains of NDV are rare. In this study, a virulent genotype VIII strain of NDV, designated GXGB2011, was isolated from a vaccinated game fowl flock showing clinic signs of infection in Pinxiang county, Guangxi, China. The whole genome of the isolate was completely sequenced and was found to be comprised of 15,192 nucleotides (nt), encoding the six structural proteins in the order of 3'-NP-P-M-F-HN-L-5'. The pattern of cleavage site 112 RRQKR↓F117 in the fusion (F) protein and the intracerebral pathogenicity index (ICPI) value of 1.5 showed that the strain GXGB2011 was a velogenic NDV. The results of the challenge experiment with the 5-week-old SPF chickens showed that the strain was highly pathogenic with 100% morbidity and mortality of the challenged birds. Based on the detection of virus in different organs of the infected birds, the highest viral load in caecal tonsils was observed and viral levels in immune organs were higher than those in the respiratory organs. Bayesian reconstruction of complete genomes based on the sequences of 66 NDV reference strains showed that the strain belonged to the genotype VIII of NDV. Phylogenetic analysis showed that the strain was more closely related to the foreign strains gamefowl/U.S.(CA)/24225/98, 1ITTY94060 and IT-147/94 rather than to the first domestic strains of the emergence genotype VIII in Qinghai, China during 1979-1985. In summary, the results of the study demonstrated the re-emergence of a highly pathogenic virulent isolate of genotype VIII of NDV. These results indicate the risk that this genotype VIII of NDV may spread to commercial chickens from game fowl.

Molecular characterization of two novel sub-sublineages of pigeon paramyxovirus type 1 in China.

Pigeon paramyxovirus type 1 (PPMV-1) infection is enzootic in pigeon flocks and poses a potential risk to the poultry industry in China. To gain insight into the biological characteristics and transmission routes of circulating PPMV-1 in pigeons, 13 PPMV-1 isolates from domestic pigeons isolated during 2011-2015 in Guangxi province, China, were characterized using a pathogenicity assessment and phylogenetic analysis. All PPMV-1 isolates were mesogenic or lentogenic strains and had a mean death time (MDT) in 9-day-old SPF chicken embryos and a intracerebral pathogenicity index (ICPI) values of 54-154 h and 0.00-0.90, respectively. Analysis of the F and HN gene sequences of the PPMV-1 isolates and the Newcastle Disease (ND) vaccine strain La Sota, revealed that the nucleotide sequence similarity of the F and HN genes were all < 85% between the PPMV-1 isolates and La Sota, significantly lower than those > 98% among the PPMV-1 isolates. The amino acids sequence of the F protein at the cleavage site of the 13 PPMV-1 isolates was 112RRQKR↓F117, characteristic of virulent Newcastle disease virus (NDV). All 13 isolates were classified as sublineage 4b by phylogenetic analysis and evolutionary distances, based on the F gene sequences. It was also found that the 13 isolates were divided into two novel sub-groups of sublineage 4b, sub-sublineages 4biig and 4biih. Since these two novel sub-sublineages had two different geographic sources, we speculated that they represent two different transmission routes of PPMV-1 in China. Phylogenetic analysis of these isolates will help to elucidate the sources of the transmission and evolution of PPMV-1 and may help to control PPMV-1 infection in the pigeon industry in China.

MicroRNAs in hair cell development and deafness.

PURPOSE OF REVIEW: The identification of transcriptional activators and repressors of hair cell fates has recently been augmented by the discovery of microRNAs (miRNAs) that can function as post-transcriptional repressors in sensory hair cells. RECENT FINDINGS: miRNAs are approximately 21-nucleotide single-stranded ribonucleic acids that can each repress protein synthesis of many target genes by interacting with messenger RNA transcripts. A triplet of these miRNAs, the miR-183 family, is highly expressed in vertebrate hair cells, as well as a variety of other peripheral neurosensory cells. Point mutations in one member of this family, miR-96, underlie DFNA50 autosomal deafness in humans and lead to abnormal hair cell development and survival in mice. In zebrafish, overexpression of the miR-183 family induces extra and ectopic hair cells, whereas knockdown reduces hair cell numbers. Genetically engineered mice with a block in miRNA biosynthesis during early ear development, or during hair cell differentiation, reveal the necessity of miRNAs at these crucial time points. SUMMARY: Because miRNAs can simultaneously down-regulate dozens to perhaps hundreds of transcripts, they will soon be explored as potential therapeutic agents to repair or regenerate hair cells in animal models.

MicroRNA-183 family members regulate sensorineural fates in the inner ear.

Members of the microRNA (miRNA) 183 family (miR-183, miR-96, and miR-182) are expressed abundantly in specific sensory cell types in the eye, nose, and inner ear. In the inner ear, expression is robust in the mechanosensory hair cells and weak in the associated statoacoustic ganglion (SAG) neurons; both cell types can share a common lineage during development. Recently, dominant-progressive hearing loss in humans and mice was linked to mutations in the seed region of miR-96, with associated defects in both development and maintenance of hair cells in the mutant mice. To understand how the entire triplet functions in the development of mechanosensory hair cells and neurons of the inner ear, we manipulated the levels of these miRNAs in zebrafish embryos using synthesized miRNAs and antisense morpholino oligonucleotides (MOs). Overexpression of miR-96 or miR-182 induces duplicated otocysts, ectopic or expanded sensory patches, and extra hair cells, whereas morphogenesis of the SAG is adversely affected to different degrees. In contrast, knockdown of miR-183, miR-96, and miR-182 causes reduced numbers of hair cells in the inner ear, smaller SAGs, defects in semicircular canals, and abnormal neuromasts on the posterior lateral line. However, the prosensory region of the posterior macula, where the number of hair cells is reduced by approximately 50%, is not significantly impaired. Our findings suggest both distinct and common roles for the three miRNAs in cell-fate determination in the inner ear, and these principles might apply to development of other sensory organs.