Aberrant DNA hypermethylation contributes to myelomagenesis by silencing tumor-suppressor genes. Recently, a few reports have suggested that a novel class of small non-coding RNAs, called ...Piwi-interacting RNAs (piRNAs), may be involved in the epigenetic regulation of cancer. In this study, for the first time we provided evidence that the expression of piRNA-823 was upregulated in multiple myeloma (MM) patients and cell lines, and positively correlated with clinical stage. Silencing piRNA-823 in MM cells induced deregulation of cell cycle regulators and apoptosis-related proteins expression, accompanied by inhibition of tumorigenicity in vitro and in vivo. Moreover, piRNA-823 was directly relevant to de novo DNA methyltransferases, DNMT3A and 3B, in primary CD138(+) MM cells. The inhibited expression of piRNA-823 in MM cells resulted in marked reduction of DNMT3A and 3B at both mRNA and protein levels, which in turn led to decrease in global DNA methylation and reexpression of methylation-silenced tumor suppressor, p16(INK4A). In addition, piRNA-823 abrogation in MM cells induced reduction of vascular endothelial growth factor secretion, with consequent decreased proangiogenic activity. Altogether, these data support an oncogenic role of piRNA-823 in the biology of MM, providing a rational for the development of piRNA-targeted therapeutic strategies in MM.
Summary
Classical swine fever (CSF) is a devastating infectious disease of pigs caused by classical swine fever virus (CSFV). In China, CSF has been under control owing to extensive vaccination with ...the lapinized attenuated vaccine (C‐strain) since 1950s, despite sporadic or endemic in many regions. However, recently, CSF outbreaks occurred in a large number of swine herds in China. Here, we isolated 15 CSFV strains from diverse C‐strain‐vaccinated pig farms in China and characterized the genetic variations and antigenicity of the new isolates. The new strains showed unique variations in the E2 protein and were clustered to the subgenotype 2.1d of CSFV recently emerging in China in the phylogenetic tree. Cross‐neutralization test showed that the neutralizing titres of porcine anti‐C‐strain sera against the new isolates were substantially lower than those against both the highly virulent Shimen strain and the subgenotype 2.1b strains that were isolated in China in 2006 and 2009, respectively. In addition, experimental animal infection showed that the HLJZZ2014 strain‐infected pigs displayed lower mortality and less severe clinical signs and pathological changes compared with the Shimen strain‐infected pigs. The HLJZZ2014 strain was defined to be moderately virulent based on a previously established assessment system for CSFV virulence evaluation, and the virus shedding and the viral load in various tissues of the CSFV HLJZZ2014 strain‐infected pigs were significantly lower than those of the Shimen strain‐infected pigs. Taken together, the subgenotype 2.1d isolate of CSFV is a moderately virulent strain with molecular variations and antigenic alterations.
Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% ...of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
Summary
Background
TCS (topical corticosteroids) are the first‐line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, ...pimecrolimus and ciclosporin for OLP is still controversial.
Objectives
To compare the efficacy and safety of TCI vs. TCS for OLP.
Methods
The authors searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and four Chinese databases from 1950 to May 2018. The randomized controlled trials comparing TCI and TCS for OLP reported at least one of the following outcomes: improvement of clinical signs and/or symptoms, relapse, blood levels of TCI and adverse events.
Results
Twenty‐one trials involving 965 patients were included in the analysis. For the treatment of OLP (3–8 weeks), TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy. Tacrolimus–TCS resulted in similar outcomes, with relapse at 3 weeks to 6 months. Blood levels of TCI were usually undetectable. In addition, tacrolimus showed a statistically higher incidence of local adverse events than TCS for short‐term treatment. A few systemic adverse events occurred in the tacrolimus and ciclosporin groups, but they were not serious.
Conclusions
The evidence for tacrolimus (n = 12), pimecrolimus (n = 3) and ciclosporin (n = 6) demonstrated that treatment with TCI may be an alternative approach when OLP does not respond to the standard protocols. Tacrolimus 0·1% should be the first drug of choice when selecting TCI for short‐term treatment in recalcitrant OLP. Further well‐designed trials are warranted to evaluate the long‐term efficacy and safety of TCI.
What's already known about this topic?
The main topical drug for oral lichen planus (OLP) is topical corticosteroids (TCS).
Patients with OLP who are not responsive to TCS or are at risk of adverse events from TCS need other alternative drugs.
Topical calcineurin inhibitors (TCI), including tacrolimus, pimecrolimus and ciclosporin, have become a hot topic in a variety of mucocutaneous immune‐mediated diseases.
What does this study add?
TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy for the short‐term treatment of OLP.
The local adverse events of tacrolimus were higher than with TCS. A few systemic adverse events were reported with TCI, but they were all tolerable and not serious.
The limited evidence for pimecrolimus (three trials) and ciclosporin (six trials) requires further studies to evaluate the short‐term and long‐term efficacy and safety of TCI compared with TCS.
Linked Comment: Thongprasom. Br J Dermatol 2019; 181:1120.
Plain language summary available online
ABSTRACT
High time resolution and accuracy are of critical importance in the studies of timing analysis and time delay localization of gamma-ray bursts (GRBs), soft gamma-ray repeaters (SGRs) and ...pulsars. The Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor (GECAM) consisting of two micro-satellites, GECAM-A and GECAM-B, launched on 2020 December 10, is aimed at monitoring and locating X-ray and GRBs all over the sky. To achieve its scientific goals, GECAM is designed to have the highest time resolution (0.1 $\mu {\rm s}$) among all GRB detectors ever flown. Here, we make a comprehensive time calibration campaign including both on-ground and on-orbit tests to derive not only the relative time accuracy of GECAM satellites and detectors, but also the absolute time accuracy of GECAM-B. Using the on-ground calibration with a $\rm ^{22}Na$ radioactive source, we find that the relative time accuracy between GECAM-A and GECAM-B is about 0.15 $\mu {\rm s}$ (1σ). To measure the relative time accuracy between all detectors of a single GECAM satellite, cosmic-ray events detected on orbit are utilized since they could produce many secondary particles simultaneously record by multiple detectors. We find that the relative time accuracy among all detectors onboard GECAM-B is about 0.12 $\mu {\rm s}$ (1σ). Finally, we use the novel Li-CCF method to perform the absolute time calibration with Crab pulsar and SGR J1935+2154, both of which were jointly observed by GECAM-B and Fermi/GBM, and obtain that the time difference between GECAM-B and Fermi/GBM is 3.06 ± 6.04 $\mu {\rm s}$ (1σ).
Ecological Genomics of Marine Roseobacters MORAN, M. A; BELAS, R; HOWARD, E. C ...
Applied and Environmental Microbiology,
07/2007, Volume:
73, Issue:
14
Journal Article
Brassinosteroid (BR) homeostasis and signaling are crucial for normal growth and development of plants. BR signaling through cell-surface receptor kinases and intracellular components leads to ...dephosphorylation and accumulation of the nuclear protein BZR1. How BR signaling regulates gene expression, however, remains unknown. Here we show that BZR1 is a transcriptional repressor that has a previously unknown DNA binding domain and binds directly to the promoters of feedback-regulated BR biosynthetic genes. Microarray analyses identified additional potential targets of BZR1 and illustrated, together with physiological studies, that BZR1 coordinates BR homeostasis and signaling by playing dual roles in regulating BR biosynthesis and downstream growth responses.
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