6-O-angeloylplenolin inhibits osteoclastogenesis in vitro via suppressing c-Src/NF-κB/NFATc1 pathways and ameliorates bone resorption in collagen-induced arthritis mouse model.

One of the effective therapeutic strategies to treat rheumatoid arthritis (RA)-related bone resorption is to target excessive activation of osteoclasts. We discovered that 6-O-angeloylplenolin (6-OAP), a pseudoguaianolide from Euphorbia thymifolia Linn widely used for the treatment of RA in traditional Chinese medicine, could inhibit RANKL-induced osteoclastogenesis and bone resorption in both RAW264.7 cells and BMMs from 1 µM and protect a collagen-induced arthritis (CIA) mouse model from bone destruction in vivo. The severity of arthritis and bone erosion observed in paw joints and the femurs of the CIA model were attenuated by 6-OAP administered at both dosages (1 or 5 mg/kg, i.g.). BMD, Tb.N and BV/TV were also improved by 6-OAP treatment. Histological analysis and TRAP staining of femurs further confirmed the protective effects of 6-OAP on bone erosion, which is mainly due to reduced osteoclasts. Molecular docking indicated that c-Src might be a target of 6-OAP and phosphorylation of c-Src was suppressed by 6-OAP treatment. CETSA and SPR assay further confirmed the potential interaction between 6-OAP and c-Src. Three signaling molecules downstream of c-Src that are vital to the differentiation and function of osteoclasts, NF-κB, c-Fos and NFATc1, were also suppressed by 6-OAP in vitro. In summary, the results demonstrated that the function of c-Src was disrupted by 6-OAP, which led to the suppression of downstream signaling vital to osteoclast differentiation and function. In conclusion, 6-OAP has the potential to be further developed for the treatment of RA-related bone erosion.

Plasma osteoprotegerin predicts adverse cardiovascular events in stable coronary artery disease: the PEACE trial.

Background: Osteoprotegerin (OPG) is a secretory glycoprotein and participates in the progression of atherosclerotic lesions. We aim to explore the relationship between OPG and the prognosis of coronary artery disease (CAD). Methods: Plasma OPG concentrations were measured in 3,766 patients with stable CAD enrolled in the PEACE trial. The PEACE trial (NCT00000558) group followed up the patients and examined their future clinical outcomes. Results: In summary, 208 (5.5%) primary outcomes occurred, 295 patients (7.8%) died from all-cause death, 128 (3.4%) died from cardiovascular causes, and 94 (2.5%) experienced heart failure during a median follow-up of 1,892 days. In addition, we found that higher plasma levels of OPG were associated with a higher incidence of all-cause death, cardiovascular death, and heart failure, even after adjusting clinical cofounders. Conclusion: It was demonstrated that elevated plasma OPG levels were associated with an increased incidence of all-cause death, cardiovascular death, and heart failure in patients with stable CAD. Systematic Review Registration: https://clinicaltrials.gov/ct2/show/NCT00000558?term=NCT00000558&draw=2&rank=1, identifier: NCT00000558.

A handheld multifunctional smartphone platform integrated with 3D printing portable device: On-site evaluation for glutathione and azodicarbonamide with machine learning.

Azodicarbonamide (ADA) in flour can be easily decomposed to semi-carbazide and biuret, exhibiting strong genotoxicity in vitro and carcinogenicity. Glutathione (GSH) can be conjugated with some ketone-containing compounds and unsaturated aldehydes to form toxic metabolites. Here, a novel ratio fluorescence probe based on blue emitting biomass-derived carbon dots (BCDs) and yellow emitting 2,3-diaminophenazine (OxOPD) was prepared for the bifunctional determination of glutathione (GSH) and ADA. This strategy includes three processes: (1) Ag+ oxidizes o-phenylenediamine (OPD) to produce OxOPD. The peak at 562 nm was enhanced, and the peak at 442 nm was reduced due to fluorescence resonance energy transfer (FRET), (2) glutathione binds Ag+ and inhibits the production of OxOPD, (3) ADA oxidizes GSH to form GSSG, resulting in the release of Ag+ by GSH. Therefore, the newly designed ratio fluorescence probe can be based on the intensity ratio (I442/I562) changes and significant fluorescent color changes to detect GSH and ADA. Moreover, a smartphone WeChat applet and a yolov3-assisted deep learning classification model have been developed to quickly detect GSH and ADA on-site based on an image processing algorithm. These results indicate that smartphone ratiometric fluorescence sensing combined with machine learning has broad prospects for biomedical analysis.

Topography-Guided Versus Wavefront-Optimized LASIK for Myopia With and Without Astigmatism: A Meta-analysis.

PURPOSE: To evaluate the differences in efficacy, predictability, safety, and visual quality between topography-guided customized ablation treatment (TCAT) and wavefront-optimized (WFO) laser in situ keratomileusis (LASIK) for the treatment of myopia with and without astigmatism. METHODS: A comprehensive literature search of PubMed, Embase, the Cochrane library, Web of Science, and ClinicalTrials was used to identify randomized controlled trials (RCTs) comparing TCAT-LASIK with WFO-LASIK for myopia with and without astigmatism up to September 2020. The references of all searched literature were checked as supplements. Literature was screened according to the inclusion and exclusion criteria and relative data were extracted. RevMan software version 5.3.0 (Cochrane Collaboration) was used for meta-analysis. RESULTS: A total of seven RCTs (1,168 eyes) were included. There were no statistically significant differences in the ratio of uncorrected distance visual acuity of 20/20 or better (relative risk [RR] = 1.01, 95% CI [0.97 to 1.06], P = .64) and 20/16 or better (RR = 0.96, 95% CI [0.80 to 1.16], P = .69). Compared with WFO-LASIK, TCAT-LASIK achieved a higher proportion of postoperative manifest refractive spherical equivalent within ±0.50 diopters of the target (RR = 1.06, 95% CI [1.02 to 1.11], P = .003) and less surgically induced higher order aberrations (weighted mean difference [WMD] = -0.11, 95% CI [-0.15 to -0.0], P < .00001), spherical aberrations (WMD = -0.04, 95% CI [-0.05 to -0.03], P < .00001), and coma (WMD = -0.15, 95% CI [-0.28 to -0.01], P = .03). No patient lost two or more lines of distance-corrected visual acuity postoperatively in the two groups. CONCLUSIONS: This meta-analysis suggests that both TCATLASIK and WFO-LASIK show excellent efficacy, predictability, and safety for myopia. TCAT-LASIK exhibited more accurate postoperative refraction predictability and less surgically induced higher order aberrations, spherical aberrations, and coma. More randomized, prospective, and large sample-sized studies are needed to confirm these conclusions in the long term. [J Refract Surg. 2021;37(10):707-714.].

Histone H4 acetylation required for chromatin decompaction during DNA replication.

Faithful DNA replication is a prerequisite for cell proliferation. Several cytological studies have shown that chromosome structures alter in the S-phase of the cell cycle. However, the molecular mechanisms behind the alteration of chromosome structures associated with DNA replication have not been elucidated. Here, we investigated chromatin structures and acetylation of specific histone residues during DNA replication using the meiotic nucleus of the fission yeast Schizosaccharomyces pombe. The S. pombe meiotic nucleus provides a unique opportunity for measuring the levels of compaction of chromatin along the chromosome in a defined orientation. By direct measurement of chromatin compaction in living cells, we demonstrated that decompaction of chromatin occurs during meiotic DNA replication. This chromatin decompaction was suppressed by depletion of histone acetyltransferase Mst1 or by arginine substitution of specific lysine residues (K8 and K12) of histone H4. These results suggest that acetylation of histone H4 residues K8 and K12 plays a critical role in loosening chromatin structures during DNA replication.

Meiotic nuclear movements in fission yeast are regulated by the transcription factor Mei4 downstream of a Cds1-dependent replication checkpoint pathway.

In meiosis, the fission yeast nucleus displays an elongated morphology, moving back and forth within the cell; these nuclear movements continue for approximately 2 h before meiotic nuclear divisions. Meiotic DNA replication occurs in an early phase of the nuclear movements and is followed by meiotic prophase. Here we report that in mutants deficient in meiotic DNA replication, the duration of nuclear movements is strikingly prolonged to four to 5 h. We found that this prolongation was caused by the Cds1-dependent replication checkpoint, which represses expression of the mei4(+) gene encoding a meiosis-specific transcription factor. In the absence of Mei4, nuclear movements persisted for more than 8 h. In contrast, overproduction of Mei4 accelerated termination of nuclear movements to approximately 30 min. These results show that Mei4 is involved in the termination of nuclear movements and that Mei4-mediated regulatory pathways link a DNA replication checkpoint to the termination of nuclear movements.

Halomonas socia sp. nov., isolated from high salt culture of Dunaliella salina.

A moderately halophilic bacteria designed strain NY-011(T) was isolated from the high salt culture of Dunaliella salina in Chengdu of Sichuan Province, China. The isolate was Gram-negative, nonmotile, rod-shaped and 12.5-21.6 µm in length. Colonies on solid media are circular, wet, smooth and cream. The strain grew optimally at 37 °C, pH 7.0 and in the presence of 8 % NaCl. Acid was produced from glycerol, D-arabinose, glucose, trehalose, inositol, mannose, mannitol, sucrose, maltose and sorbitol. Catalase is produced but not oxidase. The major fatty acids are C18: 1ω7c (37.59 %), C19: 0 cyclo ω8c (18.29 %), C16: 0 (16.05 %) and C6: 0 (12.43 %). The predominant respiratory lipoquinone found in strain NY-011(T) is ubiquinone with nine isoprene units (Q-9). The genomic DNA G + C content of strain NY-011(T) was 62.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain NY-011(T) belonged to the genus Halomonas. The highest levels of 16S rRNA gene sequence similarity were found between the strain NY-011(T) and H. pantelleriensis (sequence similarity 98.43 %). However, the levels of DNA-DNA relatedness between them were only 23.1 %. In addition, the strain NY-011(T) had a phenotypic profile that readily distinguished it from H. pantelleriensis. The strain NY-011(T) therefore represents a new species of the genus Halomonas, for which the name Halomonas socia sp. nov. is proposed, with NY-011(T) (=CCTCC AB 2011033(T) = KCTC 23671(T)) as the type strain.

Cloning and expression study of a putative carotene biosynthesis related (cbr) gene from the halotolerant green alga Dunaliella salina.

Dunaliella salina, a unicelluar green alga that can tolerate an extreme variation of salt concentration is being studied as a model system to analyze the tolerance of abiotic stresses at the molecular level. Upon abnormal NaCl levels, new transcripts were abundantly expressed in cells of the alga. EST gene discovery efforts utilizing salt-shock cells had identified one cDNA designated Dscbr (GenBank accession no. DQ867041) with significant similarity to a carotene biosynthesis related gene (cbr) from Dunaliella bardawil and to early light inducible genes (elip) of higher plants. Dscbr was 976 bp in length, encoding a 190 amino acid deduced polypeptide (DsCBR) with a predicted molecular mass of 19.9 kDa and pI of 9.0. The three dimensional structure of DsCBR modeled by computer homology modeling techniques showed that the protein possessed three predicted transmembrane helices and six conserved pigment-binding residues. Real-Time Quantitative PCR clearly demonstrated that Dscbr mRNA can be rapidly induced by high light intensity and salt shocks. The results presented in this work are consistent with the earlier proposal (Jin et al. 2001 Biochim Biophys Acta 1506:244-259, 2003 Plant Physiol 132:352-364) that the DsCBR protein is an adaptive response to stress-induced photodamage within the alga chloroplast, and plays a key role in the protection and/or repair of the photosynthetic apparatus.