Loss of Myo19 increases metastasis by enhancing microenvironmental ROS gradient and chemotaxis.

Tumor metastasis involves cells migrating directionally in response to external chemical signals. Reactive oxygen species (ROS) in the form of H2O2 has been demonstrated as a chemoattractant for neutrophils but its spatial characteristics in tumor microenvironment and potential role in tumor cell dissemination remain unknown. Here we investigate the spatial ROS distribution in 3D tumor spheroids and identify a ROS concentration gradient in spheroid periphery, which projects into a H2O2 gradient in tumor microenvironment. We further reveal the role of H2O2 gradient to induce chemotaxis of tumor cells by activating Src and subsequently inhibiting RhoA. Finally, we observe that the absence of mitochondria cristae remodeling proteins including the mitochondria-localized actin motor Myosin 19 (Myo19) enhances ROS gradient and promotes tumor dissemination. Myo19 downregulation is seen in many tumors, and Myo19 expression is negatively associated with tumor metastasis in vivo. Together, our study reveals the chemoattractant role of tumor microenvironmental ROS and implies the potential impact of mitochondria cristae disorganization on tumor invasion and metastasis.

Site-Selective Polyfluoroaryl Modification and Unsymmetric Stapling of Unprotected Peptides.

Peptide stapling is recognized as an effective strategy for improving the proteolytic stability and cell permeability of peptides. In this study, we present a novel approach for the site-selective unsymmetric perfluoroaryl stapling of Ser and Cys residues in unprotected peptides. The stapling reaction proceeds smoothly under very mild conditions, exhibiting a remarkably rapid reaction rate. It can furnish stapled products in both liquid and solid phases, and the presence of nucleophilic groups other than Cys thiol within the peptide does not impede the reaction, resulting in uniformly high yields. Importantly, the chemoselective activation of Ser ß-C(sp3)-H enables the unreacted -OH to serve as a reactive handle for subsequent divergent modification of the staple moiety with various therapeutic functionalities, including a clickable azido group, a polar moiety, a lipid tag, and a fluorescent dye. In our study, we have also developed a visible-light-induced chemoselective C(sp3)-H polyfluoroarylation of the Ser ß-position. This reaction avoids interference with the competitive reaction of Ser -OH, enabling the precise late-stage polyfluoroarylative modification of Ser residues in various unprotected peptides containing other highly reactive amino acid residues. The biological assay suggested that our peptide stapling strategy would potentially enhance the proteolytic stability and cellular permeability of peptides.

Organocatalyzed Asymmetric Conjugate Addition of Alcohols to ß-Fluoroalkyl Vinylsulfones by Bifunctional Phosphonium Salt Catalyst.

Chiral secondary alcohols, serving as essential structural motifs, hold significant potential for diverse applications. The exploration of effective synthetic strategies toward these compounds is both attractive and challenging. Herein, we present an asymmetric oxa-Michael reaction involving aliphatic alcohols as nucleophiles and ß-fluoroalkyl vinylsulfones catalyzed by bifunctional phosphonium salt (BPS), achieving high yields and excellent enantioselectivities (up to 98 % yield and 98 % ee). Additionally, a sequential process including asymmetric oxa-Michael and debenzylation, facilitated by BPS/Lewis acid cooperation, was revealed for synthesizing diverse chiral secondary alcohol compounds in high yields (81-88 %) with consistent stereoselectivities. Furthermore, mechanistic explorations and subsequent results unveiled that the enantioselectivity originates from hydrogen-bonding and ion-pair interactions between the BPS catalyst and the substrates.

Complete mitochondrial genome and phylogenetic analysis of Mancinella alouina.

BACKGROUND: The Muricidae family in the Class Gastropoda comprises numerous species with a vast range of morphological features and a worldwide presence. The phylogeny of the Muricidae has been analyzed in previous studies; however, the evolutionary relationships among the main branches of the Muricidae remain unknown. METHODS AND RESULTS: In the present study, the mitochondrial genome of Mancinella alouina was sequenced. The mitochondrial genome was found to be 16,671 bp in length and made up of 37 genes (13 protein-coding genes, 22 transfer RNA and 2 ribosomal RNA genes). The genome has an A-T-rich region (66.5% A + T content) and all of the PCGs use the ATN start codon and the TAG or TAA stop codons. The mitochondrial gene arrangement of Mancinella alouina is similar to that of other Muricidae, except for Ocinebrellus inornatus and Ceratostoma burnetti. On the basis of a flexible molecular clock model, time-calibrated phylogenetic results indicate that the genus Mancinella diverged roughly 18.09 Mya, and that the family Muricidae emerged in the Late Cretaceous. CONCLUSIONS: This study reveals the structural and sequence information features of the mitochondrial genome of Mancinella alouina. This study provides evidence for the relationships within the family Muricidae at the molecular level, and infer the divergence time. The results of phylogenetic analyses strongly support the current classification.

Gender differences in the relationship between medical students' emotional intelligence and stress coping: a cross-sectional study.

BACKGROUND: Given the increasing stress levels among medical students due to the impact of COVID-19, it is crucial to effectively reduce their stress levels for their future development. To better understand medical students' stress coping, this study investigated how their emotional intelligence is related to stress coping and whether this relationship is moderated by gender differences. METHODS: A cross-sectional study was conducted. A random sample of 744 medical students from Hebei Province, China, was investigated via an emotional intelligence scale and stress coping questionnaire from March-May 2023. The response rate was 93%. SPSS and Mplus statistical software were used for the data analysis. RESULTS: The self-emotional appraisal of medical students had a significant negative effect on avoidant coping (ß = -0.173, CI 95% = [-0.243, -0.099], p < .001). However, the other dimensions of emotional intelligence (others' emotional appraisal, use of emotion, and regulation of emotion) had a significant positive impact on the active coping of female medical students (ß = 0.146, CI 95% = [0.082,0.214], p < .001; ß = 0.235, CI 95% = [0.167,0.304], p < .001; ß = 0.165, CI 95% = [0.084,0.247], p < .001). In contrast to those of female medical students, other dimensions of emotional intelligence had a significant positive impact on the avoidant coping of male medical students (ß = -0.161, CI 95% = [-0.284, -0.062]; p < 0.01; ß = 0.126, CI 95% = [0.043,0.246], p < 0.001; ß = 0.159, CI 95% = [0.054,0.277], p < 0.05; ß = -0.221, CI 95% = [-0.363, -0.129], p < 0.001). Moreover, the use of emotion had a significant positive impact on the active coping of male medical students (ß = 0.272, CI 95% = [0.182,0.382], p < .001). Furthermore, gender differences had a moderating effect on the relationship between emotional intelligence dimensions and stress coping (ß = 0.178; CI 95% = [0.068,0.292]; p < 0.05). Others' emotional appraisal has a greater impact on female students' active coping. In addition, with increasing regulation of emotion ability, female medical students reduce avoidant coping (ß = 0.169, CI 95% = [0.002,0.326]; p < 0.05). CONCLUSIONS: The current study revealed that gender is a significant moderator of the relationship between medical students' emotional intelligence and stress coping. These findings may help medical colleges focus on gender differences when improving medical students' ability to cope with stress.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

Walking more, not faster, is associated with bone health in China of community-dwelling older women:A cross-sectional study.

AIMS: To examine the association between daily steps and step intensity with bone health in Chinese community-dwelling older women. METHODS: Data from 1116 women in the Physical Activity and Health in Older Women Study in China, 2021. Three bone parameters: bone quality index (BQI), speed of sound (SOS), and broadband ultrasound attenuation (BUA) were measured in the left heel using an ultrasound bone densitometer and transformed into dichotomous variables from medians. Daily steps and step intensity (slow step time, brisk step time, peak 1-min cadence, peak 30-min cadence, and peak 60-min cadence) were measured using a triaxial accelerometer. Participants with high BQI, SOS, and BUA levels were used as references for logistic regression models to explore the association of daily steps and step intensity with bone health. RESULTS: Daily steps were positively associated with the BQI (odds ratio [OR] = 0.94, confidence interval [CI] = 0.89,1.00), SOS (OR = 0.93, CI = 0.88,0.99), and BUA (OR = 0.93, CI = 0.88,0.99) among older women. There was no significant association between peak cadence and bone health. Slow step time was positively associated with the BQI (OR = 0.94, CI = 0.90,0.99) and SOS (OR = 0.93, CI = 0.88,0.97), while brisk step time was positively associated with the BQI (OR = 0.89, CI = 0.82,0.97), SOS (OR = 0.87, CI = 0.80,0.94), and BUA (OR = 0.89, CI = 0.82,0.97). Moreover, 10,000 steps/day or more was significantly associated with the BQI (OR = 0.52, CI = 0.33,0.81), SOS (OR = 0.55, CI = 0.35,0.86), and BUA (OR = 0.45, CI = 0.28, 0.70) compared to <6000 steps/day. CONCLUSION: Increasing the number of daily steps or the duration of walking, whether fast or slow, may benefit the bone health of older women.

UNC93B1 facilitates TLR18-mediated NF-κB signal activation in Schizothorax prenanti.

Toll-like receptor 18 (TLR18), a non-mammalian TLR, has been believed to play an important role in anti-bacterial immunity of teleost fishes. UNC93B1 is a classical molecular chaperone that mediates TLRs transport from endoplasmic reticulum to the located membrane. However, TLR18-mediated signal transduction mechanism and the regulatory effect of UNC93B1 to TLR18 are still unclear in teleost fishes. In this study, the coding sequences of TLR18 and UNC93B1 were cloned from Schizothorax prenanti, named spTLR18 and spUNC93B1, respectively. The spTLR18 and spUNC93B1 are 2583 bp and 1878 bp in length, encode 860 and 625 amino acids, respectively. The spTLR18 widely expressed in various tissues with the highest expression level in liver. After stimulation of Aeromonas hydrophila, lipopolysaccharide (LPS) and Poly(I:C), the expression levels of spTLR18 were significantly increased in spleen and head kidney. The spTLR18 located in the cell membrane, while spUNC93B1 located in the cytoplasm. Luciferase and overexpression analysis showed that spTLR18 activated NF-κB and type I IFN signal pathways, and spTLR18-mediated NF-κB activation might depend on the adaptor molecule MyD88. Besides, spUNC93B1 positively regulates spTLR18-mediated NF-κB signal. Our study first uncovers TLR18-UNC93B1-mediated signal transduction mechanism, which contributes to the understanding of TLR signaling pathway in teleost fishes.

Modeling methods for busulfan-induced oligospermia and asthenozoospermia in mice: a systematic review and meta-analysis.

OBJECTIVE: Modeling methods for busulfan-induced oligoasthenozoospermia are controversial. We aimed to systematically review the modeling method of busulfan-induced oligospermia and asthenozoospermia, and analyze changes in various evaluation indicators at different busulfan doses over time. METHODS: We searched the Cochrane Library, PubMed databases, Web of Science, the Chinese National Knowledge Infrastructure, and the Chinese Biomedical Literature Service System until April 9, 2022. Animal experiments of busulfan-induced spermatogenesis dysfunction were included and screened. The model mortality and parameters of the evaluation indicators were subjected to meta-analysis. RESULTS: Twenty-nine animal studies were included (control/model: 669/1829). The mortality of mice increased with busulfan dose. Significant spermatogenesis impairment occurred within 5 weeks, regardless of busulfan dose (10-40 mg/kg). Testicular weight (weighted mean difference [WMD]: - 0.04, 95% CI: - 0.05, - 0.03), testicular index (WMD: - 2.10, 95% CI: - 2.43, - 1.76), and Johnsen score (WMD: - 4.67, 95% CI: - 5.99, - 3.35) were significantly decreased. The pooled sperm counts of the model group were reduced by 32.8 × 106/ml (WMD: - 32.8, 95% CI: - 44.34, - 21.28), and sperm motility decreased by 37% (WMD: - 0.37, 95% CI: - 0.47, - 0.27). Sperm counts decreased slightly (WMD: - 3.03, 95% CI: - 3.42, - 2.64) in an intratesticular injection of low-dose busulfan (4 - 6 mg/kg), and the model almost returned to normal after one seminiferous cycle. CONCLUSION: The model using low-dose busulfan (10 - 20 mg/kg) returned to normal after 10 - 15 weeks. However, in some spermatogenesis cycles, testicular weight reduction and testicular spermatogenic function damage were not proportional to busulfan dose. Sperm counts and motility results in different studies had significant heterogeneity. Standard protocols for sperm assessment in animal models were needed to reduce heterogeneity between studies.

An Efficient Differential Privacy-Based Method for Location Privacy Protection in Location-Based Services.

Location-based services (LBS) are widely used due to the rapid development of mobile devices and location technology. Users usually provide precise location information to LBS to access the corresponding services. However, this convenience comes with the risk of location privacy disclosure, which can infringe upon personal privacy and security. In this paper, a location privacy protection method based on differential privacy is proposed, which efficiently protects users' locations, without degrading the performance of LBS. First, a location-clustering (L-clustering) algorithm is proposed to divide the continuous locations into different clusters based on the distance and density relationships among multiple groups. Then, a differential privacy-based location privacy protection algorithm (DPLPA) is proposed to protect users' location privacy, where Laplace noise is added to the resident points and centroids within the cluster. The experimental results show that the DPLPA achieves a high level of data utility, with minimal time consumption, while effectively protecting the privacy of location information.

Associations between sedentary behaviour, physical activity and frailty in older Chinese women: A cross-sectional study.

AIMS AND OBJECTIVES: To investigate the association between sedentary behaviour (SB), physical activity (PA), and frailty and frailty subdomains in community-dwelling older women. BACKGROUND: Frailty is associated with numerous adverse health outcomes in older people, and women had a higher prevalence than men. However, older adults may face different health risks due to different combinations of frailty subdomains; therefore, specific studies on frailty subdomains are needed. DESIGN: A cross-sectional study guided by the STROBE. METHODS: In total, 1099 community-dwelling older Chinese women (60-70 years) were included. SB and PA were objectively obtained using a validated triaxial accelerometer. Frailty was defined using the Fried Phenotype (FP) Model. RESULTS: After adjusting for confounders, a significant association was found between SB, PA and the prevalence of frailty. The optimal cut-off values of total SB time, light PA (LPA) time, and moderate-to-vigorous PA (MVPA) time to discriminate between frailty and non-frailty were 625.4 min/day, 379.3 min/day and 20.1 min/day, respectively. For frailty subdomains, total SB time was positively associated with low PA. When it comes to total LPA time, the association with low PA was negative. Total MVPA time was significantly and negatively associated with exhaustion, weakness, slowness and low PA, and the optimal cutoff value was 24.4 min/day, 26 min/day, 29.5 min/day and 20.8 min/day, respectively. CONCLUSIONS: Effective management of frailty requires consideration of different combinations of frailty subdomains. Increasing MVPA and limiting SB may help deal with frailty for community-dwelling older Chinese women. Additional research is needed to determine whether PA are useful for prevention of frailty. RELEVANCE TO CLINICAL PRACTICE: The results of this study could help caregivers provide professional and specific physical activity guidance for order women, who are on a risk of or already suffered frailty.

Understanding of Ovarian Cancer Cell-Derived Exosome Tropism for Future Therapeutic Applications.

Exosomes, a subtype of extracellular vesicles, ranging from 50 to 200 nm in diameter, and mediate cell-to-cell communication in normal biological and pathological processes. Exosomes derived from tumors have multiple functions in cancer progression, resistance, and metastasis through cancer exosome-derived tropism. However, there is no quantitative information on cancer exosome-derived tropism. Such data would be highly beneficial to guide cancer therapy by inhibiting exosome release and/or uptake. Using two fluorescent protein (mKate2) transfected ovarian cancer cell lines (OVCA4 and OVCA8), cancer exosome tropism was quantified by measuring the released exosome from ovarian cancer cells and determining the uptake of exosomes into parental ovarian cancer cells, 3D spheroids, and tumors in tumor-bearing mice. The OVCA4 cells release 50 to 200 exosomes per cell, and the OVCA8 cells do 300 to 560 per cell. The uptake of exosomes by parental ovarian cancer cells is many-fold higher than by non-parental cells. In tumor-bearing mice, most exosomes are homing to the parent cancer rather than other tissues. We successfully quantified exosome release and uptake by the parent cancer cells, further proving the tropism of cancer cell-derived exosomes. The results implied that cancer exosome tropism could provide useful information for future cancer therapeutic applications.

Associations between congenital heart disease and air pollutants at different gestational weeks: a time-series analysis.

Exposure to air pollution during pregnancy has been linked to birth defects. But the directions of studies on the associations between air pollutants exposure and effect on the incidence of congenital heart disease (CHDs) were inconsistent. To date, few studies were concentrated on the effects of both particulate matter and gaseous air pollutant exposure on CHDs across the full gestational week simultaneously. Our study aimed to investigate the critical exposure windows for each air pollutant throughout 40 gestational weeks. Data on CHDs, air pollution, and meteorological factors from 2013 to 2019 were collected in Lanzhou, China. A distributed lag nonlinear model combined with a quasi-Poisson regression model was applied to evaluate the weekly exposure-lag-response association between air pollutants levels and CHDs, and the subgroup analyses were conducted by gender (baby boy and baby girl). The study included 1607 mother-infant pairs. The results demonstrated that exposure of pregnant women to particulate matter ≤ 5 µm (PM2.5) at lag 1-4 weeks was significantly associated with the risk of CHDs, and the strongest effects were observed in the lag 1 week (1.150, 95%CI 1.059-1.248). For exposure to particulate matter ≤ 10 µm (PM10) at lag 1-3 weeks, the strongest effects were observed in the lag 1 week (1.075, 95% CI 1.026-1.128). For exposure to sulfur dioxide (SO2) at lag 1-4 weeks, the strongest effects were observed in the lag 1 week (1.154, 95% CI 1.025-1.299). For exposure to carbon monoxide (CO) at lag 1-3 weeks, the strongest effects were observed in the lag 1 week (1.089, 95% CI 1.002-1.183). For exposure to ozone (O3) concentration at lag 9-15 weeks, the strongest effects were observed in the lag 15 weeks (1.628, 95% CI 1.001-2.649). The cumulative effects of PM2.5, PM10, SO2, and CO along weeks with a maximum of 1.609 (95%CI 1.000-2.589), 1.286 (95%CI 1.007-1.641), 1.648 (95%CI 1.018-2.668), and 1.368 (95%CI 1.003, 1.865), respectively. The effects were obvious in the initial gestational weeks too. Through the gender stratification analysis, the air pollutants with significant effects were PM2.5 for baby boys and PM2.5, PM10, SO2, CO, NO2, and O3 for baby girl. For the relationship between CHDs and air pollution in Lanzhou, PM2.5, PM10, SO2, CO, and O3 played an important role in the initial gestational weeks, especially for baby girl.

Loss of microRNA-147 function alleviates synovial inflammation through ZNF148 in rheumatoid and experimental arthritis.

MicroRNA-147 (miR-147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno-miR-147 antagomir was locally administrated into individual ankle compared with negative control or rno-miR-155-5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa-miR-147b-3p/hsa-miR-155-5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT-quantitative PCR, and protein expression was detected by using Western blotting. Anti-miR-147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa-miR-147b-3p/hsa-miR-155-5p function in TNF-α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa-miR-147b-3p/hsa-miR-155-5p function could downregulate the gene expression of TNF-α, IL-6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR-147's target, increased gene expression of TNF-α, IL-6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa-miR-147b-3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation-related pathways. Taken together, miR-147b-3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis.

Prevalence of sarcopenia in Chinese community-dwelling elderly: a systematic review.

BACKGROUND: Sarcopenia is associated with age-related loss of muscle mass and function and is becoming prevalent in the older Chinese population. This systematic review aims to obtain a reliable estimation of the prevalence of sarcopenia among community-dwelling Chinese populations aged 65 years and older and to characterize its epidemiology. METHODS: A literature search was performed in the Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, and CQVIP databases up to September 31, 2021. All studies that reported the prevalence of sarcopenia in Chinese community-dwelling older adults were included, and Hoy et al.'s tool was used to assess the risk of bias. The overall prevalence of sarcopenia will be calculated as the primary outcome, and subgroup analyses will be performed by study year, age, sex, muscle mass assessment method, diagnostic criteria and area. RESULTS: A total of 26 studies were included in this study, which involved 25,921 subjects, and 3597 had sarcopenia. Although significant heterogeneity between studies was reported, no statistically significant publication bias was detected. The overall prevalence of sarcopenia in community-dwelling older adults aged over 65 years in the Chinese population was 17.4% (95% CI: 14.6%-20.2%). Subgroup analysis based on study year, age and sex, muscle mass assessment method, diagnostic criteria, region and area showed that the prevalence of sarcopenia was different in each subgroup. IMPLICATIONS: The prevalence of sarcopenia in Chinese community-dwelling older adults was higher than that in previous studies. As a multidimensional survey of the prevalence of sarcopenia in older adults, this meta-analysis provides data support for the targeted management of sarcopenia among Chinese older adults.

Toxicity of silver nanoparticles on Achromobacter denitrificans: effect of concentration, temperature and coexisting anions.

The indoor culture method was carried out to study the toxic effect of silver nanoparticles (AgNPs) on Achromobacter denitrificans. Specifically, the effects of AgNPs concentration, temperature and coexisting anions were analyzed. The results showed that AgNPs exerted significant inhibition on the bacteria, which was closely correlated with its concentration and temperature. Both the ammonia oxidation and generation capacity of Achromobacter denitrificans decreased significantly with an increase in AgNPs concentration. Compared with the inhibition performance at 30 °C, NH4+-N generation rates decreased by 45.31% at 20 °C and 17.58% at 40 °C, respectively, revealing that too low or too high temperature induced to reduce the nitrogen conversion ability of Achromobacter denitrificans. While compared with temperature, the effect of coexisting ions (Cl- and SO42-) was not significant (P > 0.05). Electron microscopy observations found that AgNPs non-specifically bound to the cells (content ranging from 0.04% to 0.10%) and acted on the cell surface structure, causing wrinkles, depressions, and ruptures on the surface of cell membranes, and leakage of substances in the membranes. AgNPs increased the rate of cell apoptosis and decreased the cell body volume mainly with short-term acute effects.

Synergistic Catalysis between a Dipeptide Phosphonium Salt and a Metal-Based Lewis Acid for Asymmetric Synthesis of N-Bridged [3.2.1] Ring Systems.

We present an unprecedented synergic catalytic route for the asymmetric construction of fluorinated N-bridged [3.2.1] cyclic members of tropane family via a bifunctional phosphonium salt/silver co-catalyzed cyclization process. A broad variety of substrates bearing an assortment of functional groups are compatible with this method, providing targeted compounds bearing seven-membered ring and four contiguous stereocenters in high yields with excellent stereoselectivities. The gram-scale preparations, facile elaborations and preliminary biological activities of the products demonstrate the application potential. Moreover, both experimental and computational mechanistic studies revealed that the cyclization proceeded via a "sandwich" reaction model with multiple weak-bond cooperative activations. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging chiral heterocyclic molecules.

Visible-Light-Promoted Stereoselective C(sp3 )-H Glycosylation for the Synthesis of C-Glycoamino Acids and C-Glycopeptides.

The glycosylative modification of peptides could improve the pharmacological properties of peptide drugs and deliver them efficiently to the target sites. Compared with O-/N-glycosides, C-glycosides exhibit more metabolic stability. We here disclose the first example of visible-light-promoted and Cu-catalyzed stereoselective C-glycosylation. The mild reaction conditions are compatible with various carbohydrate substrates, as demonstrated with a series of monosaccharides and a disaccharide, and are amenable to the synthesis of a wide variety of C-glycoamino acids and C-glycopeptidomimetics with good yields and excellent stereoselectivities. The dual-functional photocatalyst formed in situ via coordination of the glycine derivative and the chiral phosphine Cu complex could not only catalyze the photoredox process but also control the stereoselectivity of the glycosylation reaction.

Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis.

Tandem mass tag (TMT)-coupled liquid chromatography coupled with tandem mass spectrometry is a powerful method to investigate synovial tissue protein profiles in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Protein was isolated from synovial tissue samples of 22 patients and labeled with a TMT kit. Over 500 proteins were identified as the differential expression protein on comparing RA and OA synovial tissue, including 239 upregulated and 271 downregulated proteins. Data are available via ProteomeXchange with identifier PXD027703. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority participated in the developmental processes and protein processing in the endoplasmic reticulum. Olfactomedin 4 (OLFM4), a secreted glycoprotein, in joint inflammation of RA was explored. OLFM4 was upregulated in RA synovial tissue samples. In fibroblast-like synoviocytes (FLS), inflammation cytokines, TNF-α, interleukin (IL)-1ß, and LPS can upregulate OLFM4. After OLFM4 knockdown under TNF-α stimulation, RA FLS proliferation was inhibited and the expression of CXCL9, CXCL11, and MMP-1 was decreased. Overall, the RA synovial tissue protein expression profile by proteomic analysis shows some unique targets in RA pathophysiology, and OLFM4 in FLS plays an important role in RA joint inflammation. OLFM4 can be a promising therapeutic target in RA synovial tissue.

Overexpression of HIF-1α enhances the protective effect of mitophagy on steroid-induced osteocytes apoptosis.

Glucocorticoid (GC; dexamethasone, DEX) -induced osteonecrosis of the femoral head (GIOFH) is a challenging orthopedic disease, and its underlying mechanism remains not clear. This study exposed murine long bone osteocyte-Y4 (MLO-Y4) cells to DEX below normoxic or hypoxic circumstances and found that cell autophagy have been reduced. At the same time, flow cytometry analysis showed increased apoptosis, which was more pronounced in hypoxic environments. Recent research also claimed that GC induces osteoporosis after osteocyte apoptosis, and subsequent microfractures lead to ischemia and hypoxia of the femoral head, resulted in GIOFH. Presently, we found that both mitophagy-related protein hypoxia-inducible factor-1α (HIF-1α) and BNIP3 were up-regulated in the hypoxic environment, and their expression was down-regulated when exposed to DEX. Besides, we demonstrated that overexpressing HIF-1α resisted DEX-induced apoptosis in a hypoxic environment. Here, we demonstrated that overexpression of HIF-1α, through its downstream marker BNIP3, reduced the suppression of DEX on mitophagy induced by hypoxia and protected bone cells from apoptosis. Also, these findings may provide a direction of the promising application for better GIOFH treatment shortly.