A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Higher Risk of Rheumatoid Arthritis in Patients With Chronic Rhinosinusitis: Prospective Association in the U.K. Biobank and Genetic Evidence by Mendelian Randomization Analysis.

BACKGROUND: Previous studies have shown that respiratory diseases are associated with an increased risk of rheumatoid arthritis (RA). However, whether there is a correlation between chronic rhinosinusitis (CRS) and RA is not known. Due to the high incidence of CRS, it remains to be clarified whether we should pay additional attention to RA risk in the huge population of CRS. METHODS: We used a 2-sample Mendelian randomization (MR) analysis to explore the causal effects of CRS on the incidence of RA. The inverse variance weighted (IVW) approach was used as the main analysis in the MR randomization study. Then, we used the data from the U.K. Biobank to examine the association between RA and CRS at the individual level in a prospective cohort. We identified patients with CRS at the time of recruitment and further followed the incidence of RA until 2021. The risk of developing RA in patients with CRS was determined by a multivariate Cox regression model. We used 3 multivariate Cox models to adjust for individual characteristics, lifestyle factors and concomitant diseases, respectively. RESULTS: The MR analysis by the IVW model suggested that the odds ratio of RA associated with genetically predicted CRS was 2.39 (95% CI [1.08-5.30]; p = .032). In the first multivariate model adjusting for individual characteristics, CRS was associated with a 47% increase of risk of developing RA (hazard ratio [HR] = 1.47; 95% CI [1.12-1.90]). In the second multivariate model adjusting for lifestyle factors, the HR of RA associated with CRS was 1.48 (95% CI [1.15-1.90]). In the third multivariate model, chronic sinusitis was associated with a 32% increase in RA risk (HR = 1.32; 95% CI [1.03-1.70]). CONCLUSION: CRS has a genetically causal effect on the incidence of RA, and the risk of RA is greatly higher in CRS at the individual level. This is the first study to reveal an association between CRS and RA. Due to the high incidence of CRS, it is recommended that additional attention should be paid to the increased RA risk in patients with CRS compared to that in common people.

Higher risk of osteoporosis in adult-onset asthma than childhood-onset asthma: from genetic and prospective evidence.

Both COA and AOA have a genetically causal effect on osteoporosis. COA and AOA were independently associated with incident osteoporosis, and the risk was greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications. PURPOSE/INTRODUCTION: Childhood-onset asthma (COA) differs with adult-onset asthma (AOA) on genetic susceptibility, severity, and co-morbidities. Whether COA or AOA is independently associated with osteoporosis is unexplored. We aimed to determine the effects of COA and AOA on osteoporosis at genetic and individual level. METHODS: We used two-sample Mendelian randomization analysis to explore the causal effects of COA and AOA on osteoporosis. In the UK Biobank cohort, we included 478,289 osteoporosis-free participants at baseline (2006-2010). Participants were classified as non-asthma, COA, and AOA at recruitment. Multivariate Cox regression analysis was used to evaluate the effects of COA, AOA, and multiple asthma medications on incident osteoporosis risk. RESULTS: COA and AOA were causally related to osteoporosis, with odds ratio of 1.007 (95% confidence interval (CI), 1.0003-1.0132) and 1.012 (95% CI, 1.002-1.023), respectively. Multivariate Cox regression analysis suggested that COA (hazard ratio (HR), 1.46; 95% CI, 1.32-1.61) and AOA (HR, 1.70; 95% CI, 1.61-1.80) were independently associated with incident osteoporosis, and the risk was greatly higher in AOA (HR, 1.51; 95% CI, 1.34-1.70). In addition to corticosteroids, monotherapy with leukotriene modifiers (HR, 1.70; 95% CI, 1.20-2.42), long-acting beta agonists (HR, 1.49; 95% CI, 1.18-1.87), and short-acting beta agonists (HR, 1.72; 95% CI1.01-2.93) were independently associated with a higher risk of osteoporosis. CONCLUSIONS: Both COA and AOA have a genetically causal effect on osteoporosis, and the risk of osteoporosis is greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications.

Structural Basis of Low-Molecular-Weight Thiol Glycosylation in Lincomycin A Biosynthesis.

The involvement of low-molecular-weight thiols in the biosynthesis of natural products is rarely reported. During lincomycin A biosynthesis, ergothioneine (EGT) is incorporated in the S-glycosylation catalyzed by LmbT. In contrast to the widely reported glycosylation of nitrogen and oxygen atoms, the glycosylation of sulfur atoms is less studied. In particular, the crystal structure of enzymes that glycosylate thiols on small molecules rather than peptides has not been reported. Here, we report the crystal structures of LmbT in apo form and in complex with GDP and EGT S-conjugated lincosamine. We found that LmbT has a characteristic glycosyltransferase type B fold, which forms a symmetric homotetramer. The substrates are bound deeply in the catalytic cleft. Consistent with the substrate structure, LmbT does not have the large peptide binding groove of the previously reported S-glycosyltransferase. Combined with site-directed mutagenesis, we propose a catalytic mechanism for the unusual EGT-mediated S-glycosylation in natural product biosynthesis.

A Near-Infrared Fluorescent and Photoacoustic Probe for Visualizing Biothiols Dynamics in Tumor and Liver.

Biothiols, including glutathione (GSH), homocysteine (Hcy) and cysteine (Cys), play crucial roles in various physiological processes. Though an array of fluorescent probes have been designed to visualize biothiols in living organisms, few one-for-all imaging agents for sensing biothiols with fluorescence and photoacoustic imaging capabilities have been reported, since instructions for synchronously enabling and balancing every optical imaging efficacy are deficient. Herein, a new near-infrared thioxanthene-hemicyanine dye (Cy-DNBS) has been constructed for fluorescence and photoacoustic imaging of biothiols in vitro and in vivo. Upon treatment with biothiols, the absorption peak of Cy-DNBS shifted from 592 nm to 726 nm, resulting in a strong NIR absorption as well as a subsequent turn-on PA signal. Meanwhile, the fluorescence intensity increased instantaneously at 762 nm. Then, Cy-DNBS was successfully utilized for imaging endogenous and exogenous biothiols in HepG2 cells and mice. In particular, Cy-DNBS was employed for tracking biothiols upregulation in the liver of mice triggered by S-adenosyl methionine by means of fluorescent and photoacoustic imaging methods. We expect that Cy-DNBS serves as an appealing candidate for deciphering biothiols-related physiological and pathological processes.

Single-atom engineering of hemicyanine and its amphiphilic derivative for optimized near infrared phototheranostics.

Near-infrared (NIR) dyes are widely used in the field of in vivo phototheranostics. Hemicyanine dyes (HDs) have recently received tremendous attention due to their easy synthesis and excellent NIR features. However, HDs can easily form non-fluorescent aggregates and their potential for phototherapy still needs further exploration due to their poor ability to generate reactive oxygen species (ROS). Herein, a series of hemicyanine dyes with different chalcogen atom (O, S, Se) substitutions were constructed to achieve optimized potential for phototheranostics. By replacing O with the heavy atom Se in the xanthene skeleton, CySe-NEt2 showed much more favourable features such as extended NIR absorption/emission wavelength, boosted 1O2 generation rate and higher photothermal effect. In addition, a poly(ethylene glycol) (PEG) group was introduced into the scaffold and yielded a nanotheranostic agent CySe-mPEG5K, which easily formed nanoparticles with appealing features such as excellent photostability, effective prevention of unpleasant H-aggregation, fast/selective tumor accumulation and minimum dark toxicity. Solid tumor growth was significantly suppressed through combined photodynamic therapy (PDT) and photothermal therapy (PTT) guided by NIR fluorescence (NIRF) and photoacoustic (PA) imaging. This study not only presents the first example of selenium-substituted hemicyanine dyes, but also offers a reliable design strategy for the development of potent NIR phototheranostic agents with multi-mode imaging-guided combination therapeutic ability.

Spinal Cord Injury: The Global Incidence, Prevalence, and Disability From the Global Burden of Disease Study 2019.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The authors aimed to estimate the incidence, prevalence and years lived with disability (YLDs) of spinal cord injury (SCI) by location, sex, age, injury site and socio-demographic index (SDI) based on the data of the Global Burden of Disease Study (GBD) 2019. SUMMARY OF BACKGROUND DATA: GBD 2019 estimates the burden of 369 diseases and injuries worldwide in 2019 and the temporal trends in the past 30 years. SCI is estimated as a result of injury from various causes. METHODS: A Bayesian meta-regression tool, DisMod-MR2.1, was used to produce the estimates. Estimated annual percentage change (EAPC) was calculated based on a linear regression mode of the age standardized rates and the calendar year to represent the temporal trends of the age standardized rates. Spearman rank order correlation was used to determine the correlation between SDI and the incidence and burden of SCI. RESULTS: Globally, there were 0.9 [95% uncertainty interval (UI), 0.7 to 1.2] million incident cases, 20.6 (95% UI, 18.9-23.6) million prevalent cases and 6.2 (95% UI, 4.5-8.2) million YLDs of total SCI in 2019. The ASPR increased (EAPC, 0.1; 95% confidence interval, -0.01 to 0.2), while the age standardized incidence rate (ASIR) (EAPC, -0.08; 95% UI, -0.24 to 0.09) and age standardized YLD rate (ASYR) (EAPC, -0.08; 95% confidence interval, -0.24 to 0.09) decreased. Males had higher ASIR and ASYR, and the rate of incidence, prevalence and YLD increased with age. Spinal injuries at neck level caused higher ASYR than injuries below neck level. A positive correlation existed between SDI and ASIR (ρ=0.1626, P <0.05), while a negative correlation was observed between SDI and EAPC of ASYR (ρ=-0.2421, P <0.01). CONCLUSION: Conclusively, the incidence and burden of SCI has increased over the last 30 years. Males and the elderly were affected to a greater degree than females and younger individuals. LEVEL OF EVIDENCE: Level III.

Target Localization in Wireless Sensor Networks Based on Received Signal Strength and Convex Relaxation.

A new positioning algorithm based on RSS measurement is proposed. The algorithm adopts maximum likelihood estimation and semi-definite programming. The received signal strength model is transformed to a non-convex estimator for the positioning of the target using the maximum likelihood estimation. The non-convex estimator is then transformed into a convex estimator by semi-definite programming, and the global minimum of the target location estimation is obtained. This algorithm aims at the L0 known problem and then extends its application to the case of L0 unknown. The simulations and experimental results show that the proposed algorithm has better accuracy than the existing positioning algorithms.

Efficacy of Bi Qi Capsules in combination with methotrexate in the treatment of rheumatoid arthritis: A protocol of double-blind randomized controlled trial.

BACKGROUND: It is known that Bi Qi Capsules (BQC) have synergistic effects when combined with Methotrexate, but there is a lack of clinical studies on the long-term efficacy and safety of the combination of the 2 in the treatment of rheumatoid arthritis (RA). Therefore, the purpose of this randomized controlled trial was to evaluate the long-term efficacy and safety of this treatment. METHODS: This was a prospective, double-blind, single-simulation, randomized controlled trial investigating the efficacy and safety of BQC in combination with Methotrexate in the treatment of RA, and was approved by the Clinical Research Ethics Committee of the hospital. Patients were randomized in a 1:1 ratio to either the observation or control group and were respectively followed up for 6 months after receiving 12 weeks of treatment. The observation indexes included: total effective rate, DAS-28 score, inflammatory indexes, and adverse reactions. Finally, the collected data was statistically analyzed by SPSS version 18.0. DISCUSSION: This study evaluated the long-term efficacy of BQC in combination with Methotrexate in the treatment of RA. The trial results of this study will provide new ideas for choosing a combination of Chinese and Western medicine protocols for the treatment of RA. TRIAL REGISTRATION: OSF Registration number: DOI 10.17605/OSF.IO/U85GX.

Efficacy of warming needle moxibustion in the treatment of ankylosing spondylitis: A protocol of a randomized controlled trial.

BACKGROUND: Ankylosing spondylitis is a recurrent autoimmune disease, which has a high disability rate and seriously affects patients' daily life. Conventional treatment cannot effectively solve the clinical problems of patients, and long-term medication is accompanied by adverse reactions. The evidence shows that warming needle moxibustion has advantages in the treatment of ankylosing spondylitis, but there is still a lack of clinical studies on warm acupuncture alone and long-term follow-up. METHODS: This is a prospective randomized controlled trial to study the efficacy and safety of needle warming through moxibustion in the treatment of ankylosing spondylitis. It was approved by the Ethics Committee of Clinical Research of our hospital. Patients were randomly assigned to an observation group or a control group. The patients were followed up for 6 months after 30 days of treatment. Observation indicators include; activity index, functional ability, Bath Ankylosing Spondylitis Metrology Index, inflammatory indicators, adverse reactions, and so on. Finally, SPASS 22.0 software is used for statistical analysis of the data. DISCUSSION: This study will evaluate the clinical efficacy of warming needle moxibustion in the treatment of ankylosing spondylitis. The results of this study will provide a reference basis for the clinical use of warm needle moxibustion in the treatment of ankylosing spondylitis. TRIAL REGISTRATION: OSF Registration number: DOI 10.17605/OSF.IO/GWPX3.

LIPUS promotes synthesis and secretion of extracellular matrix and reduces cell apoptosis in human osteoarthritis through upregulation of SOX9 expression.

Increasing studies have illustrated that low-intensity pulsed ultrasound (LIPUS) has a therapeutic effect in experimental animal models of osteoarthritis (OA). However, the function of the LIPUS on human chondrocytes of OA remains unclear. The aim of the current study was to observe the effect and explore the mechanism of LIPUS treatment on proliferation, apoptosis, and extracellular matrix (ECM) production of chondrocytes in vitro. Results showed that LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities markedly inhibited the apoptosis of chondrocytes compared with the 0 mW/cm2 intensity; however, the effect of LIPUS stimulation at 0, 30, 60, and 90 mW/cm2 intensities on the proliferation of chondrocytes had no significant difference. Furthermore, the mRNA and protein levels of COL2A1 and ACAN were upregulated in chondrocytes treated with LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities. The concentration of COL2A1 and ACAN in supernatants of chondrocytes in the 30, 60, and 90 mW/cm2 groups were obviously higher than those in the 0 mW/cm2 group. In addition, activation of SOX9 mRNA and protein expression were observed in the 30, 60, and 90 mW/cm2 groups compared with the 0 mW/cm2 group. In summary, our data demonstrated that LIPUS promotes ECM synthesis and secretion and reduces apoptosis of human OA by activation of SOX9, indicating LIPUS might bea promising therapy for the treatment of OA.

Direct Synthesis and Catalytic Application of Ordered Mesoporous Ru/C Composites with Homogeneously Dispersed Ruthenium Nanoclusters.

Direct synthesis of metal/carbon nanocomposites with ordered mesoporous frameworks has attracted increasing interest in various applications including catalysis, optics, and electronics. Herein, we demonstrate a simple one-pot co-assembly route to synthesize Ru/carbon composites by using resol, ruthenium chloride, and Pluronic F127 as a template with the assistance of 8-hydroxyquinoline. 8-Hydroxyquinoline exerts a significant influence on the mesostructure ordering and specific surface area of the Ru/carbon composites. The obtained Ru/carbon materials show well-ordered hexagonal arrays of mesopores with homogeneously dispersed sub-2 nm Ru nanoclusters throughout the carbon frameworks, which can efficiently and quantitatively hydrogenated nitrobenzene to aniline with H2 in the absence of solvent for multiple recycling runs without loss of activity.

Enhancing the oxygen permeability of BaCo(0.7)Fe(0.2)Nb(0.1)O(3-δ) membranes by coating GdBaCo(2-x)Fe(x)O(5+δ) for partial oxidation of coke oven gas to syngas.

The dense ceramic membranes BaCo(0.7)Fe(0.2)Nb(0.1)O(3-δ) (BCFN) combined with GdBaCo(2-x)Fe(x)O(5+δ) (0 ≤ x ≤ 2.0) surface modification layers was investigated for hydrogen production by partial oxidation reforming of coke oven gas (COG). As oxygen permeation of BCFN membrane is controlled by the rate surface exchange kinetics, the GdBaCo(2-x)Fe(x)O(5+δ) materials improve the oxygen permeation flux of the BCFN membrane by 20-44% under helium atmosphere at 750 °C. The maximum oxygen permeation flux reached 14.4 mL min(-1) cm(-2) in the GdBaCoFeO(5+δ) coated BCFN membrane reactor at 850 °C, and a CH(4) conversion of 94.9%, a H(2) selectivity of 88.9%, and a CO selectivity of 99.6% have been achieved. The GdBaCo(2-x)Fe(x)O(5+δ) coating materials possess uniform porous structure, fast oxygen desorption rate and good compatibility with the membrane, which showed a potential application for the surface modification of the membrane reactor.

Formability of ABX3 (X = F, Cl, Br, I) halide perovskites.

In this study a total of 186 complex halide systems were collected; the formabilities of ABX3 (X = F, Cl, Br and I) halide perovskites were investigated using the empirical structure map, which was constructed by Goldschmidt's tolerance factor and the octahedral factor. A model for halide perovskite formability was built up. In this model obtained, for all 186 complex halides systems, only one system (CsF-MnF2) without perovskite structure and six systems (RbF-PbF2, CsF-BeF2, KCl-FeCl2, TlI-MnI2, RbI-SnI2, TlI-PbI2) with perovskite structure were wrongly classified, so its predicting accuracy reaches 96%. It is also indicated that both the tolerance factor and the octahedral factor are a necessary but not sufficient condition for ABX3 halide perovskite formability, and a lowest limit of the octahedral factor exists for halide perovskite formation. This result is consistent with our previous report for ABO3 oxide perovskite, and may be helpful to design novel halide materials with the perovskite structure.