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Abstract Increasing evidence shows that food has significance beyond traditional perception (providing nutrition and energy) in maintaining normal life activities. It is indicated that the sense of taste plays a crucial part in regulating human life activities. Taste is one of the basic physiological sensations in mammals, and it is the fundamental guarantee for them to perceive, select, and ingest nutrients in order to survive. With the advances in electrophysiology, molecular biology, and structural biology, studies on the intracellular and extracellular transduction mechanisms of taste have made great progress and gradually revealed the indispensable role of taste receptors in the regulation and maintenance of normal physiological activities. Up to now, how food regulates life activities through the taste pathway remains unclear. Thus, this review comprehensively and systematically summarizes the current study about the sense of taste, the function of taste receptors, the taste–structure relationship of gustatory molecules, the cross‐talking between distinctive tastes, and the role of the gut–organ axis in the realization of taste. Moreover, we also provide forward‐looking perspectives on taste research to afford a scientific basis for revealing the scientific connotation of taste receptors regulating body health.

This study aimed to investigate the optimal extraction process for polyphenols from Camellia nitidissima Chi and to analyze the total polyphenol composition and antioxidant activities both in vivo and in vitro post-purification. Camellia nitidissima Chi was the raw material and a response surface methodology based on single factor experiments was designed to screen the optimal extraction parameters including ultrasound power, extraction temperature, ethanol concentration and solid-liquid ratio. The extract was purified using Lx-8 macroporous resin, and five specific polyphenolic monomers were qualitatively and quantitatively analyzed using high-performance liquid chromatography (HPLC). Subsequently, in vivo and in vitro antioxidant experiments were conducted on the extract. The results showed that the optimal conditions were an ultrasonic power of 290 W, an extraction temperature of 35 ℃, an ethanol concentration of 55%, and a material-liquid ratio of 1:30 g/mL. Under these conditions, the yield of polyphenols from Camellia nitidissima Chi was 3.53%, the purity was 63.73%. The content of five polyphenolic monomer compounds, namely gallic acid, chlorogenic acid, epicatechin, rutin, and ellagic acid was 0.47, 11.18, 59.03, 18.34, and 16.41 mg/g, respectively. In addition, the polyphenols extracted from Camellia nitidissima Chi demonstrated a significant ability to boost oxidative damage resistance in C. elegans. This was evidenced by a marked increase in SOD (superoxide dismutase) enzyme activity and a decrease in MDA (malondialdehyde) levels within the C. elegans specimens.

Abstract The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.

Vibration signals are essential data for the health monitoring of structures and the cyber–physical system. However, commercial vibration sensors are generally installed on struts/surfaces to gather raw data, which affects the result or causes the detachment problem. This study uses a facile 3D printing method to fabricate a smart vibration absorber with an interior multifunctional multimaterial elastic lattice (MMEL). These lattices, which work as vibration absorbers, have been demonstrated to possess the functions of self‐powered sensing and energy harvesting via the triboelectric effect. The triangular geometry parameter, materials type, etc. have been investigated to illustrate their basic mechanical and triboelectric properties and their coupled influence. Further, the results of the shock test show that MMEL can decrease the peak force from approximately 625 to 90 N and convey the Voc impulse signal simultaneously. The vibration signal has been collected through the MMEL to detect the vibration frequency and charge a watch simultaneously, demonstrating the feasibility and practical potential of the MMEL. The research provides a new method for constructing a multifunctional vibration absorber for applications.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients, and neuroinflammation is a key hallmark. Recent studies suggest that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated astrocytes pyroptosis is involved in the regulation of neuroinflammation in many neurocognitive diseases, while its role in POCD remains obscure. Carnosine is a natural endogenous dipeptide with anti-inflammatory and neuroprotective effects. To explore the effect of carnosine on POCD and its mechanism, we established a POCD model by exploratory laparotomy in 24-month-old male Sprague-Dawley rats. We found that the administrated of carnosine notably attenuated surgery-induced NLRP3 inflammasome activation and pyroptosis in astrocytes, central inflammation, and neuronal damage in the hippocampus of aged rats. In addition, carnosine dramatically ameliorated the learning and memory deficits of surgery-induced aged rats. Then in the in vitro experiments, we stimulated primary astrocytes with lipopolysaccharide (LPS) after carnosine pretreatment. The results also showed that the application of carnosine alleviated the activation of the NLRP3 inflammasome, pyroptosis, and inflammatory response in astrocytes stimulated by LPS. Taken together, these findings suggest that carnosine improves POCD in aged rats via inhibiting NLRP3-mediated astrocytes pyroptosis and neuroinflammation.

Interleukin-21 (IL-21) is produced mainly by activated CD4+ T cells and promotes the proliferation, survival and differentiation of immune cells. This study characterised a high affinity binding receptor of IL-21 (IL-21 Rα) from grass carp (Ctenopharyngodon idella, Ci) and analyzed the expression of CiIL-21 and CiIL-21 Rα. It has been shown that they were modulated by PAMPs and during infection with bacterial and viral pathogens. Recombinant CiIL-21 protein produced in bacteria was active in inducing the expression of genes involved in Th responses. A monoclonal CiIL-21 antibody was generated against the rCiIL-21 and showed good reactive specificity with the rCiIL-21 proteins expressed in E. coli cells, and HEK293 T cells and the native protein from PHA-stimulated kidney leukocytes. In addition, the IL-21-producing cells detected by the CiIL-21 monoclonal antibody were found to be increased to in the kidney, spleen and hindgut after infection with Flavobacterium columnare. Our data indicate that IL-21 is involved in the regulation of immune response to bacterial and viral infection.

Micro-newton thrusters are widely utilized in the field of astronautics. Typically, the precision of micro-newton thrust measurement fundamentally depends on the background noise level. In this research, we introduce the Multichannel Variational Mode Decomposition Input Deep Residual Shrinkage Network (MV-DRSN) to identify the effective signals merged in the background noise. Experimental studies in vacuum were conducted to investigate the effect of noise reduction on MV-DRSN. It is shown that a steady-state signal with 0.1 μN as the minimum change unit can be recovered from the noises with an amplitude of 0.8 μN with an accuracy of 96.7% using MV-DRSN. In addition, the superiority of MV-DRSN over conventional ResNet has been validated, and its effectiveness in practical scenarios is verified. The proposed method has potential for noise reduction of steady-state sensor signals.

Abstract Anti‐HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2‐positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold‐silver hollow nanoshells (AuAg HNSs) with exceptional near‐infrared (NIR) absorption capability, the small‐molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo‐and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT‐modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF‐κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Abstract The combination of the first‐line standard chemotherapeutic drug doxorubicin hydrochloride (DOX) and the molecular‐targeted drug Herceptin (HCT) has emerged as a promising strategy for human epidermal growth receptor 2 (HER‐2) overexpressing breast cancer treatment. However, insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application. Herein, an in situ forming gold nanorods (AuNRs)‐sodium alginate (ALG) hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable, dual‐stimuli‐responsive drug release, photothermal ablation, and drug‐antibody synergistic therapy. The photothermal agent AuNRs, anticancer drug DOX, and anticancer antibody HCT were mixed in ALG solution, and after injection, the soluble ALG was quickly transformed into a hydrogel in the presence of Ca2+ in the body. Significantly, the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70% under 808 nm laser irradiation. The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix. In addition, the drug release rate and the releasing degree are also sensitive to the pH. In vitro studies demonstrated that the PEI‐AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK‐BR‐3 cells. In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites. The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER‐2 overexpressing cancer therapy.

Objective Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). Methods Single‐nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone‐binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome‐wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two‐sample MR approach. For the main analysis, the inverse‐variance‐weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR–Egger method were utilized. To evaluate potential pleiotropy, MR–Egger regression was conducted. Additionally, a leave‐one‐SNP‐out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. Results The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52–3.85; p = 1.93 × 10−4]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10−4), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10−6). Conclusions Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

Abstract Objective To determine whether dynamic changes in serum total testosterone (TT) levels during controlled ovarian stimulation (COS) by a GnRH‐a (gonadotrophin‐releasing hormone agonist) long protocol may predict pregnancy in women with normal ovarian reserve in in vitro fertilization. Methods The TT measurements were added to routine hormone tests during COS. The TT dynamic changes, clinical pregnancy rate, and quality of oocytes and embryos of 109 patients were analyzed. Results Compared with the non‐pregnancy group, in the pregnancy group the TT level on Gn initial day (TTinitial‐d) increased sharply when the dominant follicle reached a diameter 10–12 mm [TTfΦ (10–12)‐d] and on human chorionic gonadotrophin (HCG) day (TTHCG‐d), also the ratios of TTfΦ (10–12)‐d to TTinitial‐d (1.23 ± 0.37 vs. 1.10 ± 0.58, p = 0.040) and TTHCG‐d to TTinitial‐d (2.32 ± 1.26 vs. 2.00 ± 1.43, p = 0.019) increased notably. Of the 2 TT ratios, the first tertile limit was regarded as the threshold of high TT ratios (1.00, 1.45). High tertiles had higher pregnancy rates than low tertiles (82.86% vs. 42.11%, p = 0.006; 71.43% vs. 44.83%, p = 0.040). The 2 TT ratios were positively associated with the number of metaphase II oocytes and good‐quality embryos. Conclusion Of COS in a long GnRH‐a protocol with optimized outcome, serum TT kinetics appears to be characterized by sharp rises at the early and late stages of follicle growth. The ratios of TTΦ (10–12)‐d to TTinitial‐d and TTHCG‐d to TTinitial‐d may be predictors for pregnancy and qualitative outcomes of oocytes and embryos.

Abstract Objectives Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. Methods BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA−210 mimic and BMSC-ExosmiRNA−210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA−210 mimic and BMSC-ExosmiRNA−210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague–Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA−210 mimic or BMSC-ExosmiRNA−210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. Results Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA−210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA−210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA−210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads. Conclusions BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Objective In numerous observational studies, there has been an indication that educational attainment (EA) can impact the intensity of pain and disability resulting from chronic musculoskeletal disorders. Nonetheless, the association observed in these studies is not entirely conclusive. The aim of this study was to investigate the genetic causal relationship between educational attainment and 12 musculoskeletal disorders using Mendelian randomization (MR). Methods The meta‐analysis of genome‐wide association studies (GWAS) identified 3952 single‐nucleotide polymorphisms (SNPs) associated with educational attainment (EA) from the Social Science Genetic Association Consortium (SSGAC). Genetic data for 12 musculoskeletal disorders, including osteonecrosis, osteoporosis, osteomyelitis, low back pain, gout, spinal stenosis, rheumatoid arthritis, meniscus derangement, rotator cuff syndrome, ankylosing spondylitis, cervicobrachial syndrome, and lateral epicondylitis, were obtained from the FinnGen consortium. We conducted a two‐sample Mendelian randomization analysis to examine the causal effect of EA on the risk of these musculoskeletal disorders using the TwoSampleMR package in R. Results Based on the inverse‐variance weighted (IVW) method, we found that a genetically predicted per standard deviation (SD) increase in EA was inversely associated with low back pain [odds ratio (OR) 0.46, 95% confidence interval (Cl) 0.51–0.61, p

Conventional wireless sensors rely on chemical batteries. Replacing or charging their batteries is tedious and costly in some situations. As usable kinetic energy exists in the environment, harvesting vibration energy and converting it into electrical energy has become a hotspot. However, the power output capability of a conventional piezoelectric energy harvester (PEH) is limited by its low operational frequency. This paper presents a new mechanism for achieving continuous triple-frequency-up voltage output in a PEH. The proposed system consists of a slender piezoelectric cantilever with two short cantilever-based stoppers. The piezoelectric cantilever undergoes a pure bending mode without contacting the stoppers. In addition, the beam switches into a new vibration mode by contacting the stoppers. The vibration modes switching yields reverses the signs of voltage outputs, inducing triple-frequency-up voltage output. Analytical and experimental investigations are presented, and it is shown that a significant triple-frequency up-conversion of the voltage output can be obtained over a wide frequency range. A peak power output of 3.03 mW was obtained. The proposed energy harvester can support a wireless sensor node.

Abstract Neuroinflammation manifests following injury to the central nervous system (CNS) and M1/M2 polarization of microglia is closely associated with the development of this neuroinflammation. In this study, multiple databases were used to collect targets regarding luteolin and microglia polarization. After obtaining a common target, a protein–protein interaction (PPI) network was created and further analysis was performed to obtain the core network. Molecular docking of the core network with luteolin after gene enrichment analysis. In vitro experiments were used to examine the polarization of microglia and the expression of related target proteins. A total of 77 common targets were obtained, and the core network obtained by further analysis contained 38 proteins. GO and KEGG analyses revealed that luteolin affects microglia polarization in regulation of inflammatory response as well as the interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways. Through in vitro experiments, we confirmed that the use of luteolin reduced the expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, p-NFκBIA (p-IκB-α), p-NFκB p65, and MMP9, while upregulating the expression of Arg-1 and IL-10. This study reveals various potential mechanisms by which luteolin induces M2 polarization in microglia to inhibit the neuroinflammatory response.

Abstract Background Diabetes mellitus (DM) and osteoarthritis (OA) are common diseases that are predicted to increase in prevalence, and DM is a risk factor for OA progression and has a negative impact on the outcome. However, the evidence remains unclear on how it affects patients’ clinical results of total knee arthroplasty (TKA) under enhanced recovery after surgery (ERAS). Methods A retrospective single-center study was conducted comparing diabetic and non-diabetic patients who underwent TKA in West China Hospital of Sichuan University between September 2016 to December 2017 under ERAS. Consecutive propensity score matching (PSM) was conducted by 1:1 (DM: non-DM) matching analysis with all baselines as covariates. The primary clinical results were the improvement of knee joint function, the incidence of postoperative complications, and the FJS-12 sensory results 5 years after the operation between DM and Non-DM groups. The secondary clinical results were the postoperative length of stay (LOS), postoperative blood test and total blood loss (TBL). Result After PSM, the final analysis included 84 diabetic patients and 84 non-diabetic patients. Diabetic patients were more likely to experience early postoperative complications (21.4% vs. 4.8%, P = 0.003), of which wound complications are the most significant (10.7% vs. 1.2%, P = 0.022). Diabetic patients experienced longer postoperative LOS with a significant increase in patients with LOS exceeding 3 days (66.7% vs. 50%, P = 0.028) and showed less postoperative range of motion (ROM) (106.43 ± 7.88 vs. 109.50 ± 6.33 degrees, P = 0. 011). Diabetic patients also reported lower Forgotten joint score (FJS-12) than non-diabetic patients (68.16 + 12.16 vs. 71.57 + 10.75, P = 0.020) in the 5-year follow-up and were less likely to achieve a forgotten knee joint (10.7% vs. 1.2%, P = 0.022). In additional, Compared with non-diabetics, diabetic patients showed lower hemoglobin (Hb) (P

Aims: Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods: We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results: TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as ‘chemical carcinogenesis - reactive oxygen species’ (LogP value = −2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = −2.811). Conclusion: This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS. Cite this article: Bone Joint Res 2023;12(6):387–396.

Objectives Perioperative enhanced recovery after surgery (ERAS) protocols can improve the quality of healthcare and reduce hospitalization for patients who underwent total hip arthroplasty (THA). The interval of staged bilateral THA under ERAS is still unclear. We attempt to ascertain the optimal interval of staged bilateral THA for reducing the perioperative complications and the cost of hospitalization. Methods We retrospectively reviewed patients who received staged bilateral THA under ERAS performed at West China Hospital of Sichuan University from 2018 to 2021. The staged time was divided into two groups using four different cutoff points: (1) ≤3 months versus >3 months, (2) ≤4 months versus >4 months, (3) ≤5 months versus >5 months and (4) ≤6 months versus >6 months. Primary outcomes included the rate of perioperative complications and the cost of hospitalization. The secondary outcomes were the length of hospital stay (LOS), the rates of transfusion and albumin (Alb) administration, hemoglobin (Hb) decrease and serum Alb decrease. The categorical variables were compared using chi‐squared and/or two‐tailed Fisher's exact tests, whereas continuous variables were compared using two‐tailed independent t‐tests, the continuous variables which were asymmetrical distributions used a Kruskal–Wallis test. Results With the application of ERAS, the rate of perioperative complications in the >5 months group was significantly lower than that in the ≤5 months group (13/195 vs. 45/307, p 5 monthly intervals spent significantly less than the ≤5 monthly intervals ($ 8695.91 vs. $ 8919.71, p

Objective The implications of the interval of staged bilateral total knee arthroplasty (TKA) procedures for postoperative complications and costs are not clear. We aimed to determine the optimal time interval between the two stages of bilateral TKA procedures under the enhanced recovery after surgery (ERAS) protocol. Methods This retrospective study of collected data included bilateral TKA cases under the ERAS protocol performed between 2018 and 2021 at the West China Hospital of Sichuan University. The staged time was subdivided into three groups according to the interval between the first TKA and second contralateral TKA: group 1: 2‐ to 6‐month, group 2: 6‐ to 12‐month, and group 3: >12 months. The primary outcome was the incidence of postoperative complications. The secondary outcomes were the length of hospital stay (LOS), hemoglobin (Hb) decrease, hematocrit (Hct) decrease, and albumin (Alb) decrease. Results We analyzed 281 patients who underwent staged bilateral TKAs between 2018 and 2021 at the West China Hospital of Sichuan University. Regarding postoperative complications, there were no statistically significant differences among the three groups (P = 0.21). For the mean LOS, the 6‐ to 12‐month group had a significantly shorter LOS compared with the 2‐ to 6‐month group (P 12 months group (P = 0.02; P

Objective The optimal dose and efficacy of tranexamic acid (TXA) and epsilon‐aminocaproic acid (EACA) in total knee arthroplasty (TKA) were under controversial, and we aimed to make comparisons between different doses of TXA and EACA in intravenous (IV) or intra‐articular (IA) applications in patients undergoing TKA. Methods This network meta‐analysis was guided by the Priority Reporting Initiative for Systematic Assessment and Meta‐Analysis (PRISMA). According to the administrations of antifibrinolytic agents, patients in eligible studies were divided into three subgroups: (i) IA applications of TXA and EACA; (ii) IV applications (g) of TXA and EACA; (iii) IV applications (mg/kg) of TXA and EACA. Total blood loss (TBL), hemoglobin (HB) drops and transfusion rates were the primary outcomes, while drainage volume, pulmonary embolism (PE) or deep vein thrombosis (DVT) risk were the secondary outcomes. A multivariate Bayesian random‐effects model was adopted in the network analysis. Results A total of 38 eligible trials with different regimens were assessed. Overall inconsistency and heterogeneity were acceptable. Taking all primary outcomes into account, 1.0–3.0 g TXA were most effective in IA applications, 1–6 g TXA and 10–14 g EACA were most effective in IV applications (g), while 30 mg/kg TXA and 150 mg/kg EACA were most effective in IV applications (mg/kg). None of the regimens showed increasing risk for pulmonary embolism (PE) or deep vein thrombosis (DVT) compared with placebo. Conclusion 0 g IA TXA, 1.0 g IV TXA or 10.0 g IV EACA, as well as 30 mg/kg IV TXA or 150 mg/kg IV EACA were most effective and enough to control bleeding for patients after TKA. TXA was at least 5 times more potent than EACA.

ABSTRACTBackground: Clinical outcome of patients with chronic myeloid leukemia (CML) has improved dramatically since the introduction of tyrosine kinase inhibitors such as imatinib mesylate (IM). However, approximately 20-30% of patients experience IM resistance. SH-4-54, which targets the SH2 domains of both proteins STAT3 and STAT5, has been reported to exhibit anticancer activity in solid tumors. However, the roles of SH-4-54 in CML remain unclear. The aim was to explore whether SH-4-54 could overcome IM resistance and identify novel targets for CML.Methods: Cell viability was measured by CCK-8 assays after treatment of K562 and K562R cells with different concentrations of SH-4-54. Annexin V-FITC and PI were applied to assess the effects of SH-4-54 on cell apoptosis. Effects of SH-4-54 on the expression of proteins downstream of BCR::ABL1 were assessed by western blotting (WB). Effects of SH-4-54 on gene expression profile of CML cells were analyzed by Next generation sequence (NGS).Results: SH-4-54 inhibited the growth of CML cell lines with increasing concentration. SH-4-54 cytotoxic effects correlated with a significant induction of apoptosis. The results of WB analysis showed the downstream proteins of BCR::ABL1, such as STAT3 and STAT5, decreased after SH-4-54 treatment; moreover, the phosphorylation of both proteins were inhibited in dose-dependent manner. Using NGS, we obtained Mrna expression profiles in SH-4-54 treated K562 and K562R cells and identified differentially expressed mRNAs. Among these, STAT3 and STAT5 were markedly downregulated.Conclusion: SH-4-54 may overcome IM resistance and represent a promising novel approach to improve the outcome of CML.

Subacute ruminal acidosis (SARA) has been demonstrated to promote the development of mastitis, one of the most serious diseases in dairy farming worldwide, but the underlying mechanism is unclear. Using untargeted metabolomics, we found hexadecanamide (HEX) was significantly reduced in rumen fluid and milk from cows with SARA-associated mastitis. Herein, we aimed to assess the protective role of HEX in Staphylococcus aureus (S. aureus)- and SARA-induced mastitis and the underlying mechanism. We showed that HEX ameliorated S. aureus-induced mastitis in mice, which was related to the suppression of mammary inflammatory responses and repair of the blood-milk barrier. In vitro, HEX depressed S. aureus-induced activation of the NF-κB pathway and improved barrier integrity in mouse mammary epithelial cells (MMECs). In detail, HEX activated PPARα, which upregulated SIRT1 and subsequently inhibited NF-κB activation and inflammatory responses. In addition, ruminal microbiota transplantation from SARA cows (S-RMT) caused mastitis and aggravated S. aureus-induced mastitis, while these changes were reversed by HEX. Our findings indicate that HEX effectively attenuates S. aureus- and SARA-induced mastitis by limiting inflammation and repairing barrier integrity, ultimately highlighting the important role of host or microbiota metabolism in the pathogenesis of mastitis and providing a potential strategy for mastitis prevention.

Objective There were limited randomized controlled trials (RCTs) of epsilon‐aminocaproic acid (EACA) versus tranexamic acid (TXA) in total knee arthroplasty (TKA). The aim of the study was to compare the efficacy and safety of TXA and EACA in the combination of intravenous (IV) and intra‐articular (IA) administration on reducing blood loss in patients following primary TKA. Methods From January 2020 to January 2021, a total of 181 patients undergoing a primary unilateral TKA were enrolled in this prospective randomized controlled trial. Patients in the TXA group (n = 90) received 20 mg/kg of intravenous TXA preoperatively, 1 g of intra‐articular TXA intraoperatively, and three doses of 20 mg/kg intravenous TXA at 0, 3, 6 h postoperatively. Patients in the EACA group (n = 91) received 120 mg/kg of intravenous EACA preoperatively, 2 g of intra‐articular EACA intraoperatively, and three doses of 40 mg/kg intravenous EACA at 0, 3, 6 h postoperatively. The primary outcomes were total blood loss (TBL), transfusion rates and drop of hemoglobin (HB) level. The secondary outcomes included postoperative hospital stays and postoperative complications. The chi‐square tests and Fisher's exact tests were utilized to compare categorical variables, while the independent‐samples t‐tests and Mann–Whitney tests were used to compare continuous variables. Results The patients who received TXA averaged less TBL than the patients who received EACA (831.83 ml vs 1065.49 ml, P = 0.015), and HB drop in TXA group was generally less than that of EACA group on postoperative day 1 and 3 (20.84 ± 9.48 g/L vs 24.99 ± 9.40 g/L, P = 0.004; 31.28 ± 11.19 vs 35.46 ± 12.26 g/L, P = 0.047). The length of postoperative stays in EACA group was 3.66 ± 0.81 day, which is longer than 2.62 ± 0.68 day in TXA group (P

Objectives Red blood cell distribution width (RDW) with prognosis in various infectious diseases. For fractured patients admitted to the intensive care units (ICU), an accurate and fast appraisal is essential. To investigate the association between RDW and prognosis in fractured patients admitted to the ICU utilizing the MIMIC‐III database. Methods A retrospective cohort from the MIMIC III database from 2001 and 2012 was constructed. RDW and other information were collected with in‐hospital mortality as the primary outcome and 90‐day mortality and hospital and intensive care unit (ICU) length of stay (LOS) as secondary outcomes. Univariate and multivariate logistic regression models with propensity score inverse probability of treatment weighting (IPTW) were used to investigate the prognostic value of RDW. A nomogram was built with significant prognostic factors to predict in‐hospital mortality, and the performance of the nomogram was evaluated and compared with other severity assessment scores. Subgroup analysis was also conducted. Results A total of 2721 fracture patients admitted to the ICU were identified. After IPTW, the group with higher RDW was significantly associated with elevated in‐hospital mortality (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.19–2.37), 90‐day mortality (OR: 1.39, 95% CI: 1.04–1.86), prolonged hospital LOS (OR: 1.25, 95% CI: 1.03–1.50), and ICU LOS significantly (OR: 1.26, 95% CI: 1.05–1.53) in the multivariate logistics model. The nomogram showed optimal discriminative ability and predictive accuracy with an area under the receiver operating characteristic curve of 0.77. Conclusion RDW independently predicted in‐hospital mortality, 90‐day mortality, and hospital and ICU LOS in fractured patients admitted to ICU. The nomogram including RDW could also be a promising tool with potential clinical benefits.

AimsDegenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive.MethodsPredicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.ResultsThe TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile.ConclusionOur results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80–90.

Aluminum (Al) placed in hot water (HW) at 90 °C is roughened due to its reaction with water, forming Al hydroxide and Al oxide, as well as releasing hydrogen gas. The roughened surface is thus hydrophilic and possesses a hugely increased surface area, which can be useful in applications requiring hydrophilicity and increased surface area, such as atmospheric moisture harvesting. On the other hand, when using HW to roughen specified areas of an Al substrate, ways to protect the other areas from HW attacks are necessary. We demonstrated that self-assembled monolayers (SAMs) of a fluorinated phosphonic acid (FPA, CF3(CF2)13(CH2)2P(=O)(OH)2) derivatized on the native oxide of an Al film protected the underneath metal substrate from HW attack. The intact wettability and surface morphology of FPA-derivatized Al subjected to HW treatment were examined using contact angle measurement, and scanning electron microscopy and atomic force microscopy, respectively. Moreover, the surface and interface chemistry of FPA-derivatized Al before and after HW treatment were investigated by time-of-flight secondary ion mass spectrometry (ToF-SIMS), verifying that the FPA SAMs were intact upon HW treatment. The ToF-SIMS results therefore explained, on the molecular level, why HW treatment did not affect the underneath Al at all. FPA derivatization is thus expected to be developed as a patterning method for the formation of hydrophilic and hydrophobic areas on Al when combined with HW treatment.

Micro-newton thrust stands are widely used in thruster ground calibration procedures for a variety of space missions. The conventional analytical model does not consider the gravity-induced extension effect and systematic error in displacement for thrust stands consisting of hanging pendulums based on flexure hinge structures. This paper proposes an improved analytical model of a hanging pendulum for thrust measurement, where an elliptical notched flexure hinge is the key component. A parametric model of the bending stiffness of the flexure hinge is developed. Equally, both the bending stiffness shift under the gravity-induced extension effect and the systematic error in displacement due to the assumed rotational center offset of the hinge are investigated. The presented stiffness equations for elliptical notched hinges can be degenerated into stiffness equations for circular notched as well as leaf-type hinges. The improved model aims to evaluate and highlight the influence of the two considered factors for use in thrust stand parameter design and thrust analysis. A finite element modeling solution is proposed to validate the proposed analytical model. The results show that the proposed model can quantify the hinge bending stiffness shift, which also demonstrates that even a small bending stiffness shift may introduce great uncertainty into the thrust analysis.

Abstract The direct electrochemistry of hepatitis B virus containing the covalently closed circular DNA (HBV cccDNA) is realized at pretreated glassy carbon electrode (PGCE). It is essential that the direct electron transfer of guanine (G) and adenine (A) on HBV cccDNA strand is captured by microwave irradiation to melt cccDNA into ssDNA. The irreversible adsorption and diffusion controlled processes of G and A are revealed by cyclic voltammetry with participating 2 protons and 2 electrons respectively. In addition, we found that there are two oxidation peaks of G and A in whole blood containing HBV. Nevertheless, there is only one oxidation peak of G in whole blood of normal people. According to this difference of oxidation peaks in whole blood sample, it can be used screen quickly HBV infection or carriers in clinic and large area of blood donors.

Summary: Polarity proteins regulate the proliferation and differentiation of neural progenitors to generate neurons during brain development through multiple signaling pathways. However, how cell polarity couples the signaling pathways remains unclear. Here, we show that coiled-coil domain-containing protein 85c (Ccdc85c) interacts with the polarity protein Par3 to regulate the proliferation of radial glial cells (RGCs) via phase separation coupled to percolation (PSCP). We find that the interaction with Ccdc85c relieves the intramolecular auto-inhibition of Par3, which leads to PSCP of Par3. Downregulation of Ccdc85c causes RGC differentiation. Importantly, the open conformation of Par3 facilitates the recruitment of the Notch regulator Numb to the Par3 condensates, which might prevent the attenuation of Notch activity to maintain RGC proliferation. Furthermore, ectopic activation of Notch signaling rescues RGC proliferation defects caused by the downregulation of Ccdc85c. These results suggest that Ccdc85c-mediated PSCP of Par3 regulates Notch signaling to control RGC proliferation during brain development.

Abstract Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.

Abstract Background Multisystem inflammatory syndrome in children (MIS-C) is a new syndrome with some clinical manifestations similar to Kawasaki disease (KD), which is difficult to distinguish. Objective The study aimed to characterize the demographic characteristics, clinical characteristics, laboratory features, cardiac complications, and treatment of MIS-C compared with KD. Study design Studies were selected by searching the PubMed, EMBASE and so on before February 28, 2022. Statistical analyses were performed using Review Manager 5.4 software and STATA 14.0. Results Fourteen studies with 2928 participants were included. MIS-C patients tended to be older and there was no significant difference in the sex ratio. In terms of clinical characteristics, MIS-C patients were more frequently represented with respiratory, gastrointestinal symptoms and shock. At the same time, they had a lower incidence of conjunctivitis than KD patients. MIS-C patients had lower lymphocyte counts, platelet (PLT) counts, erythrocyte sedimentation rates (ESRs), alanine transaminase (ALT), and albumin levels and had higher levels of aspartate transaminase (AST), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin, C-reactive protein (CRP), D-dimer, fibrinogen, ferritin, and creatinine. MIS-C patients had a higher incidence of left ventricle (LV) dysfunction, valvular regurgitation, pericardial effusion, myocarditis, and pericarditis. The incidence of coronary artery lesion (CAL) was lower in MIS-C patients [OR (95% CI): 0.52 (0.29, 0.93), p =0.03], while it was similar in the acute period. MIS-C patients had higher utilization of glucocorticoids (GCs) and lower utilization of intravenous immune globulin (IVIG). Conclusions There were specific differences between MIS-C and KD, which might assist clinicians with the accurate recognition of MIS-C and further mechanistic research.

Objective C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen and D‐Dimer are used as diagnostic biomarkers of prosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of the study was to investigate the normal trajectory of CRP, ESR, plasma fibrinogen and D‐Dimer at different time points after two‐stage exchange arthroplasty for PJI. Methods We studied 53 patients undergoing two‐stage exchange for PJI at five time points: preoperatively (T0), duration of hospital stays (T1), 30 days (T2), 30–90 days (T3), and 90–180 days (T4) after surgery. The medical records of all patients were well documented and carefully reviewed. The Shapiro–Wilk test was utilized to compare the normal distribution for continuous variables, and the nonnormally distributed data were used for Friedmann's one‐way repeat measures analysis of variances. Post hoc Dunnett's test was used to compare each pair of data to find differences from baseline. Results Compare with T0 point, the levels of CRP and ESR increased significantly and reached peak values at T1 point (all P 0.05). Conclusions The study demonstrated the normal trajectory of CRP, ESR, plasma fibrinogen and D‐Dimer at five time points in patients who underwent two‐stage exchange for PJI. Thus, the results have the possibility of providing signs of infection after the patient receives two‐stage exchange arthroplasty for PJI, which can benefit from early treatment.

Abstract Background The incidence of pulmonary embolism complications in the literature ranges from 10 to 50%, with a 0.5–10% risk of fatal pulmonary embolism. However, the biological cause of pulmonary embolism is unknown. Methods This study used data from the Genome-Wide Association Study (GWAS) of Pulmonary Embolism and Human Blood Metabolites from the UK Biobank, and the data from subjects of European ancestry were analyzed. We explored the relationship between pulmonary embolism and blood metabolites in three ways. We first analyzed the genetic correlation between pulmonary embolism and human blood metabolites using the linkage disequilibrium score regression (LDSC) and then analyzed the causal relationship between pulmonary embolism and meaningful blood metabolites obtained from the LDSC, a procedure for which we used Mendelian randomization analysis. Finally, we obtained transcriptome sequencing data for patients with a pulmonary embolism from the GEO database, analyzed differentially expressed genes (DEGs) in patients with pulmonary embolism versus healthy populations, and compared the DEGs with the resulting blood metabolite genes to further validate the relationship between pulmonary embolism and blood metabolites. Result We found six human blood metabolites genetically associated with pulmonary embolism, stearic acid glycerol phosphate ethanolamine (correlation coefficient = 0.2582, P = 0.0493), hydroxytryptophan (correlation coefficient = 0.2894, P = 0.0435), and N1-methyladenosine (correlation coefficient = 0.0439, P = 0.3728), and a significant causal relationship was discovered between hydroxytryptophan and pulmonary embolism. After screening microarray data from the GEO database, we performed differential gene analysis on the GSE19151 dataset and screened a total of 22,216 genes with P values less than 0.05, including 17,361 upregulated genes and 4854 downregulated genes. By comparing the resulting differentially expressed genes with six genes encoding blood metabolites, LIPC and NAT2 were found to be differentially expressed in association with pulmonary embolism.

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps. Cite this article: Bone Joint Res 2022;11(7):426–438.

Replanting is a widely used method for improving the health and carbon sequestration capacity of degraded forests. However, its impact on soil carbon pools remains controversial. This study investigated the effects of replanting broadleaf Phoebe bournei (Hemsl.) Yang in a typical degraded fir forest. Soil carbon content, nutrient levels, and microbial community structure and function were measured at 0, 5, 8, and 12 years after replanting. The degraded fir forests were originally limited in nitrogen and phosphorus. Phoebe bournei replanting significantly increased soil total carbon but reduced total nitrogen and phosphorus levels, resulting in increased soil carbon:nitrogen, carbon:phosphorus, and nitrogen:phosphorus ratios. Microbial biomass carbon, nitrogen, and phosphorus were all significantly reduced, whereas microbial carbon:phosphorus and nitrogen:phosphorus ratios were enhanced. Enzyme activities related to nutrient cycling and carbon decomposition (acidic invertase, polyphenol oxidase, peroxidase, urase, nitrate reductase, and acidic phosphatase activities) were significantly lowered by replanting. Microbial richness and diversity significantly increased, and microbial community composition changed significantly due to replanting. Structural equation modeling revealed the significant role of total phosphorus in microbial biomass, microbial community composition, and enzyme activity, highlighting it as the main factor accelerating soil carbon accumulation. Network analysis identified Leifsonia, Bradyrhizobium, and Mycolicibacterium members as key microbial players in the soil carbon cycle. In summary, P. bournei replanting exacerbated soil phosphorus deficiency, leading to a decrease in soil microbial biomass and changes in community structure, reduced nutrient cycling and carbon-decomposition-related enzyme activities, less litter decomposition, and increased organic carbon accumulation. These findings demonstrate the importance of nutrient limitation in promoting soil carbon accumulation and offer new insights for soil carbon regulation strategies in forestry.

Abstract Background Osteoporosis is a common metabolic bone disease that is characterized by low bone mass. However, limited efforts have been made to explore the functional relevance of the blood proteome to bone mineral density across different life stages. Methods Using genome-wide association study summary data of the blood proteome and two independent studies of bone mineral density, we conducted a genetic correlation scan of bone mineral density and the blood proteome. Linkage disequilibrium score regression analysis was conducted to assess genetic correlations between each of the 3283 plasma proteins and bone mineral density. Results Linkage disequilibrium score regression identified 18 plasma proteins showing genetic correlation signals with bone mineral density in the TB-BMD cohort, such as MYOM2 (coefficient = 0.3755, P value = 0.0328) among subjects aged 0 ~ 15, POSTN (coefficient = − 0.5694, P value = 0.0192) among subjects aged 30 ~ 45 and PARK7 (coefficient = − 0.3613, P value = 0.0052) among subjects aged over 60. Conclusions Our results identified multiple plasma proteins associated with bone mineral density and provided novel clues for revealing the functional relevance of plasma proteins to bone mineral density.

Abstract Deep vein thrombosis (DVT) refers to the abnormal coagulation of blood in a deep vein. Recently, some studies have found that metabolites are related to the occurrence of DVT and may serve as new markers for the diagnosis of DVT. In this study, we used the GWAS summary dataset of blood metabolites and DVT to perform a large-scale genetic correlation scan of DVT and blood metabolites to explore the correlation between blood metabolites and DVT. We used GWAS summary data of DVT from the UK Biobank (UK Biobank fields: 20002) and GWAS summary data of blood metabolites from a previously published study (including 529 metabolites in plasma or serum from 7824 adults from two European population studies) for genetic correlation analysis. Then, we conducted a causal study between the screened blood metabolites and DVT by Mendelian randomization (MR) analysis. In the first stage, genetic correlation analysis identified 9 blood metabolites that demonstrated a suggestive association with DVT. These metabolites included Valine (correlation coefficient = 0.2440, P value = 0.0430), Carnitine (correlation coefficient = 0.1574, P value = 0.0146), Hydroxytryptophan (correlation coefficient = 0.2376, P value = 0.0360), and 1-stearoylglycerophosphoethanolamine (correlation coefficient = − 0.3850, P value = 0.0258). Then, based on the IVW MR model, we analysed the causal relationship between the screened blood metabolites and DVT and found that there was a suggestive causal relationship between Hydroxytryptophan (exposure) and DVT (outcome) (β = − 0.0378, se = 0.0163, P = 0.0204). Our study identified a set of candidate blood metabolites that showed a suggestive association with DVT. We hope that our findings will provide new insights into the pathogenesis and diagnosis of DVT in the future.

Background and purposePrevious studies have stimulated debates on low-dose alteplase administration in acute ischemic stroke (AIS) among the Asian population. We sought to evaluate the safety and efficacy of low-dose alteplase in Chinese patients with AIS using a real-world registry.MethodsWe analyzed data from the Shanghai Stroke Service System. Patients receiving alteplase intravenous thrombolysis within 4.5 hours were included. These patients were divided into the low-dose alteplase group (0.55–0.65 mg/kg) and the standard-dose alteplase group (0.85–0.95 mg/kg). Baseline imbalances were adjusted by using the propensity score matching. The primary outcome was mortality or disability, which was defined as the modified Rankin scale (mRS) score ranging from 2 to 6 at discharge. The secondary outcomes were in-hospital mortality, symptomatic intracranial hemorrhage (sICH) and functional independence (mRS score 0–2).ResultsFrom January 2019 to December 2020, a total of 1,334 patients were enrolled and 368 (27.6%) were treated with low-dose alteplase. The median age of the patients was 71 years, and 38.8% were female. Our study showed that the low-dose group had significantly higher rates of death or disability (adjusted odds ratio (aOR) = 1.49, 95% confidence interval (CI) [1.12, 1.98]) and less functional independence (aOR = 0.71, 95%CI [0.52, 0.97]) than the standard-dose group. There was no significant difference in sICH or in-hospital mortality between the standard-dose and low-dose alteplase groups.ConclusionsLow-dose alteplase was related to a poor functional outcome without lowering the risk of sICH, compared with standard-dose alteplase for AIS patients in China.

To extract the global temporal correlations and local features together to enhance the accuracy for fault diagnosis, this paper proposes an effective convolutional Transformer (ECT), which can learn the global temporal correlations using Transformer and local features with convolution at the same time. The proposed method designs a multi-stage hierarchical structure of Transformer, which utilizes convolutional tokenization to distill dominating sequence features from raw vibration signals while increasing the dimension of token embedding across stages at the same time as that in CNNs. The spatial-reduction attention (SRA) and the linear dimension reduction projections are introduced respectively to Transformer at different stages to reduce the resource consumption of the model. Finally, the proposed method utilizes a sequence pooling strategy on the output of Transformer to eliminate the requirement of the class token and make the model accurate for classification. The specially designed structure makes the model flexible and effective for planetary gearbox fault diagnosis. Experiments performed on planetary gearbox fault simulators indicate that the ECT method has significant effectiveness and high accuracy compared with the state-of-the-art methods for planetary gearbox fault diagnosis.

Abstract Hypertension was one common comorbidity of knee osteoarthritis (KOA), but the effect of different types of antihypertensive drugs on pain and joint space width (JSW) was unclear and not compared. Four hundred ninety KOA patients using one of the beta‐blockers, ACE inhibitors, angiotensin receptor blockers, Calcium channel blockers (CCBs), or thiazide diuretics were followed for four years. The blood pressure, cumulative knee replacement rate, Womac pain, and JSW were compared among groups. All data were from the Osteoarthritis Initiative project. The CCBs group has the highest systolic blood pressure, replacement rate, and pain score at most visit timepoints. At baseline, the CCBs group was with significantly higher pain score than the beta‐blockers group (3.3 vs 1.3, p

BackgroundThis study aimed to summarize the features of perforating scleral vessels (PSVs) in patients with myopic choroidal neovascularization (CNV) (mCNV) using optical coherence tomography angiography (OCTA) and to identify the associations with the response after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.MethodsA consecutive series of naïve patients who had mCNV and received intravitreal anti-VEGF therapy with a follow-up duration of 12 months or more were enrolled. The prevalence, location, and branches of PSVs were analyzed. Projection-resolved OCTA (PR-OCTA) was used to analyze the neovascular signals between CNV and PSVs. Best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured. The proportion of CMT change relative to baseline was used to assess therapeutic response.ResultsA total of 44 eyes from 42 patients with mCNV were enrolled. PSVs were identified in 41 out of 44 eyes. Branches were identified in the PSVs of 24 eyes (57.14%), and 20 eyes did not have PSV branches (47.62%). In eight eyes (18.18%), PSVs were adjacent to mCNV, and in 36 eyes (81.82%), PSVs were not adjacent to mCNV. After anti-VEGF therapy for mCNV, BCVA increased (F = 6.119, p < 0.001) and CMT decreased (F = 7.664, p < 0.001). In the eyes where PSVs were adjacent to mCNV, BCVA improvements (F = 7.649, p = 0.009) were poor, and changes in CMT were small.ConclusionThe eyes with PSVs adjacent to mCNV showed poor therapeutic responses after intravitreal anti-VEGF therapy.

ObjectiveTo explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR).MethodsPublicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR–Egger methods. The pleiotropy of MR results was determined using MR–Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results.ResultsBased on IVW, MR–Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR–Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR.ConclusionOur results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality that urgently requires new treatments. ROCK1 plays an essential role in regulating growth and survival in AML cells. In this study, we evaluated GSK269962A, a selective ROCK1 inhibitor, in preclinical models of AML. Compared with solid tumors, GSK269962A selectively inhibited cell growth and clonogenicity of AML cells. Furthermore, GSK269962A arrested AML cells in the G2 phase and induced apoptosis by regulating multiple cell cycle- and apoptosis-associated proteins. Strikingly, GSK269962A could eliminate leukemia cells from bone marrow, liver, and spleen in an animal model of AML and significantly prolong mouse survival. Mechanistically, GSK269962A could inhibit the growth of AML by blocking ROCK1/c-Raf/ERK signaling pathway. Notably, a correlation was found between the expression levels of ROCK1 protein and the sensitivity of GSK269962A in AML. These data highlight the potential role of ROCK1 as an attractive target for treating AML, as well as the potential of GSK269962A for use in clinical trials of AML.

Abstract Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease‐activating factor 1 (APAF1)‐binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA‐binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3‐mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase‐9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.

Osteoarthritis (OA) is a slowly progressing and irreversible joint disease. The existing non-surgical treatment can only delay its progress, making the early treatment of OA a research hotspot in recent years. Melatonin, a neurohormone mainly secreted by the pineal gland, has a variety of regulatory functions in different organs, and numerous studies have confirmed its therapeutic effect on OA. Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome. Various ncRNAs show significant differentially expressed between healthy people and OA patients. ncRNAs play diverse roles in many cellular processes and have been implicated in many pathological conditions, especially OA. Interestingly, the latest research found a close interaction between ncRNAs and melatonin in regulating the pathogenesis of OA. This review discusses the current understanding of the melatonin-mediated modulation of ncRNAs in the early stage of OA. We also delineate the potential link between rhythm genes and ncRNAs in chondrocytes. This review will serve as a solid foundation to formulate ideas for future mechanistic studies on the therapeutic potential of melatonin and ncRNAs in OA and better explore the emerging functions of the ncRNAs.

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms.MethodsA cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets.ResultsThe TWAS identified 535 significant genes with P

Abstract Background Osteoarthritis (OA) is a common skeletal system disease that has been partially attributed to genetic factors. The hand is frequently affected, which seriously affects the patient’s quality of life. However, the pathogenetic mechanism of hand osteoarthritis (hand OA) is still elusive. Methods A genome-wide association study (GWAS) summary of hand OA was obtained from the UK Biobank dataset, which contains data from a total of 452,264 White British individuals, including 37,782 OA patients. The transcriptome-wide association study (TWAS) of hand OA was performed using FUnctional Summary-based ImputatiON (FUSION) with the skeletal muscle and blood as gene expression references. The significant genes identified by TWAS were further subjected to gene set enrichment analysis (GSEA) with the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. Furthermore, we compared the genes and gene sets identified by our TWAS with that of a knee OA mRNA expression profile to detect the genes and gene sets shared by TWAS and mRNA expression profiles in OA. The mRNA expression profiles of 18 normal knee cartilages and 20 OA knee cartilages were acquired from the Gene Expression Omnibus database (accession number: GSE114007). Results TWAS identified 177 genes with P

Abstract Gear fault diagnosis technologies have received rapid development and been effectively implemented in many engineering applications. However, the various working conditions would degrade the diagnostic performance and make gear fault diagnosis (GFD) more and more challenging. In this paper, a novel model parameter transfer (NMPT) is proposed to boost the performance of GFD under varying working conditions. Based on the previous transfer strategy that controls empirical risk of source domain, this method further integrates the superiorities of multi-task learning with the idea of transfer learning (TL) to acquire transferable knowledge by minimizing the discrepancies of separating hyperplanes between one specific working condition (target domain) and another (source domain), and then transferring both commonality and specialty parameters over tasks to make use of source domain samples to assist target GFD task when sufficient labeled samples from target domain are unavailable. For NMPT implementation, insufficient target domain features and abundant source domain features with supervised information are fed into NMPT model to train a robust classifier for target GFD task. Related experiments prove that NMPT is expected to be a valuable technology to boost practical GFD performance under various working conditions. The proposed methods provides a transfer learning-based framework to handle the problem of insufficient training samples in target task caused by variable operation conditions.