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The ovary is the main controller of female fertility, unfortunately, its onset of aging processes was earlier than other organs. Our previous studies showed calcium (Ca) deficiency reduced ovarian weight and declined numbers of dominant follicles in an avian model. However, whether Ca provided a functional role in follicle development of aged avian, and its further mechanism was still unknown. In this study, fifty180-day-old and fifty 700-day-old female Longyan ducks were divided into the young group and the aged group to illustrate the differences of Ca signaling and further mechanisms. We found the poor productive performance of aged ducks was correlated with follicle decreased numbers and atrophied microstructure, and restricted antioxidant ability of granulosa cells (GCs). Then, according to RNA-Seq analysis, we detected those aged ducks displayed lower Ca concentration in the ovary, while Ca channel related gene expression was increased in GCs to maintain homeostasis. Moreover, the cyclic adenosine monophosphate (cAMP) concentration and cAMP synthase family related genes were also decreased in GCs of aged ducks. Fortunately, medium supplemented with Ca channel-activator A23187 enhanced GC viability, antioxidant ability, tight junction ability, and increased cAMP concentration by improved cAMP metabolism, otherwise, the opposite changes were observed with Ca2+-chelating agent EGTA or Ca channel-inhibitor Verapamil supplementation. In conclusion, aging disordered Ca signaling to limit cAMP metabolism, then decreased antioxidant ability and inhibited proliferation and migration ability of GCs. Thus, the follicle development and reproductive performance were restricted in aged avian.

Introduction Atrial fibrillation (AF) is the prevalent cardiac arrhythmia and can significantly impair the quality of life (QoL). Although catheter ablation (CA) is an established treatment for AF,post-procedural complications or perceived inadequate control of AF may diminish the QoL for some patients, potentially even to levels lower than pre-procedure. Preliminary findings from our previous pilot trial indicate that acupuncture may positively influence QoL in AF patients post-CA. This study aims to increase the sample size to evaluate the efficacy of acupuncture as an adjunctive treatment to conventional medical therapy in improving QoL of patients with AF after CA.Methods and design This multicentre randomised clinical trial will be conducted in China. A total of 146 eligible patients will be randomly assigned in a 1:1 ratio to either the acupuncture group or the sham acupuncture group. All patients will receive standard postablation care and undergo 18 sessions of acupuncture/sham acupuncture within 12 weeks following CA, followed by a 9-month follow-up period. The primary outcome is the change in the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) summary score from baseline to months 6 after CA. Secondary outcomes include the changes in the AFEQT subscale scores at months 6, the AFEQT summary and subscale score at months 3 and 12, AF burden, AF recurrence, heart rate variability, number of cardioversions, repeat CA procedures, European Heart Rhythm Association score, number of arrhythmia-related hospitalisations, average heart rate, use of Six-Dimensional Health State Short Form to assess health status, costs incurred by disease treatment, Credibility/Expectancy Questionnaire and blinded assessments. Adverse events will also be meticulously recorded throughout the trial.Ethics and dissemination Ethics approval has been granted by the Ethics Committee of Beijing University of Traditional Chinese Medicine (approval no: 2020BZYLL0802) and seven other subcentres. The findings of the study results will be disseminated through presentations at scientific conferences or publications in peer-reviewed journals.Trial registration number ChiCTR2100049323.

Background: The cartilage stem/progenitor cells (CSPC) play a critical role in maintaining cartilage homeostasis. However, the effects of phenotypic fluctuations of CSPC on cartilage degeneration and the role of CSPC in the pathogenesis of OA is largely unknown. Methods: The cartilage samples of 3 non-OA and 10 OA patients were collected. Human CSPC (hCSPC) derived from these patients were isolated, identified, and evaluated for cellular functions. Additionally, chondrocytes derived from OA patients were isolated. The effect of Yes-associated protein (YAP) expression on hCSPC was investigated in vitro. The OA rat model was established by Hulth's method. Lentivirus-mediated YAP (Lv-YAP) or lentivirus-mediated YAP RNAi (Lv-YAP-RNAi) was injected intra-articularly to modulate YAP expression in rat joints. In addition, allogeneic rat CSPC (rCSPC) overexpressing or silencing YAP were transplanted by intra-articularly injection. We also evaluated the functions of rCSPC and the OA-related cartilage phenotype in the rat model. Finally, the transcriptome of OA rCSPC overexpressing YAP was examined to explore the potential downstream targets of YAP in rCSPC. Results: hCSPC derived from OA patients exhibited differential chondrogenesis capacity. Among them, a subset of hCSPC showed pronounced dysfunction, including impaired chondrogenic differentiation, inhibition of proliferation and migration, and downregulation of lubricin. Additionally, YAP was lowly expressed in quiescent non-OA hCSPC, upregulated in activated OA hCSPC, but significantly downregulated in dysfunctional OA hCSPC. Notably, the overexpression of YAP in OA hCSPC improved the proliferation, lubricin production, cell migration, and senescence, while silencing YAP had the opposite effect. In vivo, upregulation of YAP in the joint delayed OA progression and improved the cartilage regeneration capacity of rCSPC. Using transcriptomic analysis, we found that YAP may regulate rCSPC function by upregulating Baculoviral IAP repeat-containing 2 (BIRC2). Importantly, the knockdown of BIRC2 partly blocked the regulation of YAP on the CSPC function. Conclusion: Dysfunction of CSPC compromises the intrinsic repair capacity of cartilage and impairs cartilage homeostasis in OA. Notably, the transcriptional co-activator YAP plays a critical role in maintaining CSPC function through potential target gene BIRC2. The Translational Potential of this Article: In this study, we observed targeting the YAP-BIRC2 axis improved the CSPC function and restored the cartilage homeostasis in OA. This study provides a potential stem cell-modifying OA therapy.

Abstract Background In relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. Methods A cohort of 27 ineligible patients with R/R DLBCL participated in an open — label, single — arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one‐week discontinuation period, in conjunction with intravenous R‐GDP every 21 days. Results Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C‐R‐GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%–83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%–49.9%) and a partial response rate of 33.3% (95% CI: 29.3%–37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow‐up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression‐free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. Conclusions Chidamide combined with R‐GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.

For the problem of high-speed erosion and wear caused by microfine particles on the surface coatings of rolling stock during operation, the effects of fine particle velocity, incidence angle and particle size on the erosion wear rate of the coatings were conducted using finite element numerical simulation and erosion wear test system. The anti-erosive damage mechanism of polyurethane coatings was analyzed, which was primarily characterized by micro cutting during low angle erosion and brittle fracture mechanism during high angle erosion. Results showed that the erosion wear rate of the coating increased exponentially with particle velocity, which experienced an 87% rise when the velocity changed from 70 m/s to 80 m/s; the coating exhibited characteristics of ductile material erosion wear to a certain extent, with the erosion wear rate reaching a peak value of 0.94 mm3/g at an incidence angle of 15°. Furthermore, the coating exhibited a brittle material crushing and shedding erosion wear mechanism under vertical incidence of different particle sizes. The simulation results obtained from the computational model showed a mere 7% error when compared with experimental validation, indicating that both the model establishment and computational methods possessed high effectiveness. This model could be utilized to simplify or replace experimental approaches, providing a basis for optimizing coating structures in windy and sandy environments.

Gastroscopy, a critical tool for the diagnosis of upper gastrointestinal diseases, has recently incorporated artificial intelligence (AI) technology to alleviate the challenges involved in endoscopic diagnosis of some lesions, thereby enhancing diagnostic accuracy. This narrative review covers the current status of research concerning various applications of AI technology to gastroscopy, then discusses future research directions. By providing this review, we hope to promote the integration of gastroscopy and AI technology, with long-term clinical applications that can assist patients.

Background: Transseptal puncture (TSP) performed with the Brockenbrough (BRK) needle is technically demanding and carries potential risks. The back end of the percutaneous transluminal coronary angioplasty (PTCA) guidewire is blunt and flexible, with good support, it can puncture the right ventricle-free wall, which is thicker than the atrial-septum. The guidewire is thin and easy to manipulate. This study evaluated the performance of TSP with a PTCA guidewire and microcatheter without a needle. Methods: The back end of a PTCA guidewire was advanced into the Tiger (TIG) catheter, within the SL1 sheath, to puncture the fossa ovalis (FO) under fluoroscopy. Subsequently, the microcatheter was inserted into the left atrium (LA) above the guidewire, and the front end of the guidewire was exchanged in the LA. After the puncture site was confirmed by contrast, the TIG catheter and a 0.032 inch wire were advanced into the LA. Finally, the sheath, with the dilator, was advanced over the wire into the LA. The safety margin of this method was tested in a pig model. Results: The puncture was successful in all seven pigs tested with a puncture-to-sheath entry time of

Abstract The authors investigated the effectiveness of home‐based transcutaneous electrical acupoint stimulation (TEAS) combined with lifestyle modification on blood pressure (BP) control and explored the feasibility of the trial design in this prospective, randomized controlled trial. The authors recruited individuals with high‐normal BP who had a systolic blood pressure (SBP) of 120–139 mm Hg and a diastolic blood pressure (DBP) of 80–89 mm Hg, or both. Participants were randomly assigned to receive either lifestyle modification combined with TEAS four times weekly for 12 weeks at home (intervention group) or solely lifestyle modification (control group). The primary outcome was the change in mean SBP at week 12 from the baseline measurement. A total of 60 participants were randomized in a 1:1 ratio, and an intention‐to‐treat analysis was performed on all of the outcomes. The mean difference in the change in SBP for the intervention group (compared to the control) at week 12 was −3.85 mm Hg (95% CI: −7.58 to −.12; p = .043); for the DBP, the change was −2.27 mm Hg (95% CI: −5.76 to 1.23; p = .199). There was no difference in the proportion of progression to hypertension, quality of life, body mass index (BMI) or waist circumference. In addition, two participants reported TEAS‐related adverse events. The authors found a reduction in SBP control in the pragmatic, home‐based intervention by using TEAS combined with lifestyle modification in adults with high‐normal BP. Trial Registration: The study was registered in the Chinese Clinical Trial Registry (ChiCTR 1900024982) on August 6, 2019.

Abstract Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD−/− cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

Abstract Metabolic syndrome (MS) is a clinical syndrome with multiple metabolic disorders. As the diagnostic criteria for MS still lacking of imaging laboratory method, this study aimed to explore the differences between healthy people and MS patients through infrared thermography (IRT). However, the observation region of the IRT image is uncertain, and the research tried to solve this problem with the help of knowledge mining technology. 43 MS participants were randomly included through a cross-sectional method, and 43 healthy participants were recruited through number matching. The IRT image of each participant was segmented into the region of interest (ROI) through the preprocessing method proposed in this research, and then the ROI features were granulated by the K-means algorithm to generate the formal background, and finally, the two formal background were separately built into a knowledge graph through the knowledge mining method based on the attribute partial order structure. The baseline data shows that there is no difference in age, gender, and height between the two groups (P > 0.05). The image preprocessing method can segment the IRT image into 18 ROI. Through the K-means method, each group of data can be separately established with a 43 × 36 formal background and generated a knowledge graph. It can be found through knowledge mining and independent-samples T test that the average temperature and maximum temperature difference between the chest and face of the two groups are statistically different (P

Senescence chondrocytes play an important role in Osteoarthritis (OA) progression. However, alleviating OA progression through senescent chondrocyte intervention still faces great challenges. β-Hydroxybutyrate (BHB) exhibits anti-senescence effects in a variety of age-related dis-eases, but its role in osteoarthritis remains poorly understood. To explore the molecular mechanisms, gene sequencing was used to identify critical genes and potential cellular signaling pathways and male SD rats were used to generate an osteoarthritis model. Results showed that BHB attenuated the senescence of Osteoarthritis chondrocytes (OA-Chos) and alleviated OA progression. Gene ontology (GO) enrichment analysis revealed significant changes in cell cycle genes, with PTEN being the most significant differentially expressed gene. BHB up-regulated the expression of PTEN in OA-Chos, thereby alleviating chondrocyte senescence. Furthermore, BHB facilitated the expression of PTEN by binding to hnRNP A1 and inhibiting the phosphorylation of Akt. This study provided evidence that BHB mitigated chondrocyte senescence and delayed OA, and could thus be used as a novel therapeutic approach for osteoarthritis treatment.

IntroductionThe most prevalent bone tumor with a relatively high level of aggressiveness and malignancy is osteosarcoma. The characteristics of the serpin family in osteosarcoma have not been defined.MethodsIn this study, the predictive significance of the serpin superfamily was investigated in the osteosarcoma and Gene Expression Omnibus (GEO) databases from The Cancer Genome Atlas (TCGA).ResultsIt was discovered that SERPINH1 is a significant biological marker in osteosarcoma. According to the CCK-8, EdU, and Transwell assays as well as the IHC assay, SERPINH1 may promote osteosarcoma proliferation and migration. It is also more expressed in tumor samples than in healthy samples. SERPINH1 might forecast the effects of immunotherapy. Additionally, immune cells are interacted with through checkpoint, cytokine, and growth factor pathways in osteosarcomas with high SERPINH1 levels. The biological function, immunological characteristics, and treatment response (immunotherapy and chemotherapy responses) of patients with osteosarcoma were successfully predicted using a model related to SERPINH1. SERPINH1 and the SERPINH1-related score predict ferroptosis/pyroptosis/apoptosis/necroptosis in osteosarcoma.DiscussionThe SERPINH1-related score was an effective method for identifying osteosarcoma patients who would respond to immunotherapy and chemotherapy, as well as for predicting the survival outcomes of such patients.

Coronary artery spasm (CAS) may induce lethal ventricular arrhythmia due to severe and prolonged vessel constriction. Tyrosine kinase inhibitors are associated with the occurrence of CAS. Optimal medical treatment is the first-line therapeutic option for the management of CAS, whereas patients who experienced aborted sudden cardiac death (SCD) may benefit from implantable cardioverter-defibrillator (ICD) implantation. We report a case of a 63-year-old Chinese man receiving tyrosine kinase inhibitor treatment for liver cancer who presented with recurrent chest discomfort and syncope with an elevation of high-sensitivity troponin T. Emergent coronary angiography showed sub-total occlusion of the left anterior descending artery without other signs of CAS. Percutaneous transluminal coronary angioplasty with a drug-coated balloon was performed successfully with the guidance of intravascular ultrasound. After 5 months, the patient returned to the emergency room for chest discomfort and another episode of syncope. The electrocardiogram showed ST-segment elevation in the inferior and V5–V6 leads compared to the previous event. Coronary angiography was repeated immediately and showed significant luminal stenosis at the midportion of the right coronary artery (RCA), whereas, after administration of intracoronary nitroglycerine, a remarkable recovery of RCA patency was noticed. A diagnosis of CAS was made, and soon after that, the patient rapidly developed ventricular arrhythmia in the coronary care unit. After successful resuscitation, the patient recovered completely and received long-acting calcium channel blockers as well as nitrates therapy. ICD implantation was performed considering the high risk of recurrence of life-threatening ventricular arrhythmia. During the follow-up period, the patient has been free of angina, syncope, or ventricular arrhythmia, and ICD interrogation showed no ventricular tachycardia or ventricular fibrillation. We first reported the case of a patient with CAS induced by regorafenib treatment complicated with severe atherosclerotic coronary disease who survived from sudden cardiac arrest. ICD implantation is indicated in patients who experienced aborted SCD for the prevention of the next lethal ventricular arrhythmia.

BackgroundSince its discovery, clear cell renal cell carcinoma (ccRCC) has been the most prevalent and lethal kidney malignancy. Our research aims to identify possible prognostic genes of ccRCC and to develop efficient prognostic models for ccRCC patients based on multi-omics investigations to shed light on the treatment and prognosis of ccRCC.MethodsTo determine a risk score for each patient, we screened out differentially expressed genes using data from tumor samples, and control samples mined from The Cancer Genome Atlas (TCGA) and GTEx datasets. Somatic mutation and copy number variation profiles were analyzed to look for specific genomic changes connected to risk scores. To investigate potential functional relationships of prognostic genes, gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were carried out. We created a prognostic model by fusing risk ratings with other clinical variables. For validation, the 786-O cell line was used to carry out the dual-gRNA approach to knock down CAPN12 and MSC. This was followed by qRT-PCR to verify the knockdown of CAPN12 and MSC.ResultsFor ccRCC, seven predictive genes were discovered: PVT1, MSC, ALDH6A1, TRIB3, QRFPR, CYS1, and CAPN12. The most enriched pathways in the GSVA study and GSEA analysis promote tumorigenesis and immune system modulation. The risk score derived from prognostic genes corresponds with immune infiltration cells and helps predict how well a medicine will work. The mutation of numerous oncogenes was also linked to a high-risk score. A prognostic model with a high ROC value was created for the risk score. An in vitro study demonstrates that the suppression of CAPN12 and MSC dramatically reduced the ability of 786-O cells to proliferate in the CCK-8 proliferation assay and plate clonality assays.ConclusionsA thorough prognostic model with good performance has been developed for ccRCC patients using seven prognostic genes that were discovered to be related to ccRCC prognosis. In ccRCC, CAPN12 and MSC were significant indicators and would make good therapeutic targets.

Grain sorghum has been a significant contributor to global food security since the prehistoric period and may contribute even more to the security of both food and energy in the future. Globally, precise management techniques are crucial for increasing grain sorghum productivity. In China, with diverse ecological types, variety introduction occasionally occurs across ecological zones. However, few information is available on the effect of ecological type on genotype performance and how plant spacing configuration influences grain yield in various ecological zones. Hence, a series of two-year field experiments were conducted in 2020 and 2021 in four ecological zones of China, from the northeast to the southwest. The experiments included six widely adapted sorghum varieties under six plant spacing configurations (two row spacing modes: equidistant row spacing (60 cm) mode and wide (80 cm)-narrow (40 cm) row spacing mode; three in-row plant spacings: 10 cm, 15 cm, and 20 cm). Our results indicated that ecological type, variety, and plant spacing configuration had a significant effect on sorghum yield. Ecological type contributed the highest proportion to the yield variance (49.8%), followed by variety (8.3%), while plant spacing configuration contributed 1.8%. Sorghum growth duration was highly influenced by the ecological type, accounting for 87.2% of its total variance, whereas plant height was mainly affected by genotype, which contributed 81.6% of the total variance. All test varieties, developed in the south or north, can reach maturity within 94-108 d, just before fall sowing in central China. Generally, sorghum growth duration becomes longer when a variety is introduced from south to north. A late-maturing variety, developed in the spring sowing and late-maturing regions, possibly could not reach maturity in the early-maturing region. The row spacing modes had no significant affect on sorghum yield, but the equal-row spacing mode consistently caused higher yields with only one exception; this might imply that equal-row spacing mode was more advantageous for boosting sorghum yield potential. In contrast, decreasing in-row plant spacing showed significant positive linear associations with sorghum grain yield in most cases. In addition, these results demonstrated that sorghum is a widely adapted crop and enables success in variety introduction across ecological zones.

PurposeAcupuncture has been widely used in the treatment of knee osteoarthritis (KOA), but the selection of acupoints is indeterminate and lacks biological basis. The skin temperature of acupoints can reflect the state of local tissue and may be a potential factor for guiding acupoint selection. This study aims to compare the skin temperature of acupoints between KOA patients and the healthy population.Study design and methodsThis is a protocol for a cross-sectional case-control study with 170 KOA patients and 170 age- and gender-matched healthy individuals. Diagnosed patients aged 45 to 70 will be recruited in the KOA group. Participants in the healthy group will be matched with the KOA group based on mean age and gender distribution. Skin temperature of 11 acupoints (ST35, EX-LE5, GB33, GB34, EX-LE2, ST34, ST36, GB39, BL40, SP9, SP10) will be extracted from infrared thermography (IRT) images of the lower limbs. Other measurements will include demographic data (gender, age, ethnicity, education, height, weight, BMI) and disease-related data (numerical rating scale, pain sites, duration of pain, pain descriptors, pain activities).DiscussionThe results of this study will provide biological evidence for acupoint selection. This study is a precondition for follow-up studies, in which the value of optimized acupoint selection will be verified.Trial registrationChiCTR2200058867.

Lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) is determined as a devastating organ dysfunction elicited by an inappropriate response to infection with high morbidity and mortality rates. Previous evidence has illustrated an indispensable role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the pathogenesis of sepsis-induced multiorgan abnormalities. Specifically, this study investigated the potential role of ALDH2 in sepsis-induced AKI. After LPS administration, we observed a significant decline in renal function, increased inflammatory cytokines, oxidative stress, 4-hydroxy-2-nonenal (4-HNE) accumulation, and apoptosis via MAPK activation in ALDH2−/− mice; in contrast, pretreatment with Alda-1 (an ALDH2 activator) alleviated the LPS-induced dysfunctions in mice. Moreover, in vitro analysis revealed that ALDH2 overexpression in mouse tubular epithelial cells (mTECs) improved the inflammatory response, oxidative stress, 4-HNE accumulation, and apoptosis via MAPK inhibition, whereas ALDH2 knockdown in mTECs aggravated these parameters via MAPK activation. Therefore, ALDH2 may protect against LPS-induced septic AKI by suppressing 4-HNE/MAPK pathway.

BackgroundMacrophage is a central regulator of innate immunity. Its M2 subsets, such as interstitial synovial macrophages, have been found to play critical roles in suppressing chronic inflammation and maintaining homeostasis within the joint. These macrophages have great potential as a disease-modifying cell therapy for osteoarthritis (OA). However, this has not yet been studied.MethodsMacrophages were isolated from the bone marrow of rats. We constructed a stable macrophage that “locked” in anti-inflammatory and pro-regenerative M2a polarity (L-M2a) by simultaneously knocking out tumor necrosis factor receptor 1 (TNFR1) and overexpressing IL-4 using Cas9-ribonuclear proteins (Cas9-RNP) and electroporation. In vitro, these L-M2a macrophages were treated with OA synovial fluid or co-cultured with OA chondrocytes or fibroblast-like synoviocytes (FLS). In vivo, L-M2a macrophages were injected intra-articularly to evaluate their homing and engrafting abilities and therapeutic effects on OA progression using a rat model.ResultsL-M2a macrophages displayed a typical anti-inflammatory phenotype similar to that of M2 macrophages in vitro. In OA microenvironment, L-M2a macrophages maintained a stable anti-inflammatory phenotype, whereas unmodified M2 macrophages lost their phenotype and switched to M1 polarity. L-M2a macrophages demonstrated a potent anti-inflammatory effect in crosstalk with OA-FLSs and an anti-degenerative effect in crosstalk with senescent OA chondrocytes. In vivo, compared with M2 macrophages and exosomes, L-M2a macrophages exhibited significantly superior therapeutic effects in OA by successfully resolving inflammation, restoring tissue homeostasis, and promoting cartilage regeneration.ConclusionThe engineered L-M2a macrophages maintained a superior anti-inflammatory and pro-regenerative capacity in the inflammatory OA microenvironment and represents an ideal new strategy for the disease-modifying therapy of OA.

Abstract Background Acupuncture is widely used for pain diseases while evidence of its efficacy for sciatica is insufficient. We aim to explore the feasibility and efficacy of acupuncture with different acupoint selecting strategies for sciatica induced by lumbar disc herniation. Methods This is a multicenter, three-arm, patient-assessor-blinded randomized controlled pilot trial. Ninety patients will be assigned randomly into 3 groups including disease-affected meridians (DAM) group, non-affected meridians (NAM) group, and sham acupuncture (SA) group in a 1:1:1 ratio. The trial involves a 4-week treatment along with follow-up for 22 weeks. The primary outcome is the change of leg pain intensity measured by the visual analogue scale (VAS) from baseline to week 4 after randomization. Secondary outcomes include functional status, back pain intensity, and quality of life. Adverse events will also be recorded. Discussion The results will inspire the optimal acupuncture strategy for sciatica and help establish a better design as well as power calculation for a full-scale study. Trial registration ChiCTR2000030680 (Chinese Clinical Trial Registry, http://www.chictr.org.cn , registered on 9 March 2020).

Background Chronic Sciatica is a disabling condition causing considerable medical, social and financial implications. Currently, there is no recognised long-term effective treatment to alleviate sciatica. Acupuncture has been widely used for treating chronic pains with persistent analgesic effects. We aim to evaluate the efficacy and safety of acupuncture for chronic sciatica with follow-up in 52 weeks.Methods and analysis This is a multicenter randomised sham-controlled trial. A total of 216 patients with chronic sciatica will be enrolled and randomly assigned to the acupuncture or sham acupuncture group. There will be 10 treatment sessions applied in 4 weeks with frequency decreased over time. Patients will complete follow-ups during 52 weeks. The primary outcomes are changes in leg pain intensity and disability from baseline to week 4. Secondary outcomes include back pain intensity, frequency and bothersomeness, quality of life, and global perceived effect. Adverse events will be recorded in detail.Ethics and dissemination Ethical approval of this trial was granted from the ethics committee of Beijing University of Chinese Medicine and all study centres (No. 2020BZYLL0803). Written informed consent will be obtained from enrolled patients. Trial results will be disseminated in peer-reviewed publications.Trial registration number ChiCTR2100044585 (Chinese Clinical Trial Registry, http://www.chictr.org.cn, registered on 24 March 2021); preresults.

Additive manufacturing (AM) especially laser additive manufacturing (LAM), a novel manufacturing technique of layer-by-layer forming according to geometric model, provides a decent option for materials processing. It owns advantages of rapid prototyping, customization, high material utilization, and the ability to form complicated structures. This paper reviews popular LAM techniques of selective laser sintering/melting, laser metal deposition and laser direct writing. The development status of metallic materials including pure metal, steel, superalloy, titanium and aluminum alloy is presented. The challenges and application limitations of LAM are involved and the development trend in the future is forecasted. In summary, this paper gives an overview of metal LAM expecting to made helpful suggestions on future research and development.

Abstract Background Constipation is known as a common adverse effect of antipsychotics. Advice for its management remains inadequate. This study is designed to investigate the efficacy and safety of electro-acupuncture (EA) for antipsychotic-related constipation. Methods This is a single-centric, parallel-group, randomized controlled trial with blinded participants, outcome assessor, and statistician. One hundred twelve participants will be randomly assigned into the EA group or sham acupuncture (SA) group in a 1:1 ratio. The study will last for 22 weeks for each participant, including a 2-week baseline assessment period, an 8-week treatment period, and a follow-up for 12 weeks. The primary outcome is the change of mean weekly complete spontaneous bowel movements (CSBMs) during weeks 1 to 8 from baseline. Secondary outcomes include the change from baseline of mean weekly CSBMs during the follow-up period, mean weekly spontaneous bowel movements (SBMs), overall CSBM response rate, scores on Bristol Stool Form Scale (BSFS), straining level, Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Constipation Quality of life questionnaire (PAC-QOL), and Brief Psychiatric Rating Scale (BPRS). Adverse events and medicine use will be recorded as well. Discussion The study is designed based on a rigorous methodology to evaluate the efficacy and safety of EA for antipsychotic-related constipation. The finding will be published in peer-reviewed journals as reliable evidence. Trial registration ClinicalTrials.gov ChiCTR2000032582. Registered May 3, 2020, with the Chinese Clinical Trial Registry.

Abstract Background Acute renal colic caused by urinary calculi (ARCUC) has a considerable impact on the quality of life. Acupuncture might be a potential treatment option. However, the evidence is limited. We will conduct this trial to evaluate the efficacy and safety of acupuncture as adjunctive treatment to diclofenac for ARCUC. Methods/design A total of 80 eligible patients who are diagnosed with urinary stone renal colic will be randomly allocated to the acupuncture group or the sham acupuncture group. Each patient will receive 1 session of acupuncture or sham acupuncture. The primary outcome will be the response rate of patients achieving a reduction of > 50% on visual analog score (VAS) from baseline to 10 min after treatment. Secondary outcomes will include the VAS, remedial analgesia, re-visit and admission rate, blinding assessment, credibility and expectancy, and adverse event. All patients who receive randomization will be included in the intent-to-treat analysis. Discussion The finding of this trial will provide evidence on the efficacy and safety of acupuncture for the treatment of ARCUC. The results of this study will be published in peer-reviewed journals. Trial registration ClinicalTrials.gov ChiCTR 1900025202 . Registered on August 16, 2019.

BackgroundThe role of ferroptosis in tumor progression and immune microenvironment is extensively investigated. However, the potential value of ferroptosis regulators in predicting prognosis and therapeutic strategies for osteosarcoma (OS) patients remains to be elucidated.MethodsHere, we extracted transcriptomic and survival data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) to investigate the expression and prognostic value of ferroptosis regulators in OS patients. After comprehensive analyses, including Gene set variation analysis (GSVA), single-sample gene-set enrichment analysis (ssGSEA), Estimated Stromal and Immune cells in Malignant Tumor tissues using Expression (ESTIMATE), single-cell RNA sequencing, and biological experiments, our constructed 8-ferroptosis-regulators prognostic signature effectively predicted the immune landscape, prognosis, and chemoradiotherapy strategies for OS patients.ResultsWe constructed an 8-ferroptosis-regulators signature that could predict the survival outcome of OS. The signature algorithm scored samples, and high-scoring patients were more prone to worse prognoses. The tumor immune landscape suggested the positive relevance between risk score and immunosuppression. Interfering HILPDA and MUC1 expression would inhibit tumor cell proliferation and migration, and MUC1 might improve the ferroptosis resistance of OS cells. Moreover, we predicted chemoradiotherapy strategies of cancer patients following ferroptosis-risk-score groups.ConclusionDysregulated ferroptosis gene expression can affect OS progression by affecting the tumor immune landscape and ferroptosis resistance. Our risk model can predict OS survival outcomes, and we propose that HILPDA and MUC1 are potential targets for cancer therapy.

Abstract Background Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal diseases. Although acupuncture has become a common alternative therapy for IBS, there is insufficient evidence for its effectiveness. This study was designed to assess the efficacy and feasibility of acupuncture in the treatment of IBS. Methods/design This is a multicenter randomized controlled clinical trial. According to the ratio of 1:1:1, 90 patients with irritable bowel syndrome will be randomly divided into specific acupoints (SA) group, non-specific acupoints (NSA) group, and non-acupoints (NA) group. All patients will be treated with acupuncture 12 times within 4 weeks and followed up for 8 weeks. The primary outcome is the response rate, the percentage of patients whose average value of worst abdominal pain is 30% better and the days of loose stool is 50% less than the baseline, at week 4 after randomization. The secondary outcomes include the response rates at other time points, IBS Symptom Severity Scale (IBS-SSS), Patient Health Questionnaire-9 depression scale (PHQ-9), IBS-Quality of Life scale (IBS-QOL), IBS Adequate Relief (IBS-AR), Abdominal Pain Score, Abdominal Bloating Score, Bristol Stool Score (BBS), blinding assessment, and credibility evaluation. Adverse events will be monitored and recorded during the trial. Trial registration Chictr.org.cn ChiCTR2000030670. Registered on 9 March 2020.

Introduction Hypertension is a common risk factor for cardiovascular disease. Transcutaneous electrical acupoint stimulation (TEAS) may be effective for hypertension, but the evidence remains limited. The aim of this study is to evaluate the effectiveness and safety of the smart phone-based TEAS as adjunctive therapy for hypertension.Methods and analysis This study is a 52-week cluster randomised controlled trial with 1600 hypertension patients in 32 community health service centres. Patients who meet the inclusion criteria will be randomised into usual care group or TEAS group in a 1:1 ratio. All patients will be provided with usual care as recommended by the guidelines. In addition to this, patients in the TEAS group will receive non-invasive acupoint electrical stimulation for 30 min at home, 4 times weekly for 12 weeks. The primary outcome will be the mean difference in the changes in office systolic blood pressure from baseline to 12 weeks between TEAS and usual care groups. Secondary outcomes will include the change of mean diastolic blood pressure, proportion of patients with controlled blood pressure (blood pressure

It has been documented that human activities are causing the rapid loss of taxonomic, phylogenetic, genetic and functional diversity in soils. However, it remains unclear how modern intensive rice cultivation impacts the soil microbiome and its functionality. Here we examined the microbial composition and function differences between a buried Neolithic paddy soil and an adjacent, currently-cultivated paddy soil using high throughput metagenomics technologies. Our results showed that the currently cultivated soil contained about 10-fold more microbial biomass than the buried one. Analyses based on both 16S rRNA genes and functional gene array showed that the currently cultivated soil had significantly higher phylogenetic diversity, but less functional diversity than the buried Neolithic one. The community structures were significantly different between modern and ancient soils, with functional structure shifting towards accelerated organic carbon (C) degradation and nitrogen (N) transformation in the modern soils. This study implies that, modern intensive rice cultivation has substantially altered soil microbial functional structure, leading to functional homogenization and the promotion of soil ecological functions related to the acceleration of nutrient cycling which is necessary for high crop yields.

Abstract Background High-normal blood pressure (BP) is associated with increased all-cause, cardiovascular mortality and frequently progresses to hypertension. Transcutaneous electrical acupoint stimulation (TEAS) might be a non-pharmaceutical therapy option to control BP. This trial aims to determine the effectiveness and safety of TEAS combined with lifestyle modification for high-normal BP. Methods/design This prospective, randomized, and parallel clinical trial will be conducted in a community service center in China. Sixty participants with high-normal BP will be randomly allocated to receive TEAS plus lifestyle modification (intervention group) or lifestyle modification alone (control group) in a 1:1 ratio. In addition to lifestyle modification, the intervention group will receive TEAS at four acupoints for 30 min, 4 times weekly for 12 weeks for a total of 48 sessions at home. The control group will receive same lifestyle modification but no TEAS. The primary outcome will be the change in mean systolic blood pressure at 12 weeks from the baseline measurement. Secondary outcomes include the change of mean diastolic blood pressure, proportion of subjects with progression to hypertension, quality of life, body mass index, and waist circumference. Adverse events during the trial will be monitored. Discussion This trial will explore the feasibility and provide potential evidence for the effectiveness and safety of TEAS plus lifestyle modification for high-normal BP. Furthermore, this pilot trial is being undertaken to determine the feasibility of a full scale definitive randomized controlled trial. The results of this study will be published in a peer-reviewed journal. Trial registration Chinese Clinical Trial Registry, ChiCTR 1900024982 . Registered on August 6, 2019.

Abstract Background Atrial fibrillation (AF) is a common arrhythmia, which is closely related to cardiovascular morbidity and mortality. Although acupuncture is used in the treatment of AF, the evidence is insufficient. The objective of this pilot trial is to evaluate the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after catheter ablation (CA). Methods and design This will be a multi-center, 3-arm, pilot randomized controlled trial in China. Sixty patients in total will be randomly assigned to the specific acupoints group, the non-specific acupoints group, or the non-acupoints group in a 1:1:1 ratio. The whole study period is 6 months, including a 3-month treatment period and a 3-month follow-up period. All patients will receive 18 sessions of acupuncture over 12 weeks after CA and appropriate post-ablation routine treatment. The primary outcome is AF burden at 6 months after CA measured by electrocardiography patch that can carry out a 7-day continuous ambulatory electrocardiographic monitoring. The secondary outcomes include AF burden at 3 months after CA, recurrence of AF, quality of life, etc. The adverse events will also be recorded. Discussion This pilot study will contribute to evaluating the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after CA. The results will be used for the sample size calculation of a subsequent large-scale trial. Trial registration Chinese Clinical Trial Registry ChiCTR2000030576 . Registered on 7 March 2020.

Abstract Background Hypertension is a major pathogenic factor of cardiovascular diseases. Insufficient blood pressure control rate and sub-optimal medication adherence remain challenges for effective management of hypertension. Transcutaneous electrical acupoint stimulation (TEAS) has been used to treat various diseases, including hypertension, but the scientific evidence for its benefit remains insufficient. Therefore, we will perform a randomized, controlled clinical trial in patients with stage 1 hypertension to evaluate the effect of TEAS. Methods/design The study will be a two-arm parallel, randomized controlled trial. Sixty patients with stage 1 hypertension will be randomly assigned to the TEAS group and the control group in a 1:1 ratio. The participants in the TEAS group will receive non-invasive acupoint electrical stimulation for 30 min at four acupoints in the upper and lower extremities at home, 4 times weekly for 12 weeks for a total of 48 sessions. Participants in the control group will not receive any form of acupoint stimulation. All participants in both groups will receive lifestyle education on how to control high blood pressure, including diet, weight control, and exercise. The primary outcome measure will be the change of the mean systolic blood pressure from baseline to 12 weeks. Secondary outcomes include the change of mean diastolic blood pressure, quality of life, body mass index, and physical activity level. Discussion This pilot, randomized, controlled trial will explore the feasibility of TEAS. It will also provide potential clinical evidence for the efficacy and safety of TEAS in the treatment of patients with stage 1 hypertension. The results of this study will be published in peer-reviewed journals. Furthermore, this pilot trial as the precursor of a large scale randomized controlled trial will inform the sample size of the subsequent trial. Trial registration Chinese clinical trial registry, ChiCTR1900025042, Registered on 8 August 2019 ( http://www.chictr.org.cn/showproj.aspx?proj=41496 ).