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Background: Muscle atrophy or sarcopenia is the loss of muscle mass and strength and leads to an increased risk of disability and death including osteoporotic fractures. Currently, there are no available clinical biologic agents for the treatment of sarcopenia. Since exosomes have become increasingly attractive as a novel therapeutic approach due to their ability to facilitate cell-cell transfer of proteins and RNAs, promoting cell repair and function recovery, we hypothesized that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) might benefit muscle atrophy in age-related and dexamethasone-induced sarcopenia animal models. Methods: HucMSC-Exos were harvested by ultrafast centrifugation and identified by transmission electron microscopy, particle size analysis, and Western blot analysis. The effects of hucMSC-Exos on muscle atrophy were evaluated using age-related and dexamethasone-induced muscle atrophy mice models. Body weight, grip strength, muscle weight, and muscle histology of these mice were assessed. The expression levels of muscle RING finger 1 (MuRF1) and muscle atrophy F-box (atrogin-1) were measured by Western blot. Dexamethasone-induced C2C12 myotube atrophy was used to establish the cell model of muscle atrophy. Myotube diameter was evaluated by immunofluorescence staining. Bioinformatic analysis, RNA sequencing analysis, and Western blot analysis were performed to explore the underlying mechanisms. Results: In vivo experiments, hucMSC-Exos demonstrated a remarkable capacity to improve grip strength, increase muscle mass, and muscle fiber cross-sectional area, while concurrently reducing the expression of MuRF1 and atrogin-1 in age-related and dexamethasone-induced muscle atrophy mice. In vitro experiments, hucMSC-Exos can promote the proliferation of C2C12 cells, and rescue the dexamethasone-induced decline in the viability of C2C12 myotubes. In addition, hucMSC-Exos can increase the diameter of C2C12 myotubes, and reduce dexamethasone-induced upregulation of MuRF1 and atrogin-1. Combined with bioinformatics analysis and RNA sequencing analysis, we further showed that miR-132-3p was one of the essential miRNAs in hucMSC-Exos and played an important role by targeting FoxO3. Conclusion: Our findings suggested that hucMSC-Exos can improve age-related and dexamethasone-induced muscle atrophy in mice models. This study first demonstrated that hucMSC-Exos may ameliorate muscle atrophy via the miR-132-3p/FoxO3 axis. These data may provide novel and valuable insights into the clinical transformation of hucMSC-Exos for the treatment of sarcopenia. The translational potential of this article: HucMSC-Exos are easily available for clinical application, this study further consolidates the evidence for the clinical transformation potential of hucMSC-Exos for sarcopenia and provides its new target pathway.

In the present work, a wall-structured nickel-aluminum bronze (NAB) alloy was fabricated via electron beam directed energy deposition (EB-DED) additive manufacturing with a single-pass multi-layer deposition strategy. A comprehensive comparative analysis of microstructure, mechanical properties, and corrosion resistance was conducted against a conventionally cast NAB alloy. The inherent rapid solidification and cyclic thermal processing of the EB-DED technique profoundly influenced the microstructural evolution of the NAB alloy. The as-deposited NAB alloy exhibited a fine-grained microstructure, devoid of the martensitic β′ phase, accompanied by the spheroidization of partial κIII precipitates, and a homogeneous distribution of alloying elements. These distinctive microstructural attributes synergistically enhanced the strength, hardness, and toughness of the NAB alloy, conferring superior mechanical properties compared to its cast counterpart. Furthermore, the as-deposited alloy demonstrated remarkable corrosion resistance in a 3.5 wt% NaCl solution, significantly outperforming the cast alloy. The underlying mechanisms governing the structure-property relationships were elucidated. This comprehensive investigation provided insights into the unique characteristics and potential applications of EB-DED fabricated NAB alloys, positioning them as promising candidates for high-performance components subjected to severe mechanical and corrosive service conditions.

As a typical region of intracontinental orogeny, the Tianshan Orogenic Belt has consistently attracted significant scientific interest from geologists, both in China and internationally. The distribution of velocity anomalies beneath the Tianshan Orogenic Belt is of profound importance as it sheds light on the response of orogenic areas to activation mechanisms. In this study, crust-mantle velocity anomalies were investigated in different sections of the Tianshan Orogenic Belt, as well as the formation mechanisms of these anomalies and the dynamic evolution process of uplift and deformation. Different seismic methodologies were applied, including tomographic imaging, receiver function analysis, and GPS observations. The results of this systematic analysis indicate that regional velocity anomalous structures are closely correlated with the geological tectonic features and dynamic evolutionary processes in the Tianshan Orogenic Belt and its surrounding areas. Specifically, the characteristics of the high-velocity anomalous structures beneath the Tianshan Orogenic Belt, including the tilt direction, morphology, and location of these structures, are evidence of a unique intracontinental subduction mechanism. Furthermore, the presence of low-velocity anomalous structures in different regions of the belt indicates the existence of small mantle plumes or small-scale mantle convection caused by upwelling thermal material from the asthenosphere as well as partial melting within the crust due to magma underplating. These findings have significant implications for further understanding of the dynamic processes in the Tianshan region, including intracontinental subduction, crustal shortening deformation, lithospheric delamination, and the upwelling of asthenospheric materials. The results also serve as valuable reference data for further study of the seismic activity distribution in the Tianshan area.

Mandarin fish is an important freshwater economic fish in China, and the genome of mandarin fish population may have specific selection signatures after long-term selection, and studying these selection signatures is one of the important strategies for screening functional genes. In this study, the whole genome was resequenced from five mandarin fish populations (HLJ, HN, AH, FJ, and BJ), and a total of high-quality SNPs with 1659,318 single nucleotide polymorphisms were obtained, and the genetic differentiation index and nucleotide polymorphism ratio between populations were used to detect the selected genomic regions. The results showed that all individuals were divided into two branches, with the HLJ population forming an independent cluster, and the HN, AH, FJ, and BJ populations clustering together. Selection signal analysis on the HLJ mandarin fish population and other mandarin fish populations using the FST and π HLJ/other methods. Finally, we identified 26 important candidate genes based on the enrichment pathways related to fat traits such as Glycerolipid metabolism, acyl-CoA oxidase activity, Wnt signaling pathway, and Notch signaling pathway, including notch3, pla2g12a and acox1. This study explores the genetic diversity and genetic structure of mandarin fish from a whole-genome perspective, identifies candidate genes related to fat traits, and provides references for the protection and utilization of mandarin fish genetic resources.

PurposeGynecologic oncology laparotomy leads to severe postoperative pain. We aimed to evaluate the effects of preemptive multimodal analgesic regimen on postoperative opioid consumption for patients undergoing gynecologic oncology laparotomy.MethodsIn this prospective, randomized clinical trial, 80 female patients scheduled for gynecologic oncology laparotomy were randomized to receive preemptive multimodal analgesia consisted of transversus abdominis plane (TAP) block, cyclooxygenase−2 inhibitors, acetaminophen and intravenous morphine patient-controlled analgesia (PCA) (Study group) or conventional analgesia with cyclooxygenase−2 inhibitors and morphine PCA (Control group). The primary outcome was morphine consumption in the first 24 h after surgery. Secondary outcomes were pain scores, nausea, vomiting, time to ambulation and flatus, length of hospital stay, satisfaction score, the 40-item Quality of Recovery score (QoR-40) and the Short-Form Health Survey (SF-36) scale.ResultsMorphine consumption in the first 24 h was 6 (3–9.8) mg in the Study group and 7 (3.5–12.5) mg in the Control group (p = 0.222). The Study group showed lower morphine consumption up to 6 h, lower pain scores up to 48 h, and earlier time to ambulation and flatus. The global QoR-40 score at 48 h [182 (173–195) vs. 173.5 (154–185.5), p = 0.024], subdimension scores of physical dependence at 24 h, physical comfort and pain at 48 h were significantly improved in the Study group.ConclusionPreemptive multimodal analgesia was not superior to conventional analgesia in reducing 24 h morphine consumption; however, it showed a significantly improved pain control and early quality of recovery thus can be recommended for gynecologic oncology patients undergoing laparotomy.

Abstract The biological mechanisms underlying meat quality remain unclear. Currently, many studies report that the gastrointestinal microbiota is essential for animal growth and performance. However, it is uncertain which bacterial species are specifically associated with the meat quality traits. In this study, 16S rDNA and metagenomic sequencing were performed to explore the composition and function of microbes in various gastrointestinal segments of Tan sheep and Dorper sheep, as well as the relationship between microbiota and meat quality (specifically, the fatty acid content of the muscle). In the ruminal, duodenal, and colonic microbiome, several bacteria were uniquely identified in respective breeds, including Agrobacterium tumefaciens, Bacteroidales bacterium CF, and several members of the family Oscillospiraceae. The annotation of GO, KEGG, and CAZYme revealed that these different bacterial species were linked to the metabolism of glucose, lipids, and amino acids. Additionally, our findings suggested that 16 microbial species may be essential to the content of fatty acids in the muscle, especially C12:0 (lauric acid). 4 bacterial species, including Achromobacter xylosoxidans, Mageeibacillus indolicus, and Mycobacterium dioxanotrophicus, were positively correlated with C12:0, while 13 bacteria, including Methanobrevibacter millerae, Bacteroidales bacterium CF, and Bacteroides coprosuis were negatively correlated with C12:0. In a word, this study provides a basic data for better understanding the interaction between ruminant gastrointestinal microorganisms and the meat quality traits of hosts.

Titanium/steel multi-material, given full play to their superiorities, has tremendous value for parts exposed to complexity service environments, yet invariably, its common joining techniques are lack of design freedom. To this end, we employ electron beam freeform fabrication (EBF3) to successfully prepare this multi-material system for the first time, whose interfacial microstructure and property are systematically investigated. Applying Cu as an interlayer, instead of causing extensive cracking and delamination at the interface of Ti64/316L, can effectively suppress the formation of continuous Fe–Ti intermetallic compounds (IMCs), and thus improve the strength of Ti64/Cu/316L interfaces. For the Cu/316L interface, besides the characteristic spherical Cu-rich and Fe-rich solid solutions, a few Fe–Ti IMCs appear within the Fe-rich solid solutions owing to the long-range diffusion of minor Ti atoms. Correspondingly, the dendritic Cu-rich solid solutions can also be found at the Ti64/Cu interface, which is regarded as a critical interface due to the concomitant of complex Cu–Ti IMCs. These Cu–Ti IMCs have less negative effect on the Ti64/Cu interface property relative to Fe–Ti IMCs, and the local strain produced by the deformed α-Ti near the interface and Cu-rich solid solutions can effectively relieve the concentration of residual stress. Consequently, the Ti64/Cu interface exhibits maximum micro-hardness to 490 HV and superior shear strength to 196.5 ± 2.2 MPa, which was attributed to the reinforcement for the tip of keyhole molten pool, as well as the synergy between Cu-rich solid solution and interdendritic Cu–Ti IMCs.

Dual-wire-fed electron beam directed energy deposition (EB-DED) is a highly efficient technique for additive manufacturing (AM) of TiAl alloys, but research into the evolution of microstructure and mechanical properties within the melt pool is limited. Experimental and numerical simulations are used together to study the evolution along the vertical direction within the TiAl alloy melt pool. The chemical composition, microstructure and microhardness in the top region (TR), middle region (MR) and bottom region (BR) within the melt pool were characterized and comparatively analysed. The results showed that the Al content decreased from 52 at. % to 49 at. % from the top to the bottom, the grain size increased and then decreased, and the grain aspect ratio increased from 1 to over 3. The decreasing size factor and increasing shape factor result in variations in grain size and shape. The improvement in microhardness from 226 HV0.5 to 280 HV0.5 was quantitatively analysed as being mainly due to the reduction in Al content. The results of this study are of paramount importance in facilitating the use of the dual-wire-fed EB-DED technique for the production of high performance TiAl alloy components.

Abstract. Background:. Reports on the prevalence of psoriatic arthritis (PsA) among Chinese patients with psoriasis are very limited. This study, conducted by rheumatologists, estimated the prevalence of PsA in a large number of Chinese patients with psoriasis. Methods:. Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited. All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA. All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists. Results:. A total of 2434 psoriasis patients, including 1561 males and 873 females, were enrolled. Both the questionnaire and rheumatologists' examinations were completed in the dermatology clinics. The results identified 252 patients with PsA, comprising 168 males and 84 females. The overall prevalence of PsA among psoriasis patients was 10.4% (95% confidence interval [95% CI], 9.1%–11.7%). By sex, the prevalence was 10.8% (95% CI, 9.2%–12.5%) for males and 9.6% (95% CI, 7.7%–11.9%) for females and there was no significant sex difference in the prevalence of PsA (P = 0.38). Of the 252 PsA patients, 125 (49.6%, 95% CI, 41.3%–59.1%) were newly diagnosed by rheumatologists. Consequently, the prevalence of undiagnosed PsA among psoriasis patients was 5.2% (95% CI, 4.4%–6.2%). Conclusion:. The prevalence of PsA in the Chinese population with psoriasis is about 10.4%, which is almost double that of previous reports in the Chinese population, but lower than that in Caucasians.

The imbalance of the lateral shoulder is reflected by the clavicle angle (CA) in radiology. It remains unclear how to achieve postoperative lateral shoulder balance (LSB) after spinal deformity correction surgery. A retrospective analysis was conducted on AIS patients who underwent surgery by the same spine surgeon at our hospital from 2016 to 2020. A total of 110 patients with spinal deformity were included in the study to verify the correlation between the T1–T5 tilt angle and CA before and after surgery, as well as the relation-ship between the change in T1–T5 tilt angle before and after surgery and the change in CA before and after surgery. By comparing the correlation coefficients, it was found that there may not be a direct relationship between the pre- and postoperative tilt angles of T1–5 and CA, but their changes were closely related to the changes in CA. The change in T1 tilt angle after orthopaedic surgery was significantly correlated with the change in CA, with a correlation coefficient of 0.976, indicating a close relationship between T1 and the clavicle. As the vertebrae moved down, the correlation gradually decreased. In summary, this study suggests that there is a close relationship between T1–T5 and the clavicle and that the change in T1 tilt angle after spinal scoliosis correction surgery is significantly correlated with CA, which decreases as the vertebra moves down.

In order to reduce the environmental impact of poly(ethylene terephthalate) (PET) plastic waste, supercritical fluids were used to facilitate effective recovery via improved solvent effects. This work focuses on the mechanisms of supercritical CO2 (ScCO2) during the alcoholysis processing of PET using systematic experiments and molecular dynamics (MD) simulations. The results of the alcoholysis experiment indicated that PET chips can be completely depolymerized within only an hour at 473 K assisted with ScCO2 at an optimal molar ratio of CO2/ethanol of 0.2. Random scission of PET dominates the early stage of the depolymerization reaction process, while specific scission dominates the following stage. Correspondingly, molecular dynamics (MD) simulations revealed that the solubilization and self-diffusion properties of ScCO2 facilitate the transportation of alcohol molecules into the bulk phase of PET, which leads to an accelerated diffusion of both oligomers and small molecules in the system. However, the presence of excessive CO2 has a negative impact on depolymerization by weakening the hydrogen bonding between polyester chain segments and ethanol, as well as decreasing the swelling degree of PET. These data provide a deep understanding of PET degradation by alcohols and the enhancement of ScCO2. It should be expected to achieve an efficient and high-yield depolymerization process of wasted polyesters assisted with ScCO2 at a relatively low temperature.

Using large-scope and high-accuracy global navigation satellite system (GNSS) ionospheric monitoring, this study considered the polar ionosphere anomaly morphology caused by an interplanetary shock event that occurred on September 12, 2014. First, we used the continuous observation data of GNSS stations in the Antarctic region to estimate the carrier TEC epochs variation (dTEC) that reflects ionospheric electron density changes, and the abnormal signals were extracted. Through sequence data analyses of longitudinal chain stations, we found that the influence range of this anomaly lies in the geomagnetic region between 65$^\circ$ and 80 $^\circ$S. Furthermore, latitude chain analyses revealed that with the continuous fluctuation of the solar wind flow pressure, the polar ionospheric geomagnetic 75 $^\circ$S annular observation sequence gives a corresponding continuous fluctuation response with a range of 0.05–0.4 TECU and a westward anomaly trigger position. The average speed was close to the satellite speed during the study period, and it was determined that the anomaly occurred within an altitude region of 150–300 km. The physical mechanism of this anomaly is discussed in this article. Our results show that the GNSS dTEC and multisource data can accurately reflect the regional intensity, influence region, trigger source location, and velocity of the ionosphere anomaly.

Monitoring the status of blood-brain barrier (BBB) and inhibiting reactive oxygen species (ROS)-mediated oxidative damage are key issues in the treatment of traumatic brain injury (TBI). Here, the authors design a near-infrared-IIb emitting Mn single-atom catalyst for imaging-guided therapy to alleviate ROS mediated neuroinflammation in the brain and simultaneously obtain timely feedback of therapeutic effect, promoting the reconstruction of BBB and recovery of neurological function after TBI in mice.

Background & aims: Sarcopenia is an age-related disease that increases the risk of falls and fractures in older adults. However, there is no blood biochemical marker to help to predict or diagnose sarcopenia in clinical practice. Soluble interleukin 2 receptor (sIL-2R) was reported to be associated with muscle satellite cell dysfunction which played an important role in the pathogenesis of sarcopenia. Thereby, we aimed to explore the association between serum sIL-2R and sarcopenia in older adults at high risk of fractures. Methods: A total of 429 hospitalized older adults (age ≥55 years) were enrolled in this cross-sectional study (mean age ​= ​66.62 ​± ​6.59 years; 62.7% female). Logistic regression analysis was performed to assess the association of sIL-2R with sarcopenia, muscle mass, muscle strength, and physical performance, respectively. The optimal models for the diagnosis of sarcopenia and low hand grip strength (HGS) were established by multivariable binary logistic regression analysis with backward selection, and further were evaluated for the diagnostic values by receiver operating characteristic (ROC) curve. Results: Higher sIL-2R levels were found in sarcopenia than no-sarcopenia group in male (median 421 U/mL (interquartile range [IQR] 217 U/mL) vs median 362 U/mL (IQR 157 U/mL); n ​= ​77 vs 83; p ​

Abstract Background Calcium (Ca2+) ionophores are now mainly considered as efficient treatments for fertilization failure. Recently, its application for rescuing poor embryo development was proposed but still non-routine. This study aimed to explore whether Ca2+ ionophore improves embryo development and pregnancy outcomes in patients with poor embryo development in previous intracytoplasmic sperm injection (ICSI) cycles. Methods This study included 97 patients undergoing assisted oocyte activation (AOA) with Ca2+ ionophore (calcimycin, A23187) treatment. Preimplantation embryonic development and clinical outcomes were compared between ICSI-AOA cycles (AOA group) and previous ICSI cycles of the same patients in which poor embryo developmental potential was present (non-AOA group). Subgroups stratified by maternal age (

ABSTRACT A balanced vaginal microbiome dominated by Lactobacillus can help promote women’s reproductive health, with Lactobacillus crispatus showing the most beneficial effect. However, the potential role of vaginal microbiomes in hypertensive disorders of pregnancy (HDP) development is not thoroughly explored. In this nested case-control study based on an assisted reproductive technology follow-up cohort, we prospectively assessed the association between pregestational vaginal microbiomes with HDP by collecting vaginal swabs from 75 HDP cases (HDP group) and 150 controls (NP group) and using 16S amplicon sequencing for bacterial identification. The vaginal microbial composition of the HDP group significantly differed from that of the NP group. The abundance of L. crispatus was significantly lower, and the abundances of Gardnerella vaginalis was significantly higher, in the HDP group than in the NP group. Of note, L. crispatus-dominated vaginal community state type was associated with a decreased risk for HDP (odds ratio = 0.436; 95% confidence interval, 0.229 to 0.831) compared with others. Additionally, network analysis revealed different bacterial interactions with 61 and 57 exclusive edges in the NP and HDP groups, respectively. Compared with the HDP group, the NP group showed a higher weighted degree and closeness centrality. Several taxa, including G. vaginalis, L. iners, and bacterial vaginosis-associated bacteria (Prevotella, Megasphaera, Finegoldia, and Porphyromonas), were identified as “drivers” for network rewiring. Notable alterations of predicted pathways involved in amino acid, cofactor, and vitamin metabolism; membrane transport; and bacterial toxins were observed in the HDP group. IMPORTANCE The etiology of HDP remains unclear to date. Effective methods for the individualized prediction and prevention are lacking. Pregestational vaginal dysbiosis precedes the diagnosis of HDP, providing a novel perspective on the etiology of HDP. Early pregnancy is the critical period of placental development, and abnormal placentation initiates HDP development. Thus, disease prevention should be considered before pregnancy. Vaginal microbiome characterization and probiotic interventions before pregnancy are preferred because of their safety and potential for early prevention. This study is the first to prospectively assess associations between pregestational vaginal microbiome and HDP. L. crispatus-dominated vaginal community state type is linked to a reduced risk for HDP. These findings suggest that vaginal microbiome characterization may help identify individuals at high risk for HDP and offer potential targets for the development of novel pregestational intervention methods.

Abstract Background The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. Methods FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. Results VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS. Conclusions VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling.

Abstract Circulating leukocytes are an important part of the immune system. The aim of this work is to explore the role of preoperative circulating leukocytes in serous ovarian carcinoma and investigate whether they can be used to predict survival prognosis. Routine blood test results and clinical information of patients with serous ovarian carcinoma were retrospectively collected. And to predict survival according to the blood routine test result the decision tree method was applied to build a machine learning model. The results showed that the number of preoperative white blood cells (p = 0.022), monocytes (p

Developing hydrolytic nanozymes remains challenging. Here the authors present a rational methodology to design hydrolytic nanozyme by developing a data-informed strategy to screen and identify potential scaffold and active sites of hydrolase-like nanozyme.

Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal cancers and is projected to be the second leading cause of cancer deaths in the United States by 2030. The lack of effective treatment and increased incidence in PDAC encourage a deeper knowledge of PDAC progression. By analyzing a long noncoding RNA (lncRNA) dataset, we found that increased LINC00941 expression led to poor outcomes in PDAC patients. Furthermore, in vitro and in vivo experiments revealed that LINC00941 promoted PDAC cancer cell growth by enhancing aerobic glycolysis. Mechanistically, LINC00941 was found to interact with mammalian STE20-like protein kinase 1 (MST1), which facilitated the protein phosphatase 2A (PP2A)-mediated dephosphorylation of MST1, resulting in Hippo pathway activation and consequently, enhanced glycolysis in PDAC. These results suggest that LINC00941 plays a key role in regulating PDAC tumorigenesis, potentially highlighting novel avenues for PDAC therapy.

Bile acid reflux and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), a precursor of gastric cancer; however, the mechanism underlying this phenomenon is unclear. Here, we demonstrate that alkylation repair homolog protein 5 (ALKBH5), a major RNA N6-adenosine demethylase, is required for bile acid-induced gastric IM. Mechanistically, we revealed the N6-methyladenosine (m6A) modification profile in gastric IM for the first time and identified ZNF333 as a novel m6A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m6A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/CYLD axis and activating NF-κB signaling. Reciprocally, p65, the key transcription factor of the canonical NF-κB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feedforward circuit. Furthermore, ALKBH5 levels were positively correlated with ZNF333 and CDX2 levels in IM tissues, indicating significant clinical relevance. Collectively, our findings suggest that an m6A modification-associated positive feedforward loop between ALKBH5 and NF-κB signaling is involved in generating the IM phenotype of gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.

Hypoxia and immunosuppression contribute to tumor resistance to radiotherapy (RT). Here the authors design a nanoprobe based on NIR-IIb emitting quantum dots for image-guided RT and modified with catalase to relieve hypoxia in the tumor microenvironment, enhancing the precision and efficacy of RT and promoting anti-tumor immune responses.

BackgroundOcular melanoma is an aggressive malignancy with a high rate of metastasis and poor prognosis. Increasing evidence indicated that DNA methylation plays an important role in the occurrence and development of ocular melanoma. Hence, exploring new diagnostic and prognostic biomarkers at the genetic level may be beneficial to the prognosis of patients with ocular melanoma.MethodsWe collected DNA methylation and gene expression profiles of human UM (uveal melanoma) and CM (conjunctival melanoma) samples from various datasets. We conducted differential methylation and expression analyses to screen the potential biomarkers. Correlation analysis was performed to investigate the relationships between the expression level of DLL3 (delta-like protein 3) and the methylation level of its corresponding CpGs. We explored the prognostic and diagnostic value of DLL3 in UM and CM. Functional annotation and GSEA (gene set enrichment analysis) were applied to get insight into the possible biological roles of DLL3. A cohort of 60 ocular melanoma patients as well as UM and CM cell lines were used to validate our findings in bioinformatic analyses.ResultsWe found that DLL3 was a methylation-driven gene correlating with UM metastasis. The CpGs of DLL3 are mainly located in the gene body and their methylation level positively correlated to DLL3 expression. Multivariate Cox regression analysis revealed that DLL3 was an independent protective factor for UM patients. High DLL3 expression significantly prolonged the overall survival and disease-free survival of UM patients. DLL3 also showed a promising power to distinguish CM from normal tissues. Functional annotation exhibited that DLL3 may suppress UM progression through modulating immune activities and down-regulating various signaling pathways. External datasets, biospecimens, and cell lines further validated the aberrant expression and prognostic role of DLL3 in ocular melanoma.ConclusionMethylation-driven gene DLL3 could serve as a new potential diagnostic and prognostic biomarker in ocular melanoma. Our findings may contribute to improving the clinical outcomes of patients with UM or CM.

Meat quality is highly influenced by the kind of muscle fiber, and it can be significantly improved by increasing the percentage of slow-twitch fibers. It is still not known which genes control the formation of muscle fibers or how those genes control the process of forming in sheep until now. In this study, we used high-throughput RNA sequencing to assess the expression profiles of coding and noncoding RNAs in muscle tissue of Tan sheep and Dorper sheep. To investigate the molecular processes involved in the formation of muscle fibers, we collected two different muscle tissues, longissimus dorsi and biceps femoris, from Tan sheep and Dorper sheep. The longissimus dorsi of Tan sheep and Dorper sheep displayed significantly differential expression levels for 214 lncRNAs, 25 mRNAs, 4 miRNAs, and 91 circRNAs. Similarly, 172 lncRNAs, 35 mRNAs, 12 miRNAs, and 95 circRNAs were differentially expressed in the biceps femoris of Tan sheep and Dorper sheep according to the expression profiling. GO and KEGG annotation revealed that these differentially expressed genes and noncoding RNAs were related to pathways of the formation of muscle fiber, such as the Ca2+, FoxO, and AMPK signaling pathways. Several key genes are involved in the formation of muscle fibers, including ACACB, ATP6V0A1, ASAH1, EFHB, MYL3, C1QTNF7, SFSWAP, and FBXL5. RT-qPCR verified that the expression patterns of randomly selected differentially expressed transcripts were highly consistent with those obtained by RNA sequencing. A total of 10 lncRNAs, 12 miRNAs, 20 circRNAs, and 19 genes formed lncRNA/circRNA-miRNA-gene networks, indicating that the formation of muscle fiber in Tan sheep is controlled by intricate regulatory networks of coding and noncoding genes. Our findings suggested that specific ceRNA subnetworks, such as circ_0017336-miR-23a-FBXL5, may be critical in the regulation of the development of muscle fibers, offering a valuable resource for future study of the development of muscle fibers in this animal species. The findings increase our understanding of the variety in how muscle fibers originate in various domestic animals and lay the groundwork for future research into new systems that regulate the development of muscle.

Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci.

In this work, different interlayer remelting strategies are applied to regulate the microstructure evolution, martensitic transformation, and superelastic features of NiTi shape memory alloys prepared using the EBF3 additive manufacturing technique. The NiTi deposits prepared under different remelting beam currents are all composed of the B2 austenite, residual B19′ martensite, and submicron-scale Ti4Ni2Ox precipitates, and exhibit a one-step phase transformation (B2 ↔ B19′). Meanwhile, the crystallographic orientation, grain boundaries, and residual strain of these alloys present a distinct variation with the application of different remelting beam currents. During mechanical testing, the critical stress (σMs) of the EBF3-fabricated NiTi alloys was seen to possess a significant dependence on the martensitic transformation behavior, namely with the amount of B19′ martensite and the corresponding Ms. However, the broadening and stabilization of lamellar martensite created by dislocation pile-ups and plastic deformation in the cyclic loading–unloading procedure is the key reason for the deterioration of the superelastic response of the NiTi deposits. This work confirms that the mechanical and functional performances of NiTi alloys produced via EBF3-technique can be modified upon the application of proper interlayer remelting strategies, which can be extrapolated to the directed energy deposition of shape memory alloys or other metal components.

BackgroundPrevious studies have shown that cancer patients have higher rates of coronavirus disease 2019 (COVID-19) infection and mortality than noncancer patients. However, the differences between cancer patients undergoing regular follow-up without anticancer treatment and noncancer patients with COVID-19 have remained insufficiently investigated.MethodsA retrospective case–control study of 52 patients with COVID-19 infection was performed with a 1:3 matched proportion of cancer patients undergoing regular follow-up without anticancer treatment and noncancer patients. The demographic characteristics, clinical data, laboratory tests, treatment, and complications of patients were collected from medical records. Chi-square tests and univariate and multivariate regressions were performed to assess the differences between these two cohorts of COVID-19 patients with and without cancer and risk factors for severe events in COVID-19 patients.ResultsIncreased C-reactive protein (CRP) (>4 mg/L) (p = 0.015) and lactate dehydrogenase (LDH) (>243 IU/L) (p = 0.038) were identified as risk factors for severe events in all enrolled COVID-19 patients based on multivariate analysis, but cancer as a chronic disease (p = 1.000) was not identified as an independent risk factor for severe events in COVID-19 patients. Compared with noncancer patients, cancer patients had a significantly longer median hospitalization time (29 days vs. 19 days, p = 0.048) and a higher incidence of hypoalbuminemia complications (84.6 vs. 46.2%, p = 0.016).ConclusionsIncreased CRP and LDH were risk factors for severe events in all enrolled COVID-19 patients, and an increased incidence of hypoalbuminemia complications and longer hospitalization were noted in COVID-19 cancer patients undergoing regular follow-up without anticancer treatment compared with noncancer patients.

Gastric cancer (GC) is a disease characterized by high molecular and phenotypic heterogeneity and represents a leading cause of cancer-related death worldwide. The tumor immune microenvironment (TIME) affects the response to immunotherapy and the prognosis of patients with GC. Explorations of the TIME in GC and characterization of molecular subtypes might enhance personalized treatment and facilitate clinical decision-making. In this study, two molecular subtypes were defined through unsupervised consensus clustering based on immune-related dysregulated genes. Then, patients with different molecular subtypes of GC were shown to have distinct differences in sensitivity to immune checkpoint blockers (ICBs). The immune-related prognostic signature was established utilizing least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. Three independent external cohorts and the IMvigor210 cohort were introduced to validate the robustness of IPRS. scRNA-seq data of GC samples were used to decipher the underlying mechanisms of how IPRS contributes to the TIME. GC biospecimens were collected for RT-qPCR to further validate our findings. In summary, we characterized the abnormal TIME of GC and constructed a reliable immune-related prognostic signature correlating with the response to immunotherapy. This study may provide new strategies for developing individualized treatments for patients with GC.

Single tracks of Inconel 718 were manufactured by selective laser melting (SLM) under the same volumetric energy density (VED), but via various scanning speed and laser power, with the aim of discerning the influence of the melting mode of molten pools on their solidification behavior, microstructure and nano-hardness. For this purpose, the geometric appearance of each Inconel 718 single track was firstly investigated. The results indicate that the molten pool geometries are significantly different despite melting under the same VED condition; the typical melting modes of molten pools, including the keyhole and conduction modes, can be obtained. The solidified microstructures of both modes evolve from cellular at the bottom to cellular dendrites at the top; but the dendrites are more developed under the keyhole mode. In addition, the grains of both modes follow the epitaxial columnar crystal growth pattern along the boundary of molten pool. The preferential growth direction of grains under the conduction mode is closer to the direction, but the grains orientation of the keyhole mode tends to be and direction. Moreover, in comparison with the conduction mode, the average nano-hardness for different regions of molten pools corresponding to the keyhole mode is slightly higher.

Action detection and recognition are popular subjects of research in the field of computer vision. The task of action detection can be regarded as the sum of action location and recognition. Action features described by using information concerning the human skeleton have the advantages of robustness against external factors and requiring a small amount of calculation. This study proposes a skeleton‐based action analysis model based on a recurrent neural network framework. The model learns action features by modelling static and dynamic features of skeleton joints and the importance of different video frames by introducing an attention module. For action location, conditional random field loss function is introduced to establish the context dependency of output labels. In the aspect of action recognition, the hierarchical training mechanism with triple loss models action features at coarse‐grained and fine‐grained levels. The authors’ proposed method delivers state‐of‐the‐art results on action location and recognition tasks.

Abstract Ovarian carcinoma is the deadliest type of gynecological cancer. The unique tumor microenvironment enables specific and efficient metastasis, weakens immunological monitoring, and mediates drug resistance. Tumor associated macrophages (TAMs) are a crucial part of the TME and are involved in various aspects of tumor behavior. Lysophosphatidic acid (LPA) is elevated in the blood of ovarian carcinoma patients, as well as in the tumor tissues and ascites, which make it a useful biomarker and a potential therapeutic target. Recent studies have shown that LPA transforms monocytes into macrophages and regulates the formation of macrophages through the AKT/mTOR pathway, and PPAR γ is a major regulator of LPA-derived macrophages. In addition, TAMs synthesize and secrete LPA and express LPA receptor (LPAR) on the surface. With these data in mind, we hypothesize that LPA can convert monocytes directly into TAMs in the microenvironment of ovarian cancer. LPA may mediate TAM formation by activating the PI3K/AKT/mTOR signaling pathway through LPAR on the cell surface, which may also affect the function of PPAR γ, leading to increased LPA production by TAMs. Thus, LPA and TAMs form a vicious circle that affects the malignant behavior of ovarian cancer.

In skeleton-based human action recognition, spatial-temporal graph convolution networks (ST-GCNs) have achieved remarkable performances recently. However, how to explore more discriminative spatial and temporal features is still an open problem. The temporal graph convolution of the traditional ST-GCNs utilizes only one fixed kernel which cannot completely cover all the important stages of each action execution. Besides, the spatial and temporal graph convolution layers (GCLs) are serial connected, which mixes information of different domains and limits the feature extraction capability. In addition, the input features like joints, bones, and their motions are modeled in existing methods, but more input features are needed for better performance. To this end, this article proposes a novel multi-stream and enhanced spatial-temporal graph convolution network (MS-ESTGCN). For each basic block of MS-ESTGCN, densely connected multiple temporal GCLs with different kernel sizes are employed to aggregate more temporal features. To eliminate the adverse impact of information mixing, an additional spatial GCL branch is added to the block and the spatial features can be enhanced. Furthermore, we extend the input features by employing relative positions of joints and bones. Consequently, there are totally six data modalities (joints, bones, their motions and relative positions) that can be fed into the network independently with a six-stream paradigm. The proposed method is evaluated on two large scale datasets: NTU-RGB+D and Kinetics-Skeleton. The experimental results show that our method using only two data modalities delivers state-of-the-art performance, and our methods using four and six data modalities further exceed other methods with a significant margin.

ObjectiveThis study aims to investigate the correlation between serum uric acid levels and body fat distribution in patients with polycystic ovary syndrome (PCOS).MethodsBetween May 2017 and March 2021, a total of 199 patients with PCOS were recruited from the Department of Endocrinology and Metabolism at the Shanghai Tenth People’s Hospital. Anthropometric characteristics, metabolic parameters, and reproductive hormones were measured. Hyperuricemia was defined as serum uric acid (SUA) greater than 420 μmol/l. Dual-energy X-ray absorptiometry (DEXA) was used to measure body fat distribution.ResultsThe prevalence of hyperuricemia in patients with PCOS was 28.64%. PCOS patients with hyperuricemia are more obese and have a higher waist-to-hip ratio (WHR) and worse lipid metabolism than those without hyperuricemia. According to SUA quartiles, patients in the highest quartile had higher total testosterone (TT), body fat accumulation, and lower sex hormone-binding globulin (SHBG) than patients in the lowest quartile. SUA was correlated with percentage of total body fat, arm fat mass, leg fat mass, trunk fat mass, android/gynoid (A/G) ratio, and visceral adipose tissue (VAT) mass. After controlling possible confounders, logistic regression analysis found that only excessive VAT mass could significantly increase the risk of hyperuricemia in patients with PCOS.ConclusionIn patients with PCOS, a high level of VAT mass, but not other fat compartments, will exacerbate the risk of hyperuricemia. Attention should be paid to the role of excessive VAT in the occurrence and development of PCOS with hyperuricemia.

Skin color is an important phenotypic feature of vertebrate fitness under natural conditions. Celestial goldfish, a common goldfish breed in China, mainly shows three kinds of skin colors including white, yellow and brown. However, the molecular genetic basis of this phenotype is still unclear. In this study, high-throughput sequencing was carried out on the back skin tissues of celestial goldfish with different skin colors. About 58.46 Gb of original data were generated, filtered and blasted, and 74,297 mRNAs were obtained according to the reference transcriptome. A total of 4653 differentially expressed genes were screened out among the brown, yellow and white groups, and the expression of melanogenesis related genes in brown goldfish was significantly higher than the other two groups. There are 19 common differentially expressed genes among three groups, of which eight genes are related to pigment production, including tyrp1a, slc2a11b, mlana, gch2, loc113060382, loc113079820, loc113068772 and loc113059134. RT-qPCR verified that the expression patterns of randomly selected differentially expressed transcripts were highly consistent with those obtained by RNA sequencing. GO and KEGG annotation revealed that these differentially expressed genes were mostly enriched in pathways of the production of pigment, including melanogenesis, tyrosine metabolism, Wnt signaling pathway, MAPK signaling pathway etc. These results indicated that the external characteristics of goldfish are consistent with the analysis results at transcriptome level. The results of this study will lay a foundation for further study on the expression characteristics and gene network analysis of pigment related genes.

Pancreatic adenocarcinoma is one of the most lethal diseases with a 5-year survival rate of about 8%. ASXL2 is an epigenetic regulator associated with various tumors including colorectal cancer, breast cancer, and myeloid leukemia. However, the role of ASXL2 in pancreatic cancer remains unclear. This is the first research focusing on the prognostic value of ASXL2 in pancreatic cancer. In this research, we aimed to explore the correlation between ASXL2 and the prognosis, as well as other features in PAAD. We obtained gene expression profiles of PAAD and normal tissues from TCGA, GEO, and Xena databases. TIMER and CIBERSORT algorithms were employed to investigate the effect of ASXL2 on tumor microenvironment. GSEA along with GO and KEGG enrichment analyses were conducted to uncover the biological functions of ASXL2. The response to various chemotherapeutic drugs was estimated by algorithms in R package “pRRophetic”, while the sensitivity to immunotherapy was quantified by TIDE score. We found that ASXL2 was upregulated in the PAAD samples and elevated expression of ASXL2 was linked to poor overall survival. ASXL2 DNA methylation contributed to ASXL2 expression. Functional annotation indicated that ASXL2 was mainly involved in inflammatory response and epithelial mesenchymal transition. Patients with high ASXL2 expression were more likely to benefit from immune checkpoint blockade, gemcitabine, and mitomycin-C. Finally, external datasets and biospecimens were used and the results further validated the aberrant expression of ASXL2 in PAAD samples. In summary, our results highlight that ASXL2 is a potential prognostic and predictive biomarker in pancreatic cancer.

Stomach adenocarcinoma (STAD) is one of the most common cancers in the world. However, the prognosis of STAD remains poor, and the therapeutic effect of chemotherapy and immunotherapy varies from person to person. MicroRNAs (miRNAs) play vital roles in tumor development and metastasis and can be used for cancer diagnosis and prognosis. In this study, hsa-miR-100-5p was identified as the only dysregulated miRNA in STAD samples through an analysis of three miRNA expression matrices. A weighted gene co-expression network analysis (WGCNA) was performed to select hsa-miR-100-5p-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a miR-100-5p-related prognostic signature. Kaplan–Meier analyses, nomograms, and univariate and multivariate Cox regression analyses were used to evaluate the prognostic signature, which was subsequently identified as an independent risk factor for STAD patients. We investigated the tumor immune environment between low- and high-risk groups and found that, among component types, M2 macrophages contributed the most to the difference between these groups. A drug sensitivity analysis suggested that patients with high-risk scores may be more sensitive to docetaxel and cisplatin chemotherapy and that patients in the low-risk group may be more likely to benefit from immunotherapy. Finally, external cohorts were evaluated to validate the robustness of the prognostic signature. In summary, this study may provide new ideas for developing more individualized therapeutic strategies for STAD patients.

As new screening tools for sarcopenia, the serum sarcopenia index (SI) and creatinine/cystatin C ratio (CCR) had not been confirmd in a population with a high fragility fracture risk. This study aimed to evaluate whether SI and CCR indicators are useful for diagnosing sarcopenia and to determine their prediction values for future falls and fractures. A total of 404 hospitalized older adults were enrolled in this longitudinal follow-up study (mean age = 66.43 ± 6.80 years). The receiver operating curve (ROC) was used to assess the diagnostic accuracy of SI and CCR. Backward-selection binary logistic regression was applied to develop the optimal models for the diagnosis of new falls and fractures. SI had a significantly higher area under the curve (AUC) than CCR for predicting sarcopenia. The optimal models had acceptable discriminative powers for predicting new falls and fractures. Lower SI and CCR are the independent risks for sarcopenia, new falls, and fractures in the low-BMD population. SI and CCR, as easily accessible biochemical markers, may be useful in the detection of sarcopenia and in predicting the occurrence of new falls and fractures in patients with low BMD who have not previously experienced falls or fractures. However, further external validations are required.

ObjectivePatients with psoriasis (PsO) have a high frequency of concomitant gout and increased risk of cardiovascular diseases (CVD). We aimed to estimate the synergistic impact of gout on the risk of CVD in patients with PsO.MethodsA population-based cohort of patients registered in the National Health Insurance Research Database of Taiwan between 2000 and 2013 was stratified according to the presence of PsO and gout. Propensity score analysis was used to match age and gender at a ratio of 1:4. Cox proportional hazard models and subgroup analyses were used to estimate the hazard ratios (HRs) for CVD adjusted for traditional risk factors. The Kaplan–Meier method was used to plot the cumulative incidence curves.ResultsPatients with combined PsO and gout (n = 97), PsO alone (n = 388), gout alone (matched, n = 388) and matched controls (n = 388) were identified. Compared with the patients with PsO alone, the patients with combined PsO and gout had a significantly higher risk of CVD (relative risk 2.39, 95% CI 1.56 to 3.65). After adjustment for traditional risk factors, the risk of CVD was higher in patients with gout alone (HR 2.16, 95% CI 1.54 to 3.04) and in patients with combined PsO and gout (HR 2.72, 95% CI 1.73 to 4.28).ConclusionsGout augments the risk of CVD independently of traditional risk factors in patients with PsO.

Background: Colorectal cancer (CRC) is one of the high incidences tumours and is ranked second in cancer-related mortality. Even though great progress has been made, there are no effective therapeutic strategies for late stage and metastatic CRC patients. Acidity is one characteristic of the tumour microenvironment. However, how cancer cells respond to this acidic environment surrounding them remains largely unknown, especially in colorectal cancer. Methods: Proton sensor receptor expression was analysed in GEO and TCGA datasets. The expression of GPR4 in CRC specimens was confirmed by western blotting and immunohistochemistry (IHC). The role of GPR4 in CRC progression was analysed both in vitro and in vivo. Pharmacological intervention, immunofluorescence and gene set enrichment analyses were performed to reveal the underlying molecular mechanisms of GPR4. Findings: We found that GPR4 was upregulated in CRC samples. In addition, its high expression correlated with late stage tumours and poor overall survival in patients. Furthermore, loss-of-function assays proved that GPR4 promoted CRC carcinogenesis and metastatic ability. Mechanistically, GPR4 was activated by extracellular protons in the tumour microenvironment and enhanced RhoA activation and F-actin rearrangement, leading to LATS activity inhibition, YAP1 nuclear translocation and oncogene transcription. Interpretation: The expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRC patients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment. Keywords: Extracellular acidification, GPR4, RhoA, Hippo pathway

Abstract Background As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. Methods qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. Results Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the “reader” protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. Conclusions Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

Abstract Background To explore the role of lysophosphatidic acid receptor 1 (LPAR1) and its correlation with the PI3K/AKT pathway in the development of intratumoral heterogeneity (ITH) in human ovarian serous cystadenocarcinoma (OSC). Methods Immunohistochemical staining was performed to detect LPAR1 expression in matched primary and recurrent lesions from the same patients. Cell models of ITH were established using the limiting dilution methodology and Transwell invasion/migration assays. LPAR1 expression in the ITH cell models was silenced or upregulated with lentiviral particles, and the biological characteristics were evaluated using various in vitro and in vivo assessments of cell function. The levels of phosphorylated PI3K/AKT (p-PI3K/p-AKT) in LPAR1 knockdown and LPAR1-overexpressing cells were detected. Results The H-scores for LPAR1 staining in the lymphatic metastatic and recurrent lesions were noticeably higher than in the primary tumor lesions from the same patients (P = 0.024/0.031). High LPAR1 expression was associated with worse progression-free survival and overall survival (P = 0.017/0.039). Biological functions in vitro, including invasion, migration, and proliferation, and tumor formation in vivo were decreased in the LPAR1-silenced cells (all P

Abstract Background and objective Previous studies about the prognostic value of the HIPEC have yielded controversial results. Therefore, this study aims to assess the impact of HIPEC on patients with ovarian cancer. Results We included 13 comparative studies, and found that the overall survival (OS) and progression-free survival (PFS) in HIPEC groups were superior to groups without HIPEC treatment in the all total population (HR = 0.54,95% CI:0.45 to 0.66, HR = 0.45, 95% CI: 0.32 to 0.62). Additionally, the subgroup analysis showed that patients with advanced primary ovarian cancers also gained improved OS and PFS benefit from HIPEC (HR = 0.59,95% CI:0.46 to 0.75, HR = 0.41,95% CI:0.32 to 0.54). With regard to recurrent ovarian cancer, HIPEC was associated with improved OS (HR = 0.45,95% CI:0.24 to 0.83), but for the PFS, no correlation was observed between HIPC group and the non-HIPEC group (HR = 0.55,95% CI:0.27 to 1.11). HIPEC also led to favorable clinical outcome (HR = 0.64,95% CI:0.50 to 0.82, HR = 0.36,95% CI:0.20 to 0.65) for stage III or IV ovarian cancer with initial diagnosis. Conclusion The review indicated that HIPEC-based regimens was correlated with better clinical prognosis for patients with primary ovarian cancers. For recurrent ovarian cancers, HIPEC only improved the OS but did not elicit significant value on the PFS.

The analysis of human actions, such as recognition and person identification, is important but challenging. Previous studies usually separate person identification from action recognition. In this paper, we propose a skeleton-based end-to-end model that can simultaneously implement both person identification and action recognition and strengthen the learning of hard samples. Inspired by the recent application of recurrent neural networks and convolution neural networks to action analysis, the models of the temporal and spatial domains are created by modeling the global, local, and detailed feature-related information of the human skeleton. Moreover, during training, we add a mining and learning mechanism for hard samples that mines and focuses on them to avoid overfitting. This mining and learning mechanism enables the model to avoid a bottleneck and improve performance. The proposed model is experimentally verified on three datasets, where the results show that it can yield the state-of-the-art performance.

The development of multifunction nanoplatforms integrating accurate diagnosis and efficient therapy is of great significance for the precise treatment of tumors. Gold nanoparticles (AuNPs) possessing hallmark features of computed tomography (CT) imaging and photothermal conversion capability hold great potential in tumor theranostics. In this study, taking the advantages of outstanding biocompatibility, interesting anti-inflammatory and immunomodulatory properties, and abundant amino acid residues of silk fibroin (SF), a multifunctional Gd-hybridized AuNP nanoplatform was constructed using SF as a stabilizer and reductant via a facile one-pot biomimetic method, denoted as Gd:AuNPs@SF. The obtained Gd:AuNPs@SF possessed fascinating biocompatibility and excellent photothermal conversion efficiency. Functionalized with Gd, Gd:AuNPs@SF exhibited super tumor-contrasted imaging performance in magnetic resonance (MR) and CT imaging modalities. Moreover, Gd:AuNPs@SF, with strong NIR absorbance, demonstrated that it could effectively kill tumor cells in vitro, and was also proved to successfully ablate tumor tissues through MR/CT imaging-guided photothermal therapy (PTT) without systemic toxicity in Pan02 xenograft C57BL/6 mouse models. We successfully synthesized Gd:AuNPs@SF for MR/CT dual-mode imaging-guided PTT via a facile one-pot biomimetic method, and this biomimetic strategy can also be used for the construction of other multifunction nanoplatforms, which is promising for precise tumor theranostics.

ObjectivesThis study aimed to compare the prevalence of hypogonadism between male patients with latent autoimmune diabetes (LADA) and type 2 diabetes (T2DM) and investigate the risk factors for hypogonadism in these patients.MethodsThis cross-sectional study evaluated 367 male patients with LADA (n=73) and T2DM (n=294) who visited the endocrinology department of Shanghai Tenth People’s Hospital between January 2016 and October 2019 for diabetes management. Sex hormones, lipid profiles, sex hormone-binding globulin (SHBG), glycosylated hemoglobin A1c, beta-cell function, uric acid, and osteocalcin were determined in serum samples. Hypogonadism was defined as calculated free testosterone (cFT) less than 220 pmol/L along with the presence of symptoms (positive ADAM score).ResultsThe rate of hypogonadism in the LADA and T2DM group were 8.2, and 21.7%, respectively (p=0.017). After adjusting possible confounders, the rate of hypogonadism in the LADA group was comparable to those of the T2DM group. Univariate logistic regressions demonstrated that age, BMI, fasting C-peptide, triglycerides, total cholesterol and uric acid were associated with hypogonadism in men with diabetes, BMI, triglycerides and estradiol were independent risk for hypogonadism in men with diabetes.ConclusionThis is the first evidence to explore the rate of hypogonadism in male patients with latent autoimmune diabetes (LADA). In the population requiring admission to a large urban hospital in China, the rate of hypogonadism was comparable to those of the T2DM group after adjusting for possible confounders. BMI, triglycerides and estradiol were independently associated with the presence of HH in male diabetic patients.

CircRNAs play an important role in fat deposition, and testosterone-deficient boars exhibit significantly increased fat deposition; however, the mechanism by which testosterone regulates fat deposition through circRNAs remains unclear. In this study, circRNA-seq of backfat and abdominal fat from castrated and intact full-sib Yorkshire pigs was performed. The GO and KEGG enrichment analyses revealed that the host genes of the dorsal DE circRNAs were mainly involved in fatty acid transport, while in abdominal tissues, these genes were mainly involved in adipogenesis and inflammation. The interaction among sus_circPAPPA2, ssc-miR-2366 and GK was verified by dual fluorescence experiments and in porcine preadipocytes. The overexpression of sus_circPAPPA2 significantly inhibited the differentiation of preadipocytes. The expression of sus_circPAPPA2 was increased after adding 100 nM of testosterone, and preadipocyte differentiation was significantly inhibited. Testosterone can affect preadipocyte differentiation by upregulating the expression of sus_circPAPPA2, sponging miR-2366 and regulating the expression of genes, such as GK. These results indicate that testosterone can regulate the expression of adipocyte differentiation- and lipid metabolism-related genes by regulating the expression of circRNA, and ceRNA networks are different in the testosterone regulation of adipose deposition in different parts. This study provides basic data enhancing the understanding of the interaction between the hormone environment and mir-2366/GK to regulate trait performance in pigs.

Because of their superior mechanical performance at ultra-high temperatures, refractory niobium–silicon-based alloys are attractive high-temperature structural alloys, particularly as structural components in gas turbine engines. However, the development of niobium–silicon-based alloys for applications is limited because of the trade-off between room temperature fracture toughness and high-temperature strength. Here, we report on the fabrication of a Nb-18Si alloy with dispersion of hafnium carbide (HfC) particles through selective laser melting (SLM). XRD and SEM-BSE were used to examine the effects of scanning speed on the microstructure and the phase structure of the deposited Nb-18Si-5HfC alloy. The results show that when the scanning speed rises, the solid solubility of the solid solution improves, the interlamellar spacing of eutectics slowly decrease into nano-scale magnitude, and the corresponding hafnium carbide distribution becomes more uniform. We also discover the hafnium carbide particles dispersion in the inter-lamella structure, which contributes to its high fracture toughness property of 20.7 MPa∙m1/2 at room temperature. Hardness and fracture toughness are simultaneously improved because of the control of microstructure morphology and carbide distribution.

Abstract Background The unique clinical features of pregnancy termination in the second trimester with concurrent placenta accreta spectrum (PAS) disorders place obstetricians in a complex and delicate situation. However, there are limited data on this rare and dangerous condition. The objective of this research was to investigate and evaluate the clinical management strategies of this patient group. Methods The medical records of patients who were diagnosed and treated in our hospital from December 2005 and December 2015 were retrospectively reviewed. Results A total of 29 patients were included in this analysis. A prenatal diagnosis was suspected in 8 (27.6%) patients, and the remaining 21 (72.4%) patients were diagnosed after pregnancy termination in the second trimester. In the subgroup with a prenatal diagnosis, a planned hysterotomy was performed in 7 patients who had total placenta previa and previous cesarean delivery. The remaining patient received medical termination. A subtotal hysterectomy was performed in 3 (10.3%) patients for life-threatening bleeding during hysterotomy, and the uterus was preserved with an in situ placenta in the remaining 5 patients. In the subgroup with a postnatal diagnosis, the implanted placenta remained partly or completely in situ in all 21 patients under informed consent. Ultimately, the implanted placenta remained partly or completely in situ in 26 (89.7%) patients in the two subgroups. With the application of adjuvant treatments, including uterine artery embolization and medication followed by curettage under ultrasound guidance, the implanted placenta was passed 76.6 (range: 19 to 192) days after termination. Uterus preservation was achieved in all 26 patients. The complications associated with conservative management included delayed postnatal hemorrhaging (2 cases, 7.7%), fever (6 cases, 23.1%), G1 transaminase disorder (4 cases, 15.4%), and myelosuppression (1 case, 3.8%). Seven women (26.9%) had a spontaneous pregnancy after conservative management, and no patient experienced recurrent PAS disorders. Conclusions Leaving the implanted placenta in situ is the preferred choice for patients with PAS disorders who underwent pregnancy termination in the second trimester and desired fertility preservation. Multiple adjuvant treatment modalities, either alone or in combination, may help to promote the passing or absorption of the implanted placenta under close monitoring.

Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.