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The present study aims to reveal the osteogenic roles played by DNA damage response biomarkers through implementing isobaric tags for relative and absolute quantitation (iTRAQ) technique. First, sandblasted large-grit double acid-etched (SLA) titanium implant and strontium-incorporated (SLA-Sr) titanium implant were used for inserting in the tibiae of rats. iTRAQ technique was used to detect protein expression changes and identify differentially expressed proteins (DEPs). In total, 19,343 peptides and 4280 proteins were screened out. Among them, 91 and 138 DEPs were identified in the SLA-Sr group after implantation for 3 and 7 days, respectively. Ataxia-telangiectasia mutated (ATM) protein up-regulated on the 3rd day showed a trend of further up-regulation on the 7th day. Moreover, functional enrichment analyses were also conducted to explore the biological function of DEPs during the initial stage of osseointegration in vivo, which revealed that the biological functions of the DEPs on the 7th day were mainly related to "mismatch repair" and "mitotic G1 DNA damage checkpoint." Analysis of the Reactome signaling pathway showed that ATM was associated with TP53's regulation and activation. Finally, DNA damage repair related genes were selected for validation at mRNA and protein expression levels. Real-time reverse transcription-polymerase chain reaction and immunohistochemistry validation results demonstrated that mRNA expression level of ATM was higher in SLA-Sr group. In conclusion, SLA-Sr titanium implant could initiate DNA damage repair by activating expression levels of ATM. This study was striving to reveal new faces of better osseointegration and shedding light on the biological function and underlying mechanisms of this important procedure.

Osteoarthritis (OA) is one of the most common degenerative joint diseases and is associated with autophagy suppression. However, the molecular mechanism of autophagy regulation in the context of OA is not fully understood.We resorted to RNA-sequencing analysis to explore the differential expression of E3-ubiquitin ligase genes in healthy and osteoarthritic human cartilage. We comprehensively analyzed the function of the screened gene Hectd1 in OA development using surgery- and aging-induced OA mouse models; furthermore, we dissected the mechanism by which HECTD1 regulates autophagy and OA progression by combination of molecular biological, cell biological and biochemical approaches.HECTD1 was significantly downregulated in human OA cartilage compared to healthy cartilage. Overexpression of HECTD1 in mouse joints alleviated OA pathogenesis, whereas conditional depletion of Hectd1 in cartilage aggravated surgery- and aging-induced OA pathogenesis. Mechanistically, HECTD1 binds to Rubicon and ubiquitinates Rubicon at lysine residue 534, which targets Rubicon for proteasomal degradation. More importantly, HECTD1-mediated Rubicon degradation regulates chondrocyte autophagy, which mitigates stress-induced chondrocyte death and subsequent OA progression.HECTD1 plays a crucial role in OA pathogenesis in which HECTD1 regulates chondrocyte autophagy by ubiquitinating and targeting Rubicon for proteasomal degradation.

Colitis-associated colorectal cancer (CAC) develops from chronic intestinal inflammation. Dihydroartemisinin (DHA) is an antimalarial drug exhibiting anti-inflammatory and anti-tumor effects. Nonetheless, the therapeutic effects of DHA on CAC remain unestablished. Methods: Mice were challenged with azoxymethane (AOM) and dextran sulfate sodium (DSS) to establish CAC models. DHA was administered via oral gavage in different stages of CAC models. Colon and tumor tissues were obtained from the AOM/DSS models to investigate inflammatory responses and tumor development. Inflammatory cytokines in the murine models were detected through qRT-PCR and ELISA. Toll-like receptor 4 (TLR4) signaling-related proteins were detected by western blot. Macrophage infiltration was measured using immunostaining analysis, and apoptosis in the colon cancer cells was detected by flow cytometry and western blot. Results: DHA inhibited inflammatory responses in the early stage of the AOM/DSS model and subsequent tumor formation. In the early stage, DHA reversed macrophage infiltration in colon mucosa and decreased the expression of pro-inflammatory cytokines. DHA inhibited the activation of macrophage by suppressing the TLR4 signal pathway. In the late stage of CAC, DHA inhibited tumor growth by enhancing cell cycle arrest and apoptosis in tumor cells. Administration of DHA during the whole period of the AOM/DSS model generated an addictive effect based on the inhibition of inflammation and tumor growth, thereby improving the therapeutic effect of DHA on CAC. Conclusion: Our study indicated that DHA could be a potent agent in managing the initiation and development of CAC without obvious side effects, warranting further clinical translation of DHA for CAC treatment.

Lumbar disc degeneration is a common cause of chronic low back pain and an important contributor to various degenerative lumbar spinal disorders. However, currently there is currently no effective therapeutic strategy for treating disc degeneration. The pro-inflammatory cytokine interleukin-1β (IL-1β) mediates disc degeneration by inducing apoptotic death of nucleus pulposus (NP) cells and degradation of the NP extracellular matrix. Here, we confirmed that extracellular secretion of IL-1β via secretory autophagy contributes to disc degeneration, and demonstrate that a thermosensitive reactive oxygen species (ROS)-responsive hydrogel loaded with a synthetic growth hormone-releasing hormone analog (MR409) can protect against needle puncture-induced disc degeneration in rats. Methods: The expression levels of proteins related to secretory autophagy such as tripartite motif-containing 16 (TRIM16) and microtubule-associated protein light chain 3B (LC3B) were examined in human and rat disc tissues by histology and immunofluorescence. The effects of TRIM16 expression level on IL-1β secretion were examined in THP-1 cells transfected with TRIM16 plasmid or siRNA using ELISA, immunofluorescence, and immunoblotting. The in vitro effects of MR409 on IL-1β were examined in THP-1 cells and primary rat NP cells using ELISA, immunofluorescence, immunoblotting, and qRT-PCR. Further, MR409 was subcutaneously administered to aged mice to test its efficacy against disc degeneration using immunofluorescence, X-ray, micro-CT, and histology. To achieve controllable MR409 release for intradiscal use, MR409 was encapsulated in an injectable ROS-responsive thermosensitive hydrogel. Viscosity, rheological properties, release profile, and biocompatibility were evaluated. Thereafter, therapeutic efficacy was assessed in a needle puncture-induced rat model of disc degeneration at 8 and 12 weeks post-operation using X-ray, magnetic resonance (MR) imaging, histological analysis, and immunofluorescence. Results: Secretory autophagy-related proteins TRIM16 and LC3B were robustly upregulated in degenerated discs of both human and rat. Moreover, while upregulation of TRIM16 facilitated, and knockdown of TRIM16 suppressed, secretory autophagy-mediated IL-1β secretion from THP-1 cells under oxidative stress, MR409 inhibited ROS-induced secretory autophagy and IL-1β secretion by THP-1 cells as well as IL-1β-induced pro-inflammatory and pro-catabolic effects in rat NP cells. Daily subcutaneous injection of MR409 inhibited secretory autophagy and ameliorated age-related disc degeneration in mice. The newly developed ROS-responsive MR409-encapsulated hydrogel provided a reliable delivery system for controlled MR409 release, and intradiscal application effectively suppressed secretory autophagy and needle puncture-induced disc degeneration in rats. Conclusion: Secretory autophagy and associated IL-1β secretion contribute to the pathogenesis of disc degeneration, and MR409 can effectively inhibit this pathway. The ROS-responsive thermosensitive hydrogel encapsulated with MR409 is a potentially efficacious treatment for disc degeneration.

The aim of the research was to evaluate the dynamic changes of early posthatch starvation on residual yolk absorption, synthesis of macronutrients (protein, lipid, and glycogen), and organ development in broiler chicks. A total of 720 1-day-old chicks (Lingnan Yellow) were randomly assigned to 3 treatments: group A (nonfasted), group B (fasting for 24 h after placement), and group C (fasting for 48 h after placement). The trial lasted for 168 h, and water was provided ad libitum all the time. Sampling was performed at 0, 24, 48, 72, 120, and 168 h. Nonfasting (group A) promoted (P < 0.05) the absorption of amino acids, fatty acids, mineral elements, protein, and maternal antibody in the residual yolk of broiler chicks. The concentration of insulin-like growth factor 1 in plasma and the liver was higher (P < 0.05) in group A. Nonfasting enhanced (P < 0.05) the synthesis of protein and glycogen in the breast muscle and liver; the relative weights of the liver, pancreas, and spleen; and body weight, but retarded (P < 0.05) the synthesis of triglyceride in the liver. The results indicated that nonfasting (group A) after placement promoted the absorption of residual yolk and synthesis of protein and glycogen in the breast muscle and liver, whereas early feed deprivation promoted the synthesis of lipid in the liver. Thereby, nonfasting after placement promoted organ development and body growth of broiler chicks.

Uterine corpus endometrial carcinoma (UCEC) is often diagnosed at an early clinical stage based on abnormal vaginal bleeding. However, the prognosis of UCEC is poor. The present study was conducted to identify novel tumor grade-related genes with the potential to predict the prognosis and progression of UCEC. A total of three gene expression microarray datasets were downloaded from the Gene Expression Omnibus database, and one RNA-sequencing dataset with corresponding clinical information of patients with UCEC was obtained from The Cancer Genome Atlas database. In summary, 1,447 differentially expressed genes (DEGs) were identified between endometrial cancerous tissues and normal endometrial tissues. Weighted gene co-expression network analysis was performed to assess the associations between DEGs and clinical traits. In total, five genes were found to be highly associated with the tumorigenesis and prognosis of UCEC. Among them, BUB1 mitotic checkpoint serine/threonine kinase B, cyclin B1, cell-division cycle protein 20 and non-SMC condensing I complex subunit G were involved in cell cycle regulation pathways, and DLG-associated protein 5 was involved in the Notch receptor 3 signaling pathway based on functional enrichment analyses. Of the five genes, four were highly expressed in endometrial cancerous tissues compared with normal endometrial tissues at the protein level. In addition, the higher expression of these genes predicted a higher tumor grade and worse overall survival. In conclusion, the present study revealed a 5-gene signature that can be used to predict the progression of UCEC.

Objective: Nonsyndromic cleft lip and/or cleft palate (NSCL/P) is an isolated phenotype of orofacial clefts with skewed sex ratio in prevalence. This study aims to identify differentially expressed genes (DEGs) and microRNAs (DEMs) of NSCL/P by integrated bioinformatics analysis, revealing mechanisms for sexual dimorphism in prevalence. Materials and Methods: First, we downloaded the expression profile data from Gene Expression Omnibus database to identify DEGs and DEMs. Second, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses performed DEGs’ functions. Then, clustered DEGs were identified through protein–protein interaction networks. Combining clustered DEGs with key genes searched in GeneCards enlarged NSCL/P-related genes. Moreover, the genes were linked by transcription factors (TFs). Subsequently, connected by the above TFs, DEMs and genes were used to establish the miRNA-TF-messenger RNA (mRNA) regulatory networks. Results: The DEGs in sex-ignored group, female-only group, and male-only group were obtained, respectively. Among the DEMs, miR-378 was downregulated in females but upregulated in males. In female-only group, the miRNA-TF-mRNA regulatory networks showed miR-378-SP1-POLE2/CDK6/EZR regulatory axis was found to be key candidates of NSCL/P. Conclusions: Our findings suggest that different expression of miR-378 is consistent with the skewed sex ratio in the prevalence of NSCL/P.

Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ in their clinical and molecular features. An investigation of differentially expressed genes (DEGs) between RCC and LCC could contribute to targeted therapy for colon cancer, especially RCC, which has a poor prognosis. Here, we identified HOXB13, which was significantly less expressed in RCC than in LCC and associated with prognosis in RCC, by using 5 datasets from the Gene Expression Omnibus (GEO). Tissue sample analysis showed that HOXB13 was differentially expressed between normal and only RCC tumor tissues. HOXB13 inhibited colon cancer cell proliferation and induced apoptosis both in vitro and in vivo. Furthermore, we found that HOXB13 might be regulated by DNMT3B and suppress C-myc expression to exert antitumor effects via β-catenin/TCF4 signals in RCC. In conclusion, the current study is the first to demonstrate that HOXB13 has a tumor-suppressive effect in RCC. High expression levels of HOXB13 are associated with prolonged overall survival in patients with RCC. The DNMT3B-HOXB13-C-myc signaling axis might be a molecular target for the treatment of RCC.

We report the synthesis and characterization of a new bulk form fluoride-antimonide diluted magnetic semiconductor SrF( Zn 1 - 2 x Mn x Cu x )Sb with ZrCuSiAs-type structure, which is the same quasi-two-dimensional crystal structure as that of 1111-type iron-based superconductors. Doping only Cu into the parent compound SrFZnSb does not induce any type of magnetic ordering. Only when Mn and Cu are codoped into Zn sites, where Mn substitution for Zn and Cu substitution for Zn introduce spins and carriers, respectively, can ferromagnetic ordering form. Bulk form samples SrF( Zn 1 - 2 x Mn x Cu x )Sb with x = 0.05, 0.075, 0.10 and 0.15 exhibit ferromagnetic transition, with highest T C ∼ 40 K for the doping level of x = 0.10. Iso-thermal magnetization measurements show that they have a relatively larger coercive field ∼ 8000 Oe. The electrical resistivity measurements indicate that SrF( Zn 1 - 2 x Mn x Cu x )Sb DMSs display semiconducting behavior, with the negative magneto-resistance effect up to 27% under 9 T at 2 K.

Supplemental material, sj-pdf-1-sgo-10.1177_2158244020988542 for Effects of an Innovative Training Program for New Graduate Registered Nurses: A Comparison Study by Fengqin Xu, Liang Ma, Yinhe Wang, Jiang Yu, Dandan Li, Guohui Zhou, Yuzi Xu, Hailin Zhang and Yang Cao in SAGE Open

Background: Coronavirus disease 2019 (COVID-19) has spread globally and resulted in the COVID-19 pandemic worldwide. To depict the psychological and behavioral responses, and knowledge of nursing interns who are facing the COVID-19 epidemic in China, we conducted a knowledge, attitude, and practice (KAP) survey using a convenience sample in the First People’s Hospital of Lianyungang, Kangda College of Nanjing Medical University, Jiangsu Province, China.Methods: A combination of a face-to-face questionnaire survey and an online survey was used for nursing interns from 12 Chinese universities. The Symptom Checklist 90 was used to investigate anxiety and depression of the nursing interns during the COVID-19 epidemic. Self-designed questionnaires were used to investigate behavioral responses, COVID-19-related knowledge, and preventive measures.Results: During the COVID-19 epidemic, the mean score of anxiety of 237 surveyed nursing interns were not statistically significantly different with that of the Chinese norm (1.42 vs. 1.39, P = 0.354). However, the mean score of depression of them were lower than that of the Chinese norm (1.22 vs. 1.50, P 94%), however less knowledge regarding treatment and incubation (correct percentage Conclusion: The nursing interns showed relative lower depression in the face of COVID-19 public health emergencies, and took proper preventive measures during the epidemic, however, were lack of certain epidemiology knowledge about COVID-19.

Head and neck squamous cell carcinoma (HNSCC) is one of the most malignant cancers with poor prognosis worldwide. Emerging evidence indicates that competing endogenous RNAs (ceRNAs) are involved in various diseases, however, the regulatory mechanisms of ceRNAs underlying HNSCC remain unclear. In this study, we retrieved differentially expressed long non-coding RNAs (DElncRNAs), messenger RNAs (DEmRNAs) and microRANs (DEmiRNAs) from The Cancer Genome Atlas database and constructed a ceRNA-based risk model in HNSCC by integrated bioinformatics approaches. Functional enrichment analyses showed that DEmRNAs might be involved in extracellular matrix related biological processes, and protein–protein interaction network further selected out prognostic genes, including MYL1 and ACTN2. Importantly, co-expressed RNAs identified by weighted co-expression gene network analysis constructed the ceRNA networks. Moreover, AC114730.3, AC136375.3, LAT and RYR3 were highly correlated to overall survival of HNSCC by Kaplan–Meier method and univariate Cox regression analysis, which were subsequently implemented multivariate Cox regression analysis to build the risk model. Our study provides a deeper understanding of ceRNAs on the regulatory mechanisms, which will facilitate the expansion of the roles on the ceRNAs in the tumorigenesis, development and treatment of HNSCC.

Supplementary_Figures for Distinct Expression of miR-378 in Nonsyndromic Cleft Lip and/or Cleft Palate: A Cogitation of Skewed Sex Ratio in Prevalence by Yuzi Xu, Binbin Xie, Jue Shi, Jia Li, Chuan Zhou, Wei Lu, Fengqin Xu and Fuming He in The Cleft Palate-Craniofacial Journal

Clear cell renal cell carcinoma (ccRCC) is a major histological subtype of renal cell carcinoma and can be clinically divided into four stages according to the TNM criteria. Identifying clinical stage-related genes is beneficial for improving the early diagnosis and prognosis of ccRCC. By using bioinformatics analysis, we aim to identify clinical stage-relevant genes that are significantly associated with the development of ccRCC. First, we analyzed the gene expression microarray data sets: GSE53757 and GSE73731. We divided these data into five groups by staging information—normal tissue and ccRCC stages I, II, III, and IV—and eventually identified 500 differentially expressed genes (DEGs). To obtain precise stage-relevant genes, we subsequently applied weighted gene coexpression network analysis (WGCNA) to the GSE73731 dataset and KIRC data from The Cancer Genome Atlas (TCGA). Two modules from each dataset were identified to be related to the tumor TNM stage. Several genes with high inner connection inside the modules were considered hub genes. The intersection results between hub genes of key modules and 500 DEGs revealed UBE2C, BUB1B, RRM2, and TPX2 as highly associated with the stage of ccRCC. In addition, the candidate genes were validated at both the RNA expression level and the protein level. Survival analysis also showed that 4 genes were significantly correlated with overall survival. In conclusion, our study affords a deeper understanding of the molecular mechanisms associated with the development of ccRCC and provides potential biomarkers for early diagnosis and individualized treatment for patients at different stages of ccRCC.

A three-dimensional (3D) reduced graphene oxide–Mn3O4 nanosheet (Mn3O4@rGO) hybrid was achieved by simple electrodeposition technique. Small palladium nanoparticle were homogeneously anchored onto Mn3O4@rGO substrate through the reduction of palladium salt. The interpenetrating network architecture of Mn3O4@rGO greatly inhibited the aggregation of 2D sheets of Mn3O4 and rGO, and the open 3D orientation of the Mn3O4@rGO hybrid nanosheets on the electrode facilitated both mass transport and electron transfer as well as maximally exposed active sites. The introduction of Mn3O4 enhanced the structural and electrochemical stability of rGO. The as-synthesized Pd/Mn3O4@rGO hybrid was employed as an electrocatalyst for electrocatalytic hydrogen evolution reaction (HER). The electrocatalyst showed a low overpotential of 20 mV at 10 mA cm−2, a small Tafel slope of 48.2 mV dec−1, and a large exchange current density of 0.59 mA cm−2. Importantly, the catalyst possessed superior durability with 85.87% of catalytic activity after a long-time test (10 h). This work presents a simple and efficient stratagy to construct high-performance electrocatalysts for energy and environmental applications.

Meniscal injury is one of the most common knee joint injuries, which remains an intractable challenge in clinical practice to date. Aberrant epidermal growth factor receptor (EGFR) activation levels in both human and mice menisci following injury, prompted us to investigate the functional role of EGFR by utilizing an inducible cartilage-specific EGFR-deficient mouse model. We demonstrated that conditional EGFR deletion in mice resulted in increased partial meniscectomy-induced ECM production within the meniscus, which is comparable to utilization of the small molecule EGFR inhibitor, gefitinib, to block EGFR activity. Here, we combined intra-articular delivery of gefitinib with an implanted customized collagen scaffold to substitute for lost meniscal tissue, as well as to promote meniscal regeneration and prevent osteoarthritis (OA) progression in a rabbit meniscectomy model. Statement of Significance The main novelty of this study is the finding of a new application for small molecule EGFR inhibitor in meniscal injury therapy. This study also highlights the importance of using a customized collagen scaffold to provide robust mechanical strength and effectively promote meniscus regeneration. In summary, our study finds that intra-articular delivery of gefitinib together with implantation of a customized, multi-layer collagen scaffold not only enhanced meniscal regeneration, but also protected articular cartilage from degeneration in rabbit model. These results provide valuable insight for meniscal tissue engineering studies and clinical practice.

The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.

Objectives This study aimed to reveal the regulatory roles of microRNAs in head and neck squamous cell carcinoma (HNSCC) through comprehensive ceRNA, miRNA-transcription factor (TF)-hub gene network and survival analysis. Materials and methods Expression analysis was performed using the 'edgeR' package based on The Cancer Genome Atlas database. The ceRNA network was screened by intersecting prediction results from miRcode, miRTarBase, miRDB and TargetScan. GSE30784, GSE59102 and GSE107591 from the Gene Expression Omnibus repository were chosen for cross-validation. Hub genes were identified using a protein-protein interaction network constructed by Search Tool for the Retrieval of Interacting Genes. The Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TTRUST) was utilized to map the miRNA-TF-Hub gene network. Patient overall survival was analyzed using the ‘survival’ package in R. Structural and functional analysis of miR-204/211 was based on miRbase and RNAstructure. Results A ceRNA network of 178 lncRNAs, 19 miRNAs and 55 mRNAs was generated, and a TF regulatory network with 11 miRNAs, 11 TFs and 18 hub genes was constructed from the 52 hub genes identified through the protein–protein interaction (PPI) network. Survival analysis demonstrated that the dysregulated expression of 11 lncRNAs and 14 mRNAs was highly related to overall survival. Furthermore, miR-204 and miR-211 were significantly involved in the network with identical mature structures, indicating them as key miRNAs in HNSCC. Conclusion This study reveals the comprehensive molecular regulatory networks centralized by miRNAs in HNSCC and uncovers the crucial role of miR-204 and miR-211, which may become potential diagnostic and therapeutic targets.

Introduction. Nurses play an important role in caring for dying patients. However, little is known about the attitude towards death of the registered nurses in China. Materials and Methods. A knowledge, attitude, and the practice (KAP) survey using standardized questionnaires was conducted at eight teaching hospitals in Jiangsu Province, China. In total, 366 nursing interns were recruited and 357 turned in valid response. Data about the interns’ demographic characteristics and their attitudes to death in five domains, including fear of death, death avoidance, natural acceptance, approach acceptance, and escape acceptance, were collected. Results. Compared to the norms, the nursing interns had statistically significantly higher scores in the domains death avoidance, approach acceptance, and fear of death (14.9 vs. 11.1, 26.2 vs. 24.2, and 20.3 vs. 19.0, respectively); however, statistically significantly lower scores were in the domains natural acceptance and escape acceptance (18.4 vs. 22.0, and 13.6 vs. 15.1, respectively). Religious belief, experience of a deceased relative in family, death education, and family atmosphere of discussing death are positively associated with one or more domains of attitude towards death. Conclusion. The positive attitude towards death and death education before clinical practice are helpful for nursing interns when they care for dying patients. In general, the scores of attitude towards death are at a moderate level in the surveyed Chinese nursing interns. The death education for nursing students needs to be reinforced in China.

Background: Osteoarthritis (OA) is a complex and heterogeneous condition, and one of the most common degenerative joint diseases. A standardized OA classification based on molecular criteria has yet to be defined. We performed transcriptomic profiling to determine the different molecular signatures associated with knee OA phenotypes. Methods: Five centres clinical research with next-generation sequencing was carried out using 201 samples from patients with knee osteoarthritis. Transcriptomic analysis and unsupervised clustering methods were performed on 131 cartilage samples. To investigate tissue crosstalk of the whole knee microenvironment, transcriptomic analysis was performed in 60 synovia and 65 subchondral bone samples. Findings: We identified four OA subgroups with distinct biological signatures: 1) the glycosaminoglycan metabolic disorder subgroup highly expressed ACAN, lowly expressed VCAN, and was enriched with glycosaminoglycan metabolic functions; 2) the collagen metabolic disorder subgroup presented with osteophyte formation, highly expressed COL1A1 and COL6A1, and was enriched with collagen catabolic functions; 3) the sensory neurons activated subgroup highly expressed GRIK2 and GRM7, and was enriched with synapse assembly functions; and 4) the immunogenic subgroup presented with high inflammation and narrow joint space, highly expressed IL1AŸ and CD34, and was enriched with immune responses. We also explored immune cell composition and tissue crosstalk for three identified metabolic disorder subgroups. Interpretation: These findings challenge the classical diagnosis model based on medical imaging, revealing distinct molecular subgroups in knee OA patients, and opening the door to precision diagnosis and treatment of OA. Funding Statement: This work was financially supported by the National Key R&D Program of China (2017YFA0104902), the National Natural Science Foundation of China (81630065, 31830029, 81802195) grants and China Postdoctoral Science Foundation (2017M621913). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Informed consent was obtained from all the participants. The study was approved by the local clinical ethics committees of Zhejiang University School of Medicine and the affiliated hospital of Wenzhou Medical University (2017KYLL11).

New graduate registered nurses (NGRNs) face great challenge during the transition from school to clinical practice. The aim of the study is to evaluate the effects of a new training mode for newly recruited NGRNs in a Chinese teaching hospital. This is a quasi-randomized controlled study. One hundred and fifty NGRNs were randomly selected from a teaching hospital and assigned into two groups. The conventional training and a new training program were taken for the control group and the research group respectively. At the end of training, the two groups were evaluated and compared for theoretical knowledge and operation skills using a self-assessment questionnaire and the Chinese Registered Nurse Core Competency Scale. The theoretical knowledge (88.4 vs. 81.7, p< 0.001), operation skills (94.8 vs. 90.3, p< 0.001), and total core competencies scores (156.2 vs. 148.8, p< 0.05) in the research group were significantly higher than those in the control group. Compared to the control group, the research group had statistically significantly higher scores in education and consultation (2.47 vs. 2.40), clinical nursing (2.87 vs. 2.62), interpersonal relationship (2.56 vs. 2.43), and critical thinking and scientific research (2.78 vs. 2.61). The innovative pre-job training program for NGRNs conducted in Chinese clinical nursing skill training bases could significantly improve the training effect and is worthy of broader implementation.

A new hierarchical nanoarchitecture with integration of multiple active materials has been developed for highly efficient hydrogen evolution reaction (HER), by decorating a perpendicular hybrid of MoS2 and N-doped graphene nanosheets with CdS nanoparticles. The unique architecture promoted light trapping and absorption for highly efficient light harvesting and photocarrier generation, and offered an unblocked electron transport pathway for rapid charge separation/transport to suppress charge recombination. Its high surface area and high density of active sites result in highly efficient utilization of photogenerated carriers for productive HER. Significantly, without using noble metals as co-catalysts, the photocatalysts demonstrated rapid HER rates as high as 5.01 mmol h−1 g−1 under visible-light irradiation, which was approximately 25 times that of pure CdS. The hydrogen production remained stable after a continued test for 30 h, showing an exceedingly high performance and superior stability.

The scrupulous design and integration of multiple active materials into hierarchical nanoarchitectures is essential for the creation of photocatalytic hydrogen evolution reaction (HER) system that can mimic natural photosynthesis. Here we report the design and preparation of a “cauline leaf”-like structure for highly efficient HER, by decorating TiO2 nanofibers with vertical arrays of atomically-thin MoS2 nanosheets and CdS nanocrystals. The unique integrated “cauline leaf” design can promote light trapping and absorption for highly efficient light harvesting and photocarrier generation, and offer unblocked electron transport pathway for rapid charge separation/transport to suppress charge recombination, as well as high surface area and high density of active sites for highly efficient utilization of photo-generated carriers for productive HER. Structural characterizations by transmission electron microscopy show well-integrated nanoarchitectures. Significantly, photocatalytic studies demonstrate rapid HER rates as high as 12.3 or 6.2 mmol h−1 g−1 under simulated solar light or visible light irradiation, with apparent quantum efficiencies of 70.5% at 365 nm or 57.6% at 420 nm, and excellent long term stability, representing one of the best reported MoS2 hybrid HER photocatalysts. The study could open new opportunities for the rational design of nanoscale architectures for HER or other application.

It is challenging to prepare monolayer MoS2 with activated basal planes in a simple and efficient way. In this study, an interlayer spacing expanded counterpart, ammonia-intercalated MoS2, was obtained by a simple hydrothermal reaction of ammonium molybdate and elemental sulfur in hydrazine monohydrate solution. Then, the ammonia-intercalated MoS2 could be easily exfoliated by ultrasonication to get monolayer MoS2. Importantly, this monolayer MoS2 possessed rich S vacancies. The produced MoS2 demonstrated a proliferated active site density as well as low-loss electrical transport for efficient electrochemical hydrogen production from water. As expected, the monolayer MoS2 with S vacancies exhibited an excellent electrocatalytic hydrogen evolution reaction performance with a low overpotential (at 10 mA cm−2) of 160 mV (V vs. RHE) in acid media and a small Tafel slope of 54.9 mV dec−1. Furthermore, the catalyst displayed a good long-term stability and chemical stability during the electrochemical hydrogen production process. Computational studies prove that the S vacancies enabled the inert basal planes by introducing localized donor states into the bandgap and lowered the hydrogen adsorption free energy. This study could open new opportunities for the rational design and a better understanding of structure–property relationships of MoS2-based catalysts for water splitting or other applications.

Three-dimensional (3D) network-like graphitic carbon nitride nanobelts (g-C3N4 NBs) were facilely achieved by the hydrothermal treatment of bulk g-C3N4 in a medium strong oxalic acid solution (1 M, pH 0.89). The positions of the conduction band (CB) and valence band (VB) were upraised from −0.90 and +1.86 eV for bulk g-C3N4 to −0.92 and +1.92 eV for g-C3N4 NB networks with enhanced redox ability, respectively. With an optimized Pt loading of 3%, the g-C3N4 NB networks showed excellent visible-light photocatalytic H2 production activity (1360 μmol g−1 h−1), which was 10.9 times higher than that of optimized 2% Pt@bulk g-C3N4 (124.7 μmol g−1 h−1) using triethanolamine as a sacrificial agent. Furthermore, Pt@g-C3N4 NBs exhibited a considerable rate of H2 evolution of 33.3 μmol g−1 h−1, much higher than 1.79 μmol g−1 h−1 for Pt@bulk g-C3N4 in distilled water without any sacrificial agents, revealing a great potential for photocatalytic overall water splitting. This outstanding performance not only originates from its unique 3D nanostructure and prolonged electron lifetime, but also from the electronic structure modulation and improved redox capacities of the CB and VB. The pH effect of hydrothermal conditions on the g-C3N4 molecular structure, chemical elements, optical properties and catalytic performance is also expounded. This study demonstrates a facile and environmentally friendly strategy to design highly efficient g-C3N4 catalysts for potential applications in solar energy driven photocatalytic water splitting.

Colorectal cancer (CRC) is one of the most common malignant tumors and its development involves multi‑gene driven processes that affect the digestive system. The objective of this study was to identify tumorigenesis‑associated gene signatures using microarray expression profiling data. The gene expression profiling of GSE39582, a dataset containing 566 colon cancer samples and 19 non‑tumoral colorectal mucosae was downloaded from Gene Expression Omnibus (GEO) database. A total of 439 differentially expressed genes (DEGs) were extracted by GEO2R. Many of these DEGs were cancer‑related, involved in the regulation of cell proliferation, extracellular matrix (ECM)‑receptor interaction and phosphatidylinositol 3‑kinase (PI3K)‑Akt signaling pathway according to the results of pathway enrichment analysis in Database for Annotation, Visualization and Integrated Discovery (DAVID). Then, 10 genes were predicted to play an important role in the development of CRC. Transient receptor potential cation channel, subfamily M, and member 6 (TRPM6), a member of 10 hub genes, was confirmed to be downregulated in 16 (80%) of 20 colon cancer tissues using quantitative polymerase chain reaction (qPCR) technology. Furthermore, high expression of TRPM6 was indicative of a prolonged overall survival (OS) in CRC patients through the analysis of GSE39582. Hsa‑let‑7g and hsa‑let‑7f‑1 were believed to be the regulatory miRNAs of TRPM6 by TCGA and miRanda database. In conclusion, this study may play a critical role in promoting the discovery of potential targets for diagnosis, treatment and prognosis of CRC.

Chemoresistance is a significant factor associated with poor outcomes of osteosarcoma patients. The present study aims to identify Chemoresistance-regulated gene signatures and microRNAs (miRNAs) in Gene Expression Omnibus (GEO) database. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) included positive regulation of transcription, DNA-templated, tryptophan metabolism, and the like. Then differentially expressed genes (DEGs) were uploaded to Search Tool for the Retrieval of Interacting Genes (STRING) to construct protein-protein interaction (PPI) networks, and 9 hub genes were screened, such as fucosyltransferase 3 (Lewis blood group) (FUT3) whose expression in chemoresistant samples was high, but with a better prognosis in osteosarcoma patients. Furthermore, the connection between DEGs and differentially expressed miRNAs (DEMs) was explored. GEO2R was utilized to screen out DEGs and DEMs. A total of 668 DEGs and 5 DEMs were extracted from GSE7437 and GSE30934 differentiating samples of poor and good chemotherapy reaction patients. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform GO and KEGG pathway enrichment analysis to identify potential pathways and functional annotations linked with osteosarcoma chemoresistance. The present study may provide a deeper understanding about regulatory genes of osteosarcoma chemoresistance and identify potential therapeutic targets for osteosarcoma.

The catalytic activity of molybdenum sulfide (MoS 2 ) for hydrogen evolution reaction (HER) strongly depends on the number of exposed active edges of MoS 2 nanosheets. Making single or few-layer MoS 2 nanosheets vertically stand on a substrate is a very effective way to maximally expose the edge sites of MoS 2 nanosheets. Vertically standing single or few-layer MoS 2 nanosheets on porous TiO 2 nanofibers (TiO 2 @MoS 2 ) are successfully prepared via a simple hydrothermal reaction. Due to plenty of pores in the electrospun TiO 2 nanofibers, the MoS 2 nanosheets vertically grow from the inside to the outside, and the growth mode of the MoS 2 nanosheets rooting into the TiO 2 nanofibers endows not only intimate contact between TiO 2 and MoS 2 for fast electrons transfer but also high structural stability of TiO 2 @MoS 2 heterostructure. The vertical orientation of MoS 2 nanosheets enables the active edge sites of MoS 2 to be maximally exposed. Without using Pt cocatalyst, the TiO 2 @MoS 2 heterostructure achieves high photocatalytic hydrogen production rates of 1.68 or 0.49 mmol h −1 g −1 under UV–vis or visible light illumination, respectively. This high photocatalytic activity arises from the positive synergetic effect between the MoS 2 and TiO 2 components in this novel heterostructure. In addition, the TiO 2 @MoS 2 heterostructure exhibits a high durability as evidenced by the invariable hydrogen production rate after continuous illumination over 30 h. The work advances the development of highly efficient molybdenum sulfide-based HER catalysts.

Intervertebral disc (IVD) degeneration is one of the most widespread musculoskeletal diseases worldwide, which remains an intractable clinical challenge. The aim of this study is to investigate the therapeutic potential of the small molecule gefitinib (an epidermal growth factor receptor (EGFR) inhibitor) in ameliorating IVD degeneration. Aberrant EGFR activation levels were detected in both human and rat degenerative IVDs, which prompted us to investigate the functional roles of EGFR by utilizing inducible cartilage-specific EGFR-deficient mice. We demonstrated that conditional EGFR deletion in mice increased nucleus pulposus (NP) extracellular matrix (ECM) production and autophagy marker activation while MMP13 expression decreased. These outcomes are comparable to the use of a controlled-release injectable thermosensitive hydrogel of gefitinib to block EGFR activity in a puncture-induced rat model. We also conducted a case series study involving patients with non-small cell lung cancer and IVD degeneration who received gefitinib treatment from 2010 to 2015. Gefitinib-treated patients displayed a relative slower disc degenerating progression, in contrast to control subjects. These findings thus provide evidence that suppression of EGFR by the FDA-approved drug gefitinib can protect IVD degeneration in rats, implying the potential application of gefitinib as a small molecule drug for treating IVD degeneration.

Previous investigation demonstrated that oral administration of ginseng stem-leaf saponins in chickens could enhance the immune response. The present study was designed to evaluate the effects of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred and twenty chickens were randomly divided into 5 groups. Groups 1 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress while group 5 was injected with saline solution and served as control. Following administration of cyclophosphamide, groups 1 to 3 were orally administered ginseng stem-leaf saponins at 2.5, 5, and 10 mg/kg BW in drinking water for 7 d, respectively. After that, the spleen, thymus, bursa, and serum were collected to measure the indices of the organs and oxidative parameters. The results showed that ginseng stem-leaf saponins significantly inhibited cyclophosphamide-induced oxidative stress by increasing the organ indices, total antioxidant capacity, and the levels of glutathione, ascorbic acid, and α-tocopherol, while elevating the activity of total superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the protein carbonyl content and malondialdehyde. Therefore, ginseng stem-leaf saponins could be a promising agent against oxidative stress in the poultry industry.