Search

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase–dependent ±1–base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.

Cardiovascular complications combined with COVID-19 (SARS-CoV-2) lead to a poor prognosis in patients. The common pathogenesis of ischemic cardiomyopathy (ICM) and COVID-19 is still unclear. Here, we explored potential molecular mechanisms and biomarkers for ICM and COVID-19. Common differentially expressed genes (DEGs) of ICM (GSE5406) and COVID-19 (GSE164805) were identified using GEO2R. We performed enrichment and protein–protein interaction analyses and screened key genes. To confirm the diagnostic performance for these hub genes, we used external datasets (GSE116250 and GSE211979) and plotted ROC curves. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed using cMAP. We identified 81 common DEGs, many of which were enriched in terms of their relation to angiogenesis. Three DEGs were identified as key hub genes (HSP90AA1, HSPA9, and SRSF1) in the protein–protein interaction analysis. These hub genes had high diagnostic performance in the four datasets (AUC > 0.7). Mir-16-5p and KLF9 transcription factor co-regulated these hub genes. The drugs vindesine and ON-01910 showed good binding performance to the hub genes. We identified HSP90AA1, HSPA9, and SRSF1 as markers for the co-pathogenesis of ICM and COVID-19, and showed that co-pathogenesis of ICM and COVID-19 may be related to angiogenesis. Vindesine and ON-01910 were predicted as potential therapeutic agents. Our findings will contribute to a deeper understanding of the comorbidity of ICM with COVID-19.

Patients with poliomyelitis underwent total hip arthroplasty (THA) are known to be at higher risk of dislocation on account of muscular atrophy. This study aimed to investigate clinical outcomes, radiographic outcomes, complication rates, and survivorship of dual mobility THA in displaced femoral neck fractures of elderly with poliomyelitis. We retrospectively included 17 patients (17 hips) with residual poliomyelitis who underwent THA with dual mobility articulation. Clinical outcomes were assessed with the visual analog scale (VAS) pain score, Oxford hip score, and University of California Los Angeles activity (UCLA) score. Radiographic outcomes were examined by radiographs. Complications and re-operations following THA were recorded. The mean follow-up period was 77.05 months. The mean VAS, Oxford hip score, and UCLA score were improved significantly. In all but one patient, no complications were occurred. Re-operation was carried out in one patient due to posterior dislocation. The Kaplan–Meier survivorship with an end point of re-operation for any reason was 94.1%. THA with dual mobility system is proved to be effective in strengthening stability and reducing the risk of dislocation, which is suitable for patients with neuromuscular disease. Hence, in elderly with residual poliomyelitis, dual mobility THA is a valid choice as a treatment for displaced femoral neck fractures.

Objective: To investigate the molecular mechanism and simulated validation of Zhi Bai Di Huang Pill (ZBDHP) for the treatment of systemic lupus erythematosus (SLE) using network pharmacology and molecular docking techniques. Methods: The active ingredients of ZBDHP were obtained through the TCMSP database and the Canonical SMILES of the active ingredients were queried through Pubchem. The targets of the active ingredients were predicted in the SwissTarget database based on the SMILES. The SLE-related disease targets were obtained through the GeneCards, OMIM and DisGenets databases, and the intersection targets of ZBDHP and SLE were obtained using the Venny 2.1.0 online platform. Intersection targets build a visual protein interaction network (PPI) through the STRING database, and the core targets were identified by network topology analysis. GO analysis and KEGG pathway enrichment analysis of the intersecting targets were performed using the DAVID database. Finally, the molecular docking of the first four active ingredients and the first four core target genes were verified by Pubchem, the PDB database and CB-Dock online molecular docking technology. Results: ZBDHP screened 91 potential active ingredients and 816 potential targets. Among them, 141 genes were intersected by ZBDHP and SLE. The network topology analysis showed that the main active ingredients were Hydroxygenkwanin, Alisol B, asperglaucide, Cerevisterol, etc., and the key target genes were TNF, AKT1, EGFR, STAT3, etc. GO and KEGG enrichment analysis showed that common targets interfere with biological processes or molecular functions such as signal transduction protein phosphorylation, inflammatory response, transmembrane receptor protein tyrosine kinase activity, etc., through multiple signaling pathways, such as pathways in cancer, Kaposi sarcoma-associated herpesvirus infection, the PI3K-Akt signaling pathway, lipid and atherosclerosis, hepatitis B, etc. Molecular docking results showed that the active components of ZBDHP have good binding activity to the core targets of SLE. Conclusions: This study reveals that the ZBDHP treatment of SLE is a complex mechanistic process with multi-components, multi-targets and multi-pathways, and it may play a therapeutic role in SLE by inhibiting the production, proliferation and apoptosis of inflammatory factors. In conclusion, the present study provides a theoretical basis for further research on ZBDHP.

Background: Qianghuo Shengshi decoction (QHSSD), a traditional Chinese medicine formula, is used to treat ankylosing spondylitis (AS) in China. The pharmacological mechanism of QHSSD for AS remains to be clarified. In this study, we investigated the molecular mechanisms of QHSSD in the treatment of AS using network pharmacology and molecular docking. Methods: To obtain the chemical components and potential targets of QHSSD, we used the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. AS potential targets were found in the GeneCards, OMIM, and DisGenets databases. A Venn diagram was used to screen QHSSD and AS common potential targets. The STRING website and Cytoscape software were used to create and analyze protein–protein interactions and component–target networks. The DAVID database was used for the gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was used to visualize drug–target interactions. Results: The component–target network consisted of 119 chemical components and 193 potential targets. QHSSD was implicated in various biological processes, such as inflammation and angiogenesis, and mediated multiple signaling pathways, such as the MAPK signaling pathway. Molecular docking revealed good binding ability between medicarpin, notoptol, vitetrifolin E, and cnidilin and EGFR, TNF-α, ALB, and VEGFA. Conclusions: The chemical compositions, potential targets, and pathways involved in the QHSSD treatment of AS were successfully predicted in this study. This study provides a solid foundation for the selection of drugs to treat AS.

This study aims to identify the core genes that influence the prognosis of colon cancer (CC) and analyze their relationships with clinical characteristics.The gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified. The top ten core genes were selected by bioinformatics tools and screened through the Oncomine database. The expression of core genes in CC tissues and cells was validated by immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. Spearman correlation was used to analyze the relationship between different parameters. Overall survival was assessed by the Kaplan-Meier method. The area under the curve (AUC) and the receiver operating curve (ROC) were applied to assess the accuracy of genes for predicting prognosis.There were 1,665 DEGs that were identified from TCGA database. Bioinformatics analysis found thatHigh levels of

Osteoarthritis (OA) is a chronic joint disease, which occurs in the elderly. The regulatory mechanisms of circRNAs were involved in the occurrence and development of various diseases. However, the potential regulatory network of circRNA in OA remains further research and clarification. The expression of circ_0114876 was increased in OA tissues and inhibition of circ_0114876 could induce cell viability and suppress inflammation as well as inhibit cell apoptosis in IL-1β induced CHON-001 cells. Circ_0114876 regulated TRAF2 expression via sponging miR-671 in CHON-001 cells. Down-regulated miR-671 expression could reverse the effects of low circ_0114876 expression on cell progression and inflammation in IL-1β induced CHON-001 cells. Overexpression of TRAF2 could weaken the promotion effects of high miR-671 expression on cell progression and inflammation in IL-1β induced CHON-001 cells. Circ_0114876 targeted miR-671 to regulate cell progression and inflammation via modulating TRAF2 expression in IL-1β induced CHON-001 cells, and played an important regulatory mechanism in IL-1β-induced chondrocyte injury, providing a novel diagnostics and therapeutics in OA.

To study the levels of inflammatory cytokines in synovia fluid from osteoarthritis (OA) patients with/without type 2 diabetes mellitus (T2D). Out of 74 volunteers aged 20–88 years, 64 with knee OA (Kellgren-Lawrence grades over I) were recruited and divided into groups with (n = 20) and without (n = 44) diabetes. The nucleic acid of the patient tissue was extracted by nanometer magnetic bead method. The remaining participants were the control group (n = 10). Synovia fluid, sera, and peripheral blood mononuclear cell (PBMC) samples were collected from all participants and analyzed using ELISA Kits. T2D-OA patients and OA patients had higher basal production of interleukin-1, (IL-1), interleukin-6 (IL-6), and lower-level interleukin-10 (IL-10). However, there were no differences between T2D-OA and OA patients. IL-1, IL-10, and IL-6 in peripheral blood mononuclear cells (PBMCs) after stimulation with LPS were obviously up-regulated in both patients and controls. The production of IL-1 and IL-6 in synovia from T2D-OA and OA patients increased as in the case of variations in sera and PBMCs. Both T2D-OA and OA patients had high-levels of IL-1 and IL-6 compared with controls, especially IL-6. The presence of IL-10 could not be detected in synovia from both patients and controls. Our results suggested that OA patient also had some pro-inflammatory factors in vivo, especially in local lesion; this manifest was particularly evident in T2D-OA patients. The high-level concentration of pro-inflammatory cytokines and low-level anti-inflammatory factors could be one of the reasons why T2D-OA patients are prone to developing synovitis.

The rock mass encountered in actual geotechnical engineering usually undergoes long-term digenesis and geological tectonic action, and also subjected to repeated actions of loading and unloading repeatedly. This paper aims to study the influence of excavation unloading on the stability of a rocky slope, and the slope excavation process of Jinping Grade I Hydroelectric Station was selected as a case, and the 2D finite element software PLAXIS was used to evaluate the effect for the slope stability of without considering unloading and considering unloading, including stress, safety factor, plasticdeformation zone and slip surface of the slope. The results show that the slope excavation unloading has a significant influence on the stress, stability safety factor, plastic deformation zone and slip surface, the stability of slope with considering unloading is far less than without considering unloading significantly. Therefore, the numerical method used to simulate the excavation of rocky slopes should consider the effect of unloading fully to service the engineering design and ensure the safety of engineering construction.

Introduction Internal fixation (IF) with cannulated screws is the most widely accepted operation method for nondisplaced femoral neck fractures (FNFs) in elderly patients. However, there were higher rate of reoperation, severe complications and poorer functional outcomes reported in these patients treated with IF. The purpose of this research is to compare the prognosis, complications, reoperation and mortality of bipolar hemiarthroplasty (HA) with IF of cannulated screws in elderly patients. Methods All elderly patients (>75 years of age) with nondisplaced FNFs from January 2010 to December 2015 at our institution were included in this study. Patients treated with HA and IF with cannulated screws were compared. Outcome measures included the surgical complications, perioperative parameters, hip joint function, reoperation and mortality. Results The blood loss of HA group (150.0 ± 55.1 mL) was statistically more than IF group (40.5 ± 15.7 mL, p = 0.001). However, the blood transfusion rate was similar between two groups (p = 0.102). At the last follow-up, there were total 14 (34.1%) severe surgical complications in the IF group, compared to 9 (10.1%) in the HA group (P = 0.001). No difference was detected between two groups with respect to the HHS and VAS at the last follow-up. Compared with the HA group, the IF group had much more reoperation in the follow up period (p = 0.001). There was no statistically differences of mortality rate between HA group (39.3%, 35/89) and IF group (34.1%, 14/41) (p=0.571). Conclusions As a treatment option for nondisplaced intracapsular FNFs in elderly patients, HA showed the merits of a less surgical complications and less reoperations, while IF demonstrated a shorter surgical time and less intraoperative blood loss. Meanwhile, there was no significant difference in the hip joint function and mortality rate in midterm follow-up. Further evaluation with a longer follow-up is recommended to strengthen these findings.

ObjectiveThis study aims to identify the core genes that influence the prognosis of colon cancer, and analyze their relationships with clinical characteristics. MethodsThe gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were identified. The top ten core genes were selected by bioinformatics tools, and screened through the Oncomine database. The expressions of core genes in colon cancer cells and tissues were validated by immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. Results There were 1665 DEGs that have been identified from the TCGA database. Bioinformatics analysis found that GNGT1, NMU, PPBP, AGT, and GNG4 were differentially expressed in colon cancer tissue. Over-expression of NMU, PPBP, AGT, and GNG4 in colon cancer was associated with shortened survival time (pConclusionsThe high levels of NMU, PPBP, and GNG4 were associated with poor prognosis in colon cancer. The combination prognostic model of these three genes could be a new option.

Background: FCN-437c is a second-generation CDK4/6 inhibitor. Phase 1b clinical results indicated improved antitumor activity in patients (pts) with HR+, HER2– advanced breast cancer (ABC), treated with FCN-437c + letrozole. Methods: This Phase 2, multicenter, open-label clinical study evaluated the antitumor activity, pharmacokinetics (PK), and safety of FCN-437c + fulvestrant in post-menopausal pts (Cohort 1, treatment-naïve or 2L), FCN-437c + letrozole + goserelin in pre-menopausal pts (Cohort 2, treatment-naïve). Pts received FCN-437c (200 mg QD) in a 21-day-on and 7-day-off schedule either in combination with fulvestrant (500 mg D1) or letrozole (2.5 mg QD) + goserelin (3.6 mg once per cycle) in 28-day cycles. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), PK, and safety. Results: At study cutoff (Feb 7, 2022), 36 pts were enrolled in Cohort 1 and 31 pts were in Cohort 2; 42 (62.7%) pts had visceral metastases and 9 (13.4%) pts had bone-only metastases. In Cohort 1, 18 pts were treatment-naïve, 15 pts had received 1L treatment, and 3 pts had received ≥2L treatment. In Cohort 2, 25 pts were treatment-naïve and 6 pts had received 1L treatment. Overall, 27 pts in the per-protocol set achieved partial response (PR), resulting in an ORR of 40.9% (95% CI, 29.0-53.7). Median follow-up was 12.8 months, and median PFS (mPFS), OS, and DOR were not reached. However, at 12 months, the PFS rate was 67.7% (95% CI, 53.2-78.6) and the OS rate was 95.9% (95% CI, 84.5-99.0); the 6-month DOR rate was 96.0% (95% CI, 74.8-99.4). In Cohort 1 (n=35), 11 pts achieved PR: the ORR was 31.4% (16.9-49.3%) and mPFS was 12.9 months (95% CI, 9.2-NR); the 6-month DOR rate was 100%. In Cohort 2 (n=31), 16 pts achieved PR: the ORR was 51.6% (95% CI, 33.1-69.9%). mPFS, OS, and DOR were not reached; the 6-month DOR rate was 92.9% (95% CI, 59.08-98.96) (Table). Treatment-emergent adverse events (TEAEs) were observed in all pts. Majority of AE were G1 or 2 except for hematological TEAE. 58 (86.6%) pts reported grade ≥3 TEAEs, mainly neutropenia (74.6%), leukopenia (49.3%), hypertriglyceridemia (6.0%), lymphocyte count decrease (4.5%), and γ-glutamyltransferase increase (3.0%): most were reversed through dose interruption and symptomatic therapy. Steady-state PK parameters were analyzed after 15-21 days of QD administration: Cohort 1: median Tmax was 3 h, geomean T1/2 was 44.6 h, geomean Cmax was 1650.7 ng/mL, and geomean AUC0-24h was 29,148.08 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 2.18 and 1.74, respectively, compared with first dose. Cohort 2: median Tmax was 4 h, geomean T1/2 was 35.7 h, geomean Cmax was 1314.34 ng/mL, and geomean AUC0-24h was 22,889.96 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 1.95 and 1.63, respectively, compared with first dose. Conclusion: FCN-437c in combination with fulvestrant or letrozole + goserelin demonstrates antitumor activity and safety and is well tolerated in pts with HR+, HER2– ABC. This combination therapy will be further investigated in 2 ongoing Phase 3 trials (NCT05438810 and NCT05439499). Clinical trial number: NCT05004142. Research Sponsor: Avanc Pharmaceutical Co., Ltd Table. Clinical outcomes for patients in the per-protocol set. Citation Format: JiaJie Shi, Wei Li, Zhongsheng Tong, Aimin Zang, Xiaohua Zeng, Shui Wang, Tao Huang, Ying Wang, Yanqiu Song, Lihua Kang, Zheng Lv, Yehui Shi, Hua Yang, Jing Wu, Yongmei Yin, Yan Liang, Jie Tan, Jie Ming, Yaping Yang, Simin Luo, Xiujuan Gui, Ai-Min Hui, Zhuli Wu, Ling Tian, Yuchen Yang, Lei Diao, Wenjing Zhang, Yongjiao Zhang, Yunjiang Liu. Phase 2 Study of the CDK4/6 Inhibitor FCN-437c in Combination With Fulvestrant or Letrozole and Goserelin in Patients With HR+, HER2– Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-21.

© 2021 Elsevier LtdBreast cancer is one of the frequently occurring malignant tumors in the world. Breast resection, high tumor recurrence rate and high dose chemotherapy cause great pain to patients. Is there a way to prevent tumor recurrence efficiently while promoting new tissue generation after tumor resection? Based on this, an injectable biocompatible thiolated chitosan (CSSH) hydrogel with pH-response was designed to be used for accurate treatment of tumor cells in the initial stage of tissue resection and for tissue reconstruction later. To improve the mechanical strength of hydrogels, reduce the toxic and side effects, and delay the release of doxorubicin (DOX), halloysite nanotubes (HNTs) were modified to obtain thiolated HNTs (HNTs-SH), then loaded DOX (DOX@HNTs-SH), and further cross-linked CSSH to form DOX@CSSH/HNTs-SH Gel. The results showed that HNTs-SH can be evenly dispersed in the gel matrix, which improve the compressive strength of the hydrogels. In vitro DOX release experiments showed that the hydrogels were pH sensitive, DOX released slowly at normal physiological pH, but released quickly in the acidic microenvironment of tumors. Cell experiments showed that DOX@CSSH/HNTs-SH Gel released DOX can be taken up by MCF-7, thereby effectively inhibited its growth. In vivo recurrence experiments showed that the carriers can reduce the toxic and side effects of DOX, and effectively inhibited the recurrence and repair the defect tissue after tumor resection. Therefore, the drug-loaded gel is expected to be used as a carrier for local accurate and effective drug release, especially for inhibiting recurrence and repairing defective tissues after tumor resection.

Background Performing postoperative laboratory tests following joint arthroplasty is a regular practice. However, the role of routine postoperative laboratory tests in primary hip arthroplasty is currently in doubt. This study aimed to assess the role of routine postoperative laboratory tests for femoral neck fractures in elderly patients who underwent hip hemiarthroplasty and to evaluate the risk factors for postoperative laboratory testing abnormalities and related interventions. Methods This retrospective study reviewed 735 consecutive patients with femoral neck fractures (FNFs) who underwent hip hemiarthroplasty at a single tertiary academic organization. Patient characteristic features and laboratory testing values were recorded. Logistic regression models were calculated to identify risk factors. Results A total of 321 elderly patients (> 75 years of age) were ultimately enrolled for analysis. Abnormal postoperative laboratory tests were found in 265 patients (82.6%). Only a minority of the included patients (7.5%) needed medical intervention to treat postoperative laboratory testing abnormalities. Multivariate logistic regression analysis reported that a higher Charlson comorbidity index (CCI) (P = 0.03), abnormal preoperative haemoglobin level (P P P = 0.05) were risk factors for abnormal postoperative laboratory tests. Furthermore, a higher CCI has been identified as a risk factor for patients needing clinical interventions related to laboratory abnormalities. Conclusions Because 92.5% of laboratory tests did not influence postoperative management, the authors suggest that routine laboratory tests after hip hemiarthroplasty for FNFs are less instructive for the majority of elderly patients. Nevertheless, for patients with identified risk factors, postoperative laboratory tests are still required to identify the abnormalities that need to be managed.

This paper uses the finite element analysis software COMSOL to build the models of short string and long string composite insulators and the typical defects of composite insulators are simulated. For the short string insulator, this paper designs the air gap of different positions with different dimensions, simulates the electric field of air gap. This paper also analyses the whole and local moisture of insulator mandrel, designs the different moisture degrees for the insulator mandrel. Meanwhile, the axial electric field at the mandrel - sheath interface is simulated by combining the moisture defects with the air gap defects.

Background The esophageal cancer patients with bone metastasis present with an extremely poor prognosis. The aim of this study was to establish a comprehensive insight into whether chemotherapy is justifiably being prescribed to esophageal cancer patients with bone metastasis. Methods A population-based retrospective study was conducted with data from the Surveillance, Epidemiology, and End Results (SEER) national database. By performing 1:1 paired match propensity score matching (PSM), we minimized the baseline discrepancies between groups. Univariate and multivariate Cox regression analyses were used to identify factors associated with survival. Kaplan–Meier survival curves were used to assess the effects of chemotherapy on survival. Results The final PSM cohort consisted of 730 patients, including 365 patients in the chemotherapy group and 365 patients in the non-chemotherapy group. There was a significant difference in overall survival (OS, p

In-vessel retention (IVR) is considered as an effective mitigation strategy in realms of nuclear safety. Extensive experimental investigations have been done on the natural convection characteristics of corium pools according to the IVR concept, using various simulant materials. Based on the known COPRA (Corium Pool Research Apparatus) molten salt experiments, in which the eutectic salt (50 mol% NaNO3-50 mol% KNO3) and the non-eutectic salt (20 mol% NaNO3-80 mol% KNO3) were used as simulant materials, this paper evaluates extensively the simulant effect of simulant material on natural convection behaviors inside the corium pools through numerical simulation. The Wall-Modeled LES (WMLES) method was employed for the turbulence calculation. The distributions of corium pool temperature and heat flux as well as the crust thickness from the numerical simulations were validated with experimental data. Through numerical simulations, this work provides detailed temperature fields and velocity fields inside a large internally heated corium pool, and further discusses in depth the interplay between the heat transfer characteristics and the natural convection behaviors. This work can provide references for the selection of simulant material in the future experimental research.

The short-term prediction of the electricity consumption of the distribution network during the peak summer period is of great significance to the safe and stable operation of the distribution network and to reduce the burden on the grid staff. This paper obtains and organizes the operating data of distribution transformers in a city in southern China, takes the active load rate as the electricity consumption index, and uses ARIMA and PCR models to make short-term electricity consumption prediction. The results show that ARIMA prediction results are significantly better than PCR. The research results of this paper have certain guiding significance for the actual work of distribution network.

Some anti-cancer drugs have poor solubility and availability, and are easily eliminated by rapid metabolism in vivo. To fix the drugs at the administration site and delay their release, a release platform with multi-level and multi-function was designed. The results showed that the curcumin (Cur) loaded liposomes (Cur@Lip) were coated sequentially with positive Chitooligosaccharides (Cur@Lip-Cos) and negative phospholipids (Cur@Lip-Cos-PC), to enhance water solubility, encapsulation efficiency, and delayed the release of the Cur, stability and cell intake of the liposomes, and the bioactivity of the system. The Cur@Lip-Cos could significantly enhance the inhibitory effect of MCF-7, better than the Cur@Lip-Cos-PC. The Lips were then fixed in an injectable thiolated chitosan hydrogel for local immobilization and sustained release which can effectively delay the release of Cur to inhibit MCF-7 growth. In summary, the innovative and biomimetic liposomal hydrogels are expected to provide more ideas for the design of drug carriers.

Adipose-derived stem cells are one of the potential sources of cells for the treatment of cartilage defects. This study aimed to investigate the molecular mechanisms that account for the chondrogenic differentiation of human adipose-derived stem cells (hADSCs). We employed integrin β1 (ITGB1) overexpression to induce chondrogenic differentiation of hADSCs. Next-generation sequencing was used to determine the mRNAs and circular RNAs (circRNAs) expression profiles in ITGB1-overexpresing and negative control cells. The potential functions of differentially expressed mRNAs were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Moreover, differentially expressed circRNAs with the greatest fold change were validated by polymerase chain reaction (PCR), Sanger sequencing, and quantitative real-time PCR (qRT-PCR). These three circRNAs and their downstream microRNAs and mRNAs were used to construct a circRNA-microRNA-mRNA interaction network. The results showed that we identified 713 differentially expressed circRNAs (150 upregulated and 563 downregulated in ITGB1-overexpressing hADSCs versus negative control cells, respectively). Meanwhile, 2383 mRNAs were differentially expressed between two groups (1672 upregulated and 711 downregulated in ITGB1-overexpressing cells compared with the negative control cells). The GO and KEGG analysis results showed that the differentially expressed mRNAs were enriched in biological processes, cellular components, and molecular functions, especially in the phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase signaling pathways. Three differentially expressed circRNAs, including hsa_circ_0071127, hsa_circ_0008637, and hsa_circ_0020028, were validated by qRT-PCR. Moreover, the circRNA-microRNA-mRNA network predicted that fibroblast growth factor 2 (FGF2) was a common node regulated by these three circRNAs through several microRNAs, including miR-195-3p, miR-205-3p, and miR-152-3p. We further found that the knockdown of hsa_circ_0020028, but not the two other circRNAs, significantly reduced FGF2 mRNA expression in hADSCs. Furthermore, the knockdown of hsa_circ_0020028 significantly inhibited the protein expression of FGF2, chondrogenic differentiation markers (COL II, aggrecan, and SOX9), and PI3K/AKT signaling in ITGB1-overexpressing hADSCs. This study uncovered the differentially expressed mRNA and circRNA profiles in the chondrogenic differentiation of hADSCs induced by ITGB1 overexpression. Our findings demonstrate that hsa_circ_0020028 regulates the ITGB1 overexpression-mediated chondrogenic differentiation of hADSCs through regulation of FGF2-related signaling pathways.

Samples from fifty-five surface water resources and twenty-five drinking water treatment plants in Europe, Africa, Asia, and USA were used to analyse the fluorescence composition of global surface waters and predict aromaticity and treatability from fluorescence excitation emission matrices. Nine underlying fluorescence components were identified in the dataset using parallel factor analysis (PARAFAC) and differences in aromaticity and treatability could be predicted from ratios between components H

Aging-related inflammation is tightly linked with the development of osteoarthritis (OA). As the pro-inflammatory cytokine, IL-1β has been associated with physical dysfunction and frailty. It is still elusive whether and how IL-1β blockade improves the outcome of OA. Here we develop a cationic solid lipid nanoparticles (SLNs) system that effectively mediate non-viral delivery of plasmid DNA (pDNA) into cells. Compared with other DNA transfer technologies including lipofetamin 2000, SLNs-pDNA system is less toxic and exerts identical effectiveness on DNA transfer. Loaded with integrin β1 overexpression pDNA, the SLNs-pDNA mainly localized in cytoplasm and enforced expression of integrin β1 in rat chondrocytes. Moreover, upon exposure to IL-1β stimulation, SLNs-pDNA treatment attenuates the apoptosis rat chondrocytes and augments tissue repair. Our data thus demonstrate that SLNs-pDNA functions as a potential therapeutic nanomedicine in the treatment of osteoarthritis.

Distribution transformers (DT) are the core equipment of distribution power network. During the operation of DT, the internal temperature distribution is not uniform. Hotspot temperature is the most representative parameter. It can reflect the temperature change and insulation aging rate of the DT to guide the actual operation. The hot-spot temperature can be calculated by building the thermal circuit model of transformers. Both the IEEE and IEC standards provide methods for building the thermal circuit model based on the top oil temperature rise and the bottom oil temperature rise. These thermal circuit models are all single-phase model. They assumed that there is no heat exchange for each phase of transformers when the three-phase load are same. However, these models are not applicable to the three-phase unbalanced transformers. The three-phase unbalanced operation of DT is unavoidable in practice. In order to solve this problem, a modified three-phase thermal circuit model for DT was proposed in this paper. It considered the influence of the three-phase unbalanced operation. It modified the traditional thermal circuit model which is based on the top oil temperature rise. The modified model was compared with the standard models through the actual examples. The results showed that the modified model proposed in this paper can reflect the hot-spot temperature of each phase for DT. Compared with the traditional thermal circuit models, the modified model considered the effect of three-phase unbalanced operation. It can accurately calculate the hot-spot temperature of the DT in theory.

Network reconfiguration is always used to find the optimal structure of a distribution network, with less power loss, higher power quality, and better load balancing. In this paper, optimal network reconfiguration using beetle antennae search based on the Prim algorithm is proposed to find the optimal structure of a distribution system. This problem can be formulated as a multi-objective optimization problem and beetle antennae search is used to solve it, applying Prim algorithm to make sure that a radial network structure would remain after reconfiguration and all loads would be energized. Roulette wheel selection is used in the path selection procedure to avoid trapping in local optimum. The proposed method is validated in a system. The results proved that the proposed method completes the integrated optimization of network reconfiguration and leads to significant reduction on the calculation amount and fast convergence, which is suitable for engineering application.

Due to the wide variety of 10kV distribution network equipment and the complex operating environment, various defects have emerged frequently. Because the distribution network is directly connected to users, the distribution network equipment defects will lead to the occurrence of distribution network failures if not processed in time, affecting the safe and stable operation of the power grid. In this paper, a genetic algorithm(GA)-based method is used to find useful association rules from the defect data set of distribution network equipment. In this method, genetic algorithm is used to avoid scanning transaction database multiple times and improve the efficiency of mining association rules. Moreover, the confidence factor is used to objectively measure the interest of the association rules without providing a minimum support threshold. In this paper, the defect association analysis of the main distribution equipment in a region is carried out, and the association results are obtained, which can help the maintenance personnel to find the family defects of the equipment and speculate the type of defects, providing support for the maintenance and repair of equipment.

Background The purpose of this study was to develop an optimal diabetes-osteoarthritis (DM-OA) mouse model to validate that diabetes aggravates osteoarthritis (OA) and to evaluate the microarchitecture, chemical composition, and biomechanical properties of subchondral bone (SB) as a consequence of the DM-OA-induced damage induced. Methods Mice were randomly divided into three groups: DM-OA group, OA group, and sham group. Blood glucose levels, body weight, and food intake of all animals were recorded. Serum calcium (Ca) and osteocalcin (OCN) levels were compared in the three groups. The messenger ribonucleic acid (mRNA) and protein expression of key regulators for bone metabolism were detected. A semi-quantitative grading system [Osteoarthritis Research Society International (OARSI)] was used to evaluate cartilage and SB degeneration. Microspectroscopy, microindentations, micro-computed tomography (CT) imaging, and fracture load of compression testing were also used to evaluate trabecular SB properties. Results Glycemic monitoring and pancreas pathological results indicated stable high blood glucose and massive destruction of pancreas and islet cells in the DM-OA group. Serum levels of bone specific alkaline phosphatase (ALP-B) and tartrate-resistant acid phosphatase 5b (TRACP-5b) in the DM-group were higher than those of the other two groups while levels of serum Ca and OCN were lower. Meanwhile, the protein and mRNA expression of osteoblast-specific biomarkers [osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio, collagen type I (COL-I), Runt-related transcription factor 2 (RUNX-2), OCN] were suppressed, and osteoclast-specific biomarkers [sclerostin (SOST)] was elevated in the DM-OA group. The mineral-to-collagen ratio, microindentation elastic modulus, hardness, micro-architectural parameters, bone mineral density, and fracture load of SB trabecular bone of the DM-OA group joint were lower than those of the other two groups. On the other hand, The OARSI score, trabecular spacing, and structural model index of the DM-OA group joint were higher than those of the other two groups. Conclusions The glycemic and pancreatic pathological results indicated that the DM-OA model was a simple and reliable model induced by streptozotocin (STZ) and surgery. The results revealed the mechanisms through which diabetes accelerates OA; that is, by damaging and deteriorating the functions of SB, including its microarchitecture, chemical composition, and biomechanical properties.

Background Knowledge regarding the pathogenesis of osteoarthritis (OA) is very limited. Previous studies have shown that matrix metalloproteinase (MMP) 8 and MMP9 were upregulated in patients with diabetic OA. However, their regulatory functions and mechanisms in diabetic OA are not fully understood. Methods Diabetic OA rats were constructed using a high-fat diet combined with streptozotocin (STZ) induction. Safranin O-Fast green staining was used to detect the pathological changes in rat knee cartilage. MMP8 and MMP9 overexpression vectors or siRNAs were injected into diabetic OA rats to overexpress or knockdown the expression of MMP8 and MMP9, which was verified by real-time quantitative PCR (RT-qPCR). The expression of MMP8 and MMP9, chondrocyte differentiation markers collagen type II alpha 1 (COL2A1) and collagen type I alpha 1(COL1A1), and antiapoptotic protein BCL2 were detected using immunohistochemistry (IHC), and the number of apoptotic cells was detected by the transferase-mediated d-UTP nick-end-labeling (TUNEL) assay. Results High-fat diet combined with STZ-induced rats exhibited joint cartilage damage, morphological changes, and increased expression of MMP8 and MMP9. Overexpression of MMP8 and MMP9 in the joint cavity further aggravated the pathological morphological changes, decreased the expression of COL2A1 and COL1A1, increased the expression of BCL2, and promoted cell apoptosis in diabetic OA rats. The use of siRNA to inhibit MMP8 and MMP9 levels in the cartilage joints significantly reversed the decrease in COL2A1 and COL1A1 expression and partially reversed BCL2 expression and chondrocyte apoptosis. Conclusion MMP8 and MMP9 promoted rat diabetic OA model. The underlying mechanism may be related to inhibiting cartilage differentiation and promoting chondrocyte apoptosis.

As a promising mitigation strategy, In-vessel-retention (IVR) has been an important research focus in realms of nuclear safety analysis. For IVR analysis, it’s of importance to study the natural convection behaviors of the corium pool formed in the lower plenum of the reactor vessel. Because of the different densities between corium compositions, typically the corium pool is believed to evolve to two-layer configurations, with a heavier oxide layer at bottom and a metal layer on top. To know better the convection behaviors of the layered corium pools, research was performed both experimentally and numerically. The test section for the experiment is a two-dimensional semi-ellipsoidal slice, which measures a span of 1.2m, a total pool depth of 0.75m and a thickness of 0.2m. Two immiscible fluid, i.e. fluorinert fluid FC-40 and water, were chosen to simulate the oxide layer and the metal layer respectively. Based on the experimental settings, numerical simulations were performed, and the results were compared with the experimental data. Further, discussions were made on the focusing effect, the relationship between the temperature and the velocity field, and also the coupling modes in the two-layer system. These results offer more details to the knowledge of layered corium pools and can be helpful for IVR analysis.

Adipose-derived mesenchymal stem cell (ADSC) with a high capacity of chondrogenic differentiation was a promising candidate for cartilage defect treatment. This study’s objective is to study the roles of integrin β1 (ITGB1) in regulating ADSC chondrogenic differentiations as well as the underlying mechanisms. The identity of ADSC was confirmed by flow cytometry. ITGB1 gene was overexpressed in human ADSC (hADSC) by transfection with LV003-recombinant plasmids. Gene mRNA and protein levels were examined using quantitative RT-PCR and western blotting, respectively. Differentially expressed mRNAs and proteins were characterized by next-generation RNA sequencing and label-free quantitative proteomics, respectively. ERK signaling and AKT signaling in hADSCs were inhibited by treating with SCH772984 and GSK690693, respectively. ITGB1 gene overexpression substantially increased collagen type II alpha 1 chain (COL2A1), aggrecan (ACAN), and SRY-box transcription factor 9 (SOX9) expression but suppressed collagen type I alpha 1 chain (COL1A1) expression in hADSCs. Next-generation RNA sequencing identified a total of 246 genes differentially expressed in hADSCs by ITGB1 overexpression, such as 183 upregulated and 63 downregulated genes. Label-free proteomics characterized 34 proteins differentially expressed in ITGB1-overexpressing hADSCs. Differentially expressed genes and proteins were enriched by different biological processes such as cell adhesion and differentiation and numerous signaling pathways such as the ERK signaling pathway. ERK inhibitor treatment caused substantially enhanced chondrogenic differentiation in ITGB1-overexpressing hADSCs. ITGB1 promoted the chondrogenic differentiation of human ADSCs via the activation of the ERK signaling pathway.

The Large Eddy Simulation (LES) methods were employed to analyze the turbulent heat transfer characteristics in detail for volumetrically heated corium pools. The main components and property parameters were calculated for the one-layer and two-layer configurations in the HPR1000 reactor. The numerical simulations were performed based on the WMLES turbulence model, phase change model, as well as the VOF model to describe thermal behaviors in the corium pool such as natural convection flow, pool temperature field and heat flux distribution. Then based on the Kelvin-Helmholtz (KH) instability theory, the calculated velocity vector difference between the two-layer flows at the interface was lower than the KH instability critical value. The high Rayleigh number natural convection in the bottom oxide pool was still not able to entrain the top metal layer. The molten salt (20 mol% NaNO3-80 mol% KNO3) and the Lead-Bismuth eutectic (44.5 wt% Pb-55.5 wt% Bi) were chosen as the appropriate simulant materials for the two-layer corium pool. The simulation results presented similar thermal characteristics compared with those from the prototypical reactor two-layer case, which could provide guidance for further research.

This paper presents the results from COPRA eutectic molten salt tests, which were carried out to investigate the simulant effect on corium pool natural convection heat transfer characteristics. A eutectic 50%NaNO3-50%KNO3 molten salt was used to simulate the prototypical corium. Compared with the previous non-eutectic 20% NaNO3-80%KNO3 molten salt experimental data, the effects caused by simulant composition on melt pool temperature, heat flux distribution and crust behavior were studied. The comparison showed that the temperature distribution of eutectic melt pool was lower than the non-eutectic one, while the heat flux was higher than that of non-eutectic melt pool. Applying the same pool height, heating power and boundary condition, smaller modified Rayleigh number was obtained in the eutectic case. It indicated that the mush zone effect of non-eutectic melt suppressed the thermal stratification and impeded the heat transfer through the vessel wall. These results can be expected to provide further data to understand the natural convection behavior of corium pool.