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In the target localization of skywave over-the-horizon radar (OTHR), the error of the ionospheric parameters is one main error source. To reduce the error of ionospheric parameters, a method using both the information of reference sources (e.g., terrain features, ADS-B) in ground coordinates and the corresponding OTHR measurements is proposed to estimate the ionospheric parameters. Describing the ionospheric electron density profile by the quasi-parabolic model, the estimation of the ionospheric parameters is formulated as an inverse problem, and is solved by a Markov chain Monte Carlo method due to the complicated ray path equations. Simulation results show that, comparing with using the a prior value of the ionospheric parameters, using the estimated ionospheric parameters based on four airliners in OTHR coordinate registration process, the ground range RMSE of interested targets is reduced from 2.86 to 1.13 km and the corresponding improvement ratio is up to 60.39%. This illustrates that the proposed method using reference sources is able to significantly improve the accuracy of target localization.

Maternal hypercholesterolemia during pregnancy is associated with an increased risk of preterm birth which is defined as

Objective To evaluate the effects of antiretroviral therapy(ART)for the prevention of mother-to-child transmission(PMTCT)of acquired immune deficiency syndrome(AIDS)on the growth and development of 18-month-old children born by human immunodeficiency virus(HIV)-positive pregnant women in Lingshan County,Guangxi Zhuang Autonomous Region,and provide scientific evidence for improving the ART medication plan for PMTCT.Methods Lingshan County,ranking the first in the HIV-epidemic counties of Guangxi,was selected as the research site.According to the design of retrospective case-control study,we assigned all the subjects into the case group and the control group:(1)The case group included the HIV-positive pregnant women who had received ART for PMTCT and their HIV-negative infants in Lingshan County from 2010 to 2017.The historical cards and PMTCT data of them were collected from the national PMTCT database.(2)The control group included the healthy pregnant women and their healthy babies born in the Lingshan Maternity and Infant Hospital in 2017,and the children's growth and development data were collected.The stunted growth in children was defined as at least one of the three main indicators of body height,body weight,and head circumference below the normal range.Results The number of HIV-positive mothers and their infants in the case group was 391 and 368,respectively,and 87.21%(341/391)and 95.38%(351/368)of mothers and infants respectively received ART medication.The HIV positive rate,mortality rate,and mother-to-child transmission rate of 18-month-old children were 1.36%(5/368),4.35%(16/368),and 2.01%(5/249),respectively.The incidence of stunted growth of 18-month-old children in the case group and the control group was 42.12%(155/368)and 23.06%(101/438),respectively,with significant difference(

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development., Author summary Upon the emergence of new infectious disease, animal model becomes a pivotal tool for study of disease mechanism and development of therapeutics. In this study, we propose a versatile approach that allows rapid generation of mouse model for novel infectious disease once the receptor of the pathogen is identified. We demonstrated this approach by generating a mouse model for COVID-19 in a month’s time. These mice were capable of recapitulating severe COVID-19 in patients, and successfully applied in the development of a therapeutic antibody cocktail for the disease. This not only suggests the usefulness of this mouse model for the research on COVID-19, but also exhibit the utility of the proposed approach for establishing animal model for infectious disease.

Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis (AS). With the role of regulatory T cells (Tregs) in immune regulation attracting attention, it has been widely accepted that Treg decrease and dysfunction are involved in AS pathogenesis. Chinese medicine (CM) has the advantages of being dual-directional, multi-targeted, and having minimal side effects in immune regulation. The anti-atherosclerosis effects of CM via Treg modulation have been revealed in clinical and animal studies. Therefore, this article reviews existing research on Tregs, the relationship between Tregs and AS, and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating Tregs. Although the underlying mechanisms remain to be elucidated, CM treatment targeting Treg cells might provide a promising and novel future approach for prevention and treatment of AS.

To evaluate the efficacy of iliolumbar fixation in the treatment of U-shaped sacral fractures.A retrospective study was conducted on the 14 complex U-shaped sacral fractures which had been treated from January 2014 to December 2019, involved 10 males and 4 females, aged 24 to 48 (35.4±6.5) years. Fracture healing time, nerve function, clinical function and complications were observed in the patients.All patients were followed up for 9 to 16(26.0±5.9) months. The complete weight-bearing time for bone healing was(12.4±2.0) weeks. One case of surgical incision infection occurred after operation, and one case of sacrum nailspenetrated to the outer plate of sacrum. No complications such as pressure ulcers, loosening or rupture of internal fixation occurred. According to Gibbons scoring, the neurological function recovered from preoperative 2.9±0.9 to postoperative 2.1±1.1, there were statistically significant differences between preoperative and postoperative (Sacral lumbar fixation is an effective method for the treatment of U-shaped sacrum fractures. It has the advantages of strong internal fixation and satisfactory functional recovery.

BackgroundOvarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM).ResultsWe identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors.ConclusionsIn this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.

Recent studies have reported that T-cell differentiation protein 2 (MAL2) is an important regulator in cancers. Here, we downloaded data from multiple databases to analyze MAL2 expression and function in pan-cancers, especially in ovarian cancer (OC). Gene Expression Profiling Interactive Analysis (GEPIA) databases was used to examine MAL2 expression in 13 types of cancer. Kaplan–Meier plotter database was used to analyze the overall survival rate of MAL2 in pan-cancers. The Catalog of Somatic Mutations in Cancer (COSMIC), cBioPortal, and UCSC databases were used to examine MAL2 mutation in human cancers. Metascape, STRING, and GeneMANIA websites were used to explore MAL2 function in OC. Furthermore, ggplot2 package and ROC package were performed to analyze hub gene expression and undertake receiver operating characteristic (ROC) analysis. Drug sensitivity of MAL2 in OC was examined by the GSCALite database. In order to verify the results from databases above, real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting were conducted to detect the expression of MAL2 in OC cells. CRISPR/Cas9 system was used to knockout the MAL2 gene in the OC cell lines HO8910 and OVCAR3, using specific guide RNA targeting the exons of MAL2. Then, we performed proliferation, colony formation, migration, and invasion assays to investigate the impact of MAL2 in OC cell lines in vivo and in vitro. Epithelial-mesenchymal transition (EMT)-associated biomarkers were significantly altered in vitro via western blotting and qRT-PCR. Taken together, we observed that MAL2 was remarkably dysregulated in multiple cancers and was related to patient overall survival (OS), mutation, and drug sensitivity. Furthermore, experimental results showed that MAL2 deletion negatively regulated the proliferation, migration, invasion, and EMT of OC, indicating that MAL2 is a novel oncogene that can activate EMT, significantly promote both the proliferation and migration of OC in vitro and in vivo, and provide new clues for treatment strategies.

BACKGROUND Clear cell sarcoma (CCS) of soft tissue, or malignant melanoma of soft parts, is a rare disease. We aimed to identify prognostic factors linked to patient survival in CCS by analyzing demographic and clinical features using the Surveillance, Epidemiology, and End Results (SEER) database. This study aimed to identify prognostic factors associated with CCS that would be of clinical value. MATERIAL AND METHODS We collected data from patients diagnosed with CCS between 1973 and 2009 from the SEER database. The Kaplan-Meier method and Cox regression analysis were performed to identify prognostic factors for patient survival. RESULTS A total of 175 patients with CCS were identified from the SEER database. The 5-year survival rate was 62.9%, and the 10-year survival rate was 51.3%. Patients with CCS with local stage, and with tumor size ≤3 cm were more likely to have good survival rates. CONCLUSIONS The findings from this study showed that the identifiable prognostic factors in patients with CCS were stage and tumor size. Local stage and tumor size ≤3 cm were favorable prognostic factors for patient survival in CCS.

JNK1 plays an important role in osteoclastogenesis in response to the osteoclastogenic cytokine receptor activator for nuclear factor-κB ligand (RANKL). JNK1 is widely accepted as an autophagy regulator under stress conditions. However, the role of JNK1-mediated autophagy in osteoclastogenesis remains largely unknown. In the current study, our data showed that JNK1 inhibition by a pharmacological inhibitor or RNA interference significantly reduced the autophagic response induced by RANKL in osteoclast precursors (OCPs) derived from bone marrow-derived macrophages. Overexpression of the key autophagy protein Beclin1 rescued autophagy deficiency and osteoclastogenesis in the presence of a JNK inhibitor (SP600125). In contrast, JNK activator (anisomycin)-induced autophagy was blocked by Beclin1 knockdown in OCPs. In addition, JNK1 inhibition increased apoptosis and blocked autophagy, whereas overexpression of Beclin1 reversed the enhanced apoptosis induced by JNK1 inhibition in OCPs. Furthermore, RANKL could induce the phosphorylation of Bcl-2, subsequently dissociating Beclin1 from the Bcl-2-Beclin1 complex, which could be blocked by JNK1 inhibition. Collectively, this study revealed that JNK1 regulated osteoclastogenesis by activating Bcl-2-Beclin1-autophagy signaling in addition to the classic c-Jun/activator protein 1 pathway, which provided the first evidence for the contribution of JNK1 signaling to OCP autophagy and the autophagic mechanism underlying JNK1-regulated osteoclastogenesis. An important osteoclastogenesis-regulating signaling pathway (JNK1-Bcl-2-Beclin1-autophagy activation) was identified, which provides novel potential targets for the clinical therapy of metabolic bone diseases.-Ke, D., Ji, L., Wang, Y., Fu, X., Chen, J., Wang, F., Zhao, D., Xue, Y., Lan, X., Hou, J. JNK1 regulates RANKL-induced osteoclastogenesis via activation of a novel Bcl-2-Beclin1-autophagy pathway.

Although conventional slotted limited-angle torque motors (LATMs) have a high torque density, its fatal shortcoming of non-uniform torque profile makes it difficult to apply for precise positioning systems. This paper presents a novel radial-flux slotted LATM with asymmetrical teeth for the torque performance improvement including average output torque and angular operation range. A magnetic equivalent circuit (MEC) for radial-flux slotted LATMs is first derived and implemented in the design process. Then, the finite-element analysis is utilized to validate the related analytical equations and to make the comparison of the torque performance between the radial-flux conventional and proposed LATMs. Finally, a prototype machine of the proposed LATM is accomplished, and its torque characteristic experiment is carried out to confirm the torque performance improvement. The related experimental results are presented and discussed.

This paper aims to disclose the noticeable effect of local tangential force on vibration performance in fractional-slot concentrated-winding permanent magnet synchronous machines (PMSMs). The mechanism to induce vibrations by tangential force is revealed at first. It is found that tangential force is able to deflect the yoke through the tooth's lever arm effect. This phenomenon is detailedly explained through finite element simulation and analytical description of the microscopic deformation in this paper. With the aid of a 10-pole/12-slot PMSM, the quantitative contribution of tangential force to the vibration is also investigated through simulation, vibration synthesis, and experiments. Results show that due to the strong lever arm effect and not so small force amplitudes as commonly expected, the contribution of tangential force to final vibration is comparable to that of radial force. Besides that, the synthesized vibrations indicate the contribution of tangential force decreases with the increase of non-zero spatial order, in a way similar to radial force. In order to underpin the findings, more situations such as with different pole-slot combinations are also analyzed at last.

The Ni(OH)2/NiOOH nanoparticles (NPs) electrodeposited on a glassy carbon electrode (GCE) in Ni(NO3)2 and NH3·H2O aqueous solution for the electrode materials. Then the nickel hydroxide/oxyhydroxide acetate was formed in acetate solution. The effects of deposition conditions such as the concentration of Ni(NO3)2 solution, the number of sedimentary cycles, the concentration of acetate in the soaking liquid and the soaking time are discussed in detail. The electrochemical properties of the material have been investigated by cyclic voltammetry, Tafel curve, EIS and amperometric i–t curve techniques. The result displays excellent electrocatalytic activity towards the electrocatalytic oxidation of urea in alkaline solution. Furthermore, the modified electrode for oxidation reaction has the advantages of simple preparation, good electrochemical properties and stabilisation.

Purpose The optimal internal fixation device for unstable intertrochanteric fracture remains a matter of controversy. By performing network meta-analysis, we developed a ranking of the following four surgical methods: proximal femoral nail antirotation, InterTan nail, gamma nail (GN) and sliding hip screws. We compare the complication rates in patients with unstable intertrochanteric fractures. Materials and methods After an exhaustive search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for relevant studies, randomized controlled trials meeting selection criteria were entered into our network meta-analysis. Statistical analyses were conducted using Stata software, version 13.0 (Stata Corporation, College Station, Texas, USA). Results We included 12 randomized controlled trials. Compared to Sliding hip screw, there were no substantial differences in rates of complications in unstable intertrochanteric fractures patient undergoing various treatments (all p > 0.05). Nevertheless, the surface under the cumulative ranking curve (SUCRA) for GN (80.6%) was significantly higher than those of the other three methods. Conclusion GN had the highest probability of reducing the total incidence of complications among the four interventions for treating unstable intertrochanteric fractures.

Food–drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug–drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague–Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre‐treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC‐MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC50 value of 38.89 μM, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 μM, aKi =73.33 μM, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC(0– t ) value of rats in the experimental group was increased from 2406.28 ± 519.69 μg/h/L to 4005.04 ± 1172.76 μg/h/L, the C max value was increased from 310.23 ± 85.76 μg/L to 508.71 ± 152.48 μg/L, and the Vz / F and CLz / F were decreased from 23.03 ± 4.81 L/kg to 16.2 ± 8.42 L/kg, 4.26 ± 0.91 L/h/kg to 2.57 ± 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co‐administered in the clinic., The metabolism of rivaroxaban was inhibited by naringenin in a dose‐dependent manner in rat liver microsomes. Naringenin also exhibited inhibitory effect on rivaroxaban with increased AUC(0– t ), C max values and decreased V z / F, CLz / F values in rat.

Disulfiram (DSF) is an effective copper (Cu2+)-dependent antitumor agent. In the present study, we explored use of transferrin (Tf)-modified DSF/copper sulfide (CuS) nanocomplex (Tf-DSF/CuS) for glioma therapy. Tf was used as glioma targeting motifs, DSF as an anticancer agent, and CuS as a source of Cu2+ ions and a photothermal agent. DSF was loaded on CuS by metal-chelation, and released from the nanocomplex under acidic condition. The Tf-DSF/CuS complex exhibited high cytotoxic effect in vitro. Notably, cytotoxic activity was correlated with pH triggered release of Cu2+ which initiated non-toxicity to toxicity switch of DSF. Ultrasound-targeted microbubble destruction (UTMD) technique was used for highly selective accumulation of intravenous injected Tf-DSF/CuS in the glioma orthotopic tumor as compared with the free drugs and non-targeted DSF/CuS groups. Magnetic resonance imaging and pathological examinations showed that Tf-DSF/CuS effectively suppressed tumor growth, with an inhibition ratio of ~85%. Additionally, DSF load did not compromise photothermal conversion ability of CuS nanoparticles. Efficacy of the photothermal ablation therapy of Tf-DSF/CuS was evaluated under 808 nm laser irradiation both in vitro and in vivo. These findings show that copper-sulfide based disulfiram nanoparticles are effective agents for anti-glioma therapy.

BackgroundIntrathoracic displacement of a humeral head fracture is extremely rare.Only slightly more than 30 cases have been reported. Because few cases have been reported, there is no consensus on how to treat this injury. The etiology, injury mechanism, related lesions and treatment of the injury are diverse.Case presentationA 73-year-old woman presented with multiple fractures of the left ribs, bilateral lung contusions, extensive emphysema of the anterior and posterior chest wall, massive left hemopneumothorax, fracture-dislocation of the proximal humerus and intrathoracic displacement of the humeral head.The patient was sent to the operating room for emergency thoracotomy surgery. The head of the humerus was confirmed to be completely removed from the thoracic cavity during the operation. After discussion with the orthopedic surgeon, the humeral head was discarded considering avascular necrosis, and open reduction and internal fixation were not performed.Three weeks later, the orthopedic surgery team performed reverse shoulder arthroplasty.During follow-up, the patient’s shoulder was free from pain, and its range of movement (ROM) included 110° flexion, 70° abduction, 35° external rotation and 50° internal rotation.Conclusions Intrathoracic displacement of the humeral head due to proximal humeral fracture is a very rare and serious trauma that requires multidisciplinary treatment. Considering the extremely high risk of humeral head necrosis, actively removing broken bone fragments of the humeral head in the early stage is recommended, and we advocate for shoulder arthroplasty for elderly patients. Detailed preoperative evaluations and individualized operation plans should be made to achieve the best effect.

Acephalic spermatozoa syndrome (ASS) is a rare teratozoospermia that leads to male infertility. Previous work suggested a genetic origin. Variants of Sad1 and UNC84 domain containing 5 (SUN5) are the main genetic cause of ASS; however, its pathogenesis remains unclear. Here, we performed whole-exome sequencing in 10 unrelated ASS and identified 2 homozygous variants, c.381delA[p.V128Sfs7*] and c.675C>A[p.Y225X], and 1 compound variant, c.88 C > T[p.R30X] and c.381 delA [p.V128Sfs7*], in SUN5 in 4 patients. The c.381delA variant had been identified as pathogenic in previous reports, while c.675C>A and c.88 C > T were two novel variants which could lead to a premature termination codon (PTC) and resulted in loss of SUN5, and may also be pathogenic. SUN5 mRNA and protein were present at very low levels in ASS patients with SUN5 nonsense mutation. Furthermore, the distribution of outer dense fiber protein 1 (ODF1) and Nesprin3 was altered in sperm of ASS patients with SUN5 variants. The co-immunoprecipitation analysis indicated that SUN5 and ODF1, SUN5 and Nesprin3, and ODF1 and Nesprin3 interacted with each other in transfected HEK293T cells. Thus, we propose that SUN5, Nesprin3, and ODF1 may form a ‘triplet’ structure through interactions at neck of sperm. When gene variants resulted in a loss of SUN5, the ‘triplet’ structure disappears and then the head-tail junction becomes fragile, leading to the occurrence of ASS.

Ovarian cancer is one of the most common gynecological malignancies and has the highest mortality rate among all gynecological malignant tumors. Advanced ovarian cancer patients can obtain a survival benefit from chemotherapy, including platinum drugs and paclitaxel (PTX). In more recent years, the administration of poly-ADP ribose polymerase inhibitor (PARPi) to patients with BRCA mutations has significantly improved the progression-free survival (PFS) of ovarian cancer patients. Nevertheless, primary drug resistance or the acquisition of drug resistance eventually leads to treatment failure and poor outcomes for ovarian cancer patients. The mechanism underlying drug resistance in ovarian cancer is complex and has not been fully elucidated. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a critical role in the development of ovarian cancer. Accumulating evidence has indicated that ncRNAs have important regulatory roles in ovarian cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically highlight the emerging roles and the regulatory mechanisms by which ncRNAs affect ovarian cancer chemoresistance. Additionally, we suggest that ncRNAs can be considered as potential diagnostic and prognostic biomarkers as well as novel therapeutic targets for ovarian cancer.

Background The tumor microenvironment (TME) has a significant influence on prognosis and immunotherapy. There are no studies on the systematic analysis of bladder cancer TME and its effect on immune checkpoint inhibitor therapy. Methods We comprehensively evaluated the TME infiltration pattern of bladder cancer in 1,889 patients and conducted extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TME of bladder cancer. The principal component analysis algorithm was used to calculate the immune cell (IC)score to quantify the level of IC infiltration. We used the receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), and Subnetwork Mappings in Alignment of Pathways (SubMAP) algorithms to evaluate whether the ICscore can predict the benefits of immune checkpoint inhibitors in bladder cancer patients. Results We identified three different TME phenotypes using unsupervised clustering methods. To explore the potential biological pathways that drive the formation of these microenvironmental phenotypes, we demonstrated the clinical and pathological characteristics, biological signaling pathways, cancer immune circulation, copy number, and somatic mutation differences among the different subtypes. In addition, univariate and multivariate Cox regression analyses showed that the ICscore is a reliable and independent prognostic marker. The ICscore can also predict immune checkpoint inhibitor responsiveness as patients with higher ICscores showed a significant therapeutic advantage in immunotherapy. Conclusions This study increases our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance on more effective personalized immunotherapeutic strategies.

Cytochrome P450 2C9 (CYP2C9) is one of the most important drugs metabolizing enzymes and accounts for the metabolism of about 13%–17% of clinical drugs. Like other members in CYP2 family, CYP2C9 gene exhibits great genetic polymorphism among different races and individuals. CYP2C9*18 is one CYP2C9 allelic variant identified in a Southeast Asian population and is estimated to cause the amino acid substitutions of I359L and D397A in CYP2C9 enzyme simultaneously. Limited by the low expression level in bacteria and COS‐7 cells, no valuable enzyme kinetics have been reported on this CYP2C9 variant. In this study, the baculovirus‐based system was used for the high expression of recombinant CYP2C9 s in insect cells. As a result, together with I359L substitution, D397A could significantly decrease the protein expression of CYP2C9.18 in insect cells, although substitution of D397A alone had no effect on the expression of CYP2C9 in vitro. As compared with that of wild‐type enzyme, both CYP2C9.18 variant and D397A variant could decrease more than 80% of the catalytic activity of CYP2C9 enzyme toward three probe substrates, suggesting that caution should be exercised when patients carrying CYP2C9*18 taking medicines metabolized by CYP2C9 enzyme with a narrow therapeutic window., CYP2C9.18 (D397A together with I359L) exhibits the lowest protein expression level of CYP2C9 in insect cells. D397A substitution leads to the impact on the residues in substrate recognition site 6.

Background: The goals of improving quality of life and increasing longevity are receiving growing amounts of attention. Body weight and lipid metabolism are closely related to various complications of diabetes. The aim of this study was to rank SGLT inhibitors according to their efficacy with regard to weight and evaluate the effect of SGLT inhibitors on lipid metabolism at 24 weeks of treatment. Methods: The Web of Science, PubMed, Cochrane Library, Embase, and Clinical Trials databases were electronically searched to collect randomized controlled trials involving patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the selected studies and extracted the outcome indexes. ADDIS 1.16.5 and STATA 16 software were used to perform the network meta-analysis and draw the plots. Results: Ultimately, 36 studies were selected and included in this study. We found that all SGLT inhibitors were effective at reducing weight; canagliflozin was the most effective. SGLT inhibitors and placebo were not associated with significantly different serum cholesterol levels. SGLT inhibitors lowered serum triglyceride levels and increased serum high-density and low-density lipoprotein cholesterol levels. SGLT inhibitors also reduced the level of alanine aminotransferase. Conclusions: SGLT inhibitors can bring about weight loss in patients with T2DM and can also improve lipid metabolism. Therefore, patients with hyperlipidemia who have been unsuccessful at losing weight should consider taking SGLT inhibitors. In addition, SGLT inhibitors are hepatoprotective and appear to be safe for patients with mild to moderate liver dysfunction. Trial Registration: CRD42020198516.

To compare the clinical efficacy of three minimally invasive methods of anterior column screw, plate and screw rod system in the treatment of anterior pelvic ring fracture.From December 2015 to September 2018, 77 patients with pelvic anterior ring fracture were treated and followed up, including 45 males and 32 females, aged 19 to 73 years. According to AO / OTA classification, there were 26 cases of type B1, 20 cases of type B2, 17 cases of type B3 and 14 cases of type C. According to the different internal fixation methods, they were divided into three groups:anterior column screw group(35 cases), plate group(20 cases), and screw rod system group(22 cases). The operation time, intraoperative fluoroscopy times, blood loss, fracture reduction quality, complications and curative effect of the three groups were compared.All 77 patients were followed up for 12 to 33 (16.5±5.7) months. The operation time, intraoperative blood loss and incision length of anterior column screw group were significantly shorter than those of plate group and screw rod system group, and intraoperative fluoroscopy times of plate group were significantly less than those of anterior column screw group and screw rod system group (Minimally invasive internal fixation with anterior column screw, plate and screw rod system can obtain good clinical effect, but anterior column screw fixation has less trauma and lower incidence of surgicalcomplications.

Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proven to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent antitumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/DSF@ZnO) to solubilize and stabilize DSF, and, more importantly, achieve pH triggered Zn

Background Ovarian cancer is one of the most common gynecologic cancers and has high mortality rate due to the lack of early diagnosis method and efficient therapeutic agents. circCELSR1 is up-regulated in ovarian cancer, but its role and mechanisms in ovarian cancer are unclear. Methods Gene expression of circCELSR1, miR-598 and BRD4 in ovarian cells was examined by qRT-PCR. Protein level was determined by Western blotting. Bioinformatic analysis and luciferase assay determined the molecular binding among circCELSR1, miR-598 and BRD4 3′ UTR. Cell proliferation, migration, invasion and apoptosis were determined by colony formation, wound healing assay, transwell assay and flow cytometry analysis, respectively. An abdominal cavity metastasis nude mice model was used to determine the in vivo function of circCELSR1. Results circCELSR1 and BRD4 were promoted, but miR-598 was suppressed in various ovarian cancer cells. circCELSR1 bound to miR-598 and promoted expression of its downstream target BRD4. Knockdown of circCELSR1 suppressed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but promoted apoptosis in ovarian cancer cells, and these effects were reversed by miR-598 inhibition or BRD4 overexpression. circCELSR1 inhibition decreased the expression of BRD4 and its downstream proliferation/migration related genes by targeting miR-598. Furthermore, knockdown of circCELSR1 suppressed ovarian cancer growth and metastasis in nude mice. Conclusion Knockdown of circCELSR1 inhibited BRD4-mediated proliferation/migration related signaling via sponging miR-598, thereby repressing ovarian cancer progression. This study provides a new regulatory mechanism of ovarian cancer may facilitate the development of therapeutic agents for ovarian cancer.

Background: During the COVID-19 period, there was a huge gap in the understanding of masks between east and west. At the same time, the mechanism of the mask and the effect after use, also appeared differences. The Objective of this Meta-analysis is to systematically evaluate the efficacy of masks for influenza in the community. Methods: The Web of Science, PubMed, The Cochrane Library, EMBASE and Clinical Trials will be electronically searched to collect randomized controlled trials regarding the efficacy of masks for influenza in the community through Apr 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. Revman 5.3 software will be used for the meta-analysis. Results: The outbreak is continuing, and we need to be prepared for a long fight. If masks are effective, we need to promote their use as soon as possible. If masks are ineffective, strong evidence should be given. This is an urgent task and our team will finish it as soon as possible. Conclusion: Provide stronger evidence to solve the problem, should we wear masks or not right now.

Background Lung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD). Methods Proteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds. Results Proteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance. Conclusion Ubiquitin ligase CAHF1B can induce cisplatin resistance in LUAD by promoting the ubiquitination degradation of NCOR2.

Rationale: Photothermal therapy employs the photoabsorbers to generate heat under the near-infrared (NIR) irradiation for thermal tumor ablation. However, NIR irradiation might damage the adjacent tissue due to the leakage of the photoabsorbers and the residual materials after treatment might hinder the local healing process. A bifunctional hydrogel that holds both photothermal property and potent pro-healing ability provides a viable option to resolve this issue. Methods: In this study, we developed a bioinspired green hydrogel (BVSF) with the integration of bioproduct biliverdin into natural derived silk fibroin matrix for antiglioma photothermal therapy and wound healing. Results: The BVSF hydrogel possessed excellent and controllable photothermal activity under NIR irradiation and resulted in effective tumor ablation both in vitro and in vivo. Additionally, the BVSF hydrogel exerted anti-inflammatory effects both in vitro and in vivo, and stimulated angiogenesis and wound healing in a full-thickness defect rat model. Conclusion: Overall, this proof-of-concept study was aimed to determine the feasibility and reliability of using an all-natural green formulation for photothermal therapy and post-treatment care.

Ubiquitin ligases have been shown to regulate drug sensitivity. This study aimed to explore the role of the ubiquitin ligase WD repeat and HMG-box DNA binding protein 1 (WDHD1) in regulating cisplatin sensitivity in lung adenocarcinoma (LUAD). A quantitative analysis of the global proteome identified differential protein expression between LUAD A549 cells and the cisplatin-resistant strain A549/DDP. Public databases revealed the relationship between ubiquitin ligase expression and the prognosis of patients with LUAD. Quantitative real-time polymerase chain reaction and Western blotting were used to estimate the WDHD1 expression levels. Analysis of public databases predicted the substrate of WDHD1. Western blotting detected the effect of WDHD1 on microtubule-associated protein RP/EB family member 2 (MAPRE2) and DSTN. Functional analysis of MAPRE2 verified the interaction between WDHD1 and MAPRE2, as well as the interacting sites by methyl-thiazolyl-tetrazolium assay and flow cytometry, immunoprecipitation, protein stability, and immunofluorescence. Cell and animal experiments confirmed the effect of WDHD1 and MAPRE2 on cisplatin sensitivity in LUAD. Clinical data evaluated the impact of WDHD1 expression level on cisplatin sensitivity. Quantitative analysis of the global proteome revealed ubiquitin-dependent protein catabolism to be more active in A549/DDP cells than in A549 cells. WDHD1 expression was higher in A549/DDP cells than in A549 cells, and knocking out WDHD1 increased the sensitivity of A549/DDP cells to cisplatin. WDHD1 overexpression negatively correlated with the overall survival of LUAD patients. We observed that MAPRE2 was upregulated when WDHD1 was knocked out. A MAPRE2 knockout in A549 cells resulted in increased cell viability while decreasing apoptosis when the A549 cells exposed to cisplatin. WDHD1 and MAPRE2 were found to interact in the nucleus, and WDHD1 promoted the ubiquitination of MAPRE2. Following cisplatin exposure, the WDHD1 and MAPRE2 knockout groups facilitated cell proliferation and migration, inhibited apoptosis in A549/DDP cells, decreased apoptosis, and increased tumor size and growth rate in animal experiments. Immunohistochemistry showed that Ki67 levels increased, and levels of apoptotic indicators significantly decreased in the WDHD1 and MAPRE2 knockout groups. Clinical data confirmed that WDHD1 overexpression negatively correlated with cisplatin sensitivity. Thus, the ubiquitin ligase WDHD1 induces cisplatin resistance in LUAD by promoting MAPRE2 ubiquitination.

Warfarin is the most commonly used anticoagulant in the clinical treatment of thromboembolic diseases. The dose of warfarin varies significantly within populations, and the dose is closely related to the genetic polymorphisms of the CYP2C9 and VKORC1 genes. In this study, a new CYP2C9 nonsynonymous mutation (8576C > T) was detected after the genetic screening of 162 patients took warfarin. This mutation, named as the new allele CYP2C9*62, can result in an arginine to cysteine amino acid substitution at position 125 of the CYP2C9 protein (R125C). When expressed in insect cells, the protein expression of CYP2C9.62 was significantly lower than that of the wild-type, and its metabolic activity was also significantly decreased after the addition of three typical CYP2C9 probe drugs, suggesting that the new mutant can dramatically affect the metabolism of CYP2C9 drugs in vitro.