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Abstract Small-caliber (≤ 6 mm) vascular grafts are commonly used to treat vascular diseases, yet intimal hyperplasia at the distal end-to-side anastomosis remains a significant complication with long-term use. Helical flow has been shown to reduce the risk of cardiovascular complications effectively. Integrating helical flow through an inbuilt helical ridge in vascular grafts is intended to improve hemodynamic performance and mitigate issues such as flow-induced thrombosis and intimal hyperplasia. However, inadequate helical flow strength may limit its effectiveness. This study proposes a novel design for an inbuilt helical ridge in small-caliber grafts to achieve enhanced helical flow. Two novel small-caliber vascular grafts with variable-pitch helical ridges, incorporating both decreasing and increasing pitches, were designed. Their effectiveness was assessed through numerical simulations and in vitro experiments to evaluate their performance in arterial graft applications. The small-caliber vascular grafts incorporating variable-pitch helical ridges significantly improved helical flow structure and distribution, optimized wall shear stress distribution, and reduced platelet adhesion compared to conventional and constant-pitch helical ridge grafts. Among the various new designs, the small-caliber vascular graft featuring decreasing variable-pitch helical ridges has demonstrated better performance. This design is well-suited for small-caliber bypass surgeries, as it is effective in improving hemodynamic performance by improving helical flow into asymmetric structures and increasing helical flow density distribution.

BackgroundMetabolic Visceral Fat Score (METS-VF) recently introduced is posited to be a superior metric for assessing visceral adipose tissues (VAT) compared to traditional obesity indexes. This study aims to elucidate the correlation between METS-VF and the incidence of gallstones.MethodsIn this cross-sectional study, the data from the National Health and Nutrition Examination Survey (NHANES) during the period from 2013 to 2020 were analyzed. And the correlation between METS-VF and the incidence of gallstones was explored through multivariate logistic regression analysis, receiver operating characteristic (ROC) curve, subgroup analysis and restricted cubic spline (RCS) regression.ResultsThis study included 5,975 participants, of whom 645 (10.8%) were gallstone formers. As the quartile range of METS-VF increased, a notable rise in the prevalence of gallstones was observed (3.2% vs. 7.4% vs. 12.1% vs. 20.6%, p

To investigate the impact and flexure behavior of carbon fiber reinforced polymers/aluminum-honeycomb sandwich panel, low-velocity impact, compression-after-impact (CAI), and three-point flexure tests are conducted carefully. Four kinds of carbon fiber prepregs are selected to make face sheets by hot press preparation. Further, the digital image correlation technique is employed to record the damage evolution under the compression and flexure loads. The results show that the sandwich structure has two stages of impact response, first, the brittle behavior of the upper panel, and then the resistance of both sandwich and lower panel to absorb energy. In the CAI test, the failure position shifts from the ends to the impact cross section, and the compressive strength can be reduced by 40% only by 1 J impact. The strength of in-plane flexure is at least twice greater than that of out-of-plane flexure. The damage and deformation of in-plane flexure are found mainly in the upper panel and sandwich core, and the lower panel bends significantly.

Abstract Background The therapeutic status of allogeneic stem cell transplantation (allo-SCT) as a post-remission treatment for patients with high-risk acute myeloid leukemia (AML) was well-accepted. However, the optimal treatment for patients with low/favorable- or intermediate-risk AML who achieve complete remission has remained controversial. Therefore, we conducted a network meta-analysis to discuss this disputed problem. Methods We compared the effects of treatment strategies including allo-SCT, autologous stem cell transplantation (auto-SCT) and consolidation chemotherapy (CT) for patients with low/favorable- or intermediate-risk AML. The pooled HRs and 95% CIs for overall survival and disease-free survival were estimated with Stata12 and R software. Thirty clinical studies with 6682 patients were included in the meta-analysis. Results The results indicated that the treatment outcome of allo-SCT was the best, followed by auto-SCT, and CT was likely the worst in the total AML patients. In patients with low/favorable-risk AML, the treatment outcome of auto-SCT was likely ranked first, followed by allo-SCT, and CT was the worst. In patients with intermediate-risk AML, the treatment outcome of haploidentical stem cell transplantation (haplo-SCT) was the best, followed by allo-SCT (excluding haplo-SCT), and auto-SCT and CT were the worst. However, the median age of the haplo-SCT group was much younger than that of the control group, which may be one of the reasons for the better prognosis of the haplo-SCT group. Conclusions Patients with low/favorable- and intermediate-risk (non-high-risk) AML should prioritize allo-SCT if they are eligible for transplantation, and auto-SCT is optional. However, in the subgroup analysis, auto-SCT was the optimal treatment choice for patients with low/favorable-risk AML, and allo-SCT was the priority selection for patients with intermediate-risk AML, especially young patients. These findings could provide references for clinical practice.

To investigate the impact behavior and residual strength of glass fiber-reinforced polymer (GFRP) laminates embedded with/without steel wire mesh, low-velocity-impact (LVI) and post-impact tensile tests are conducted carefully. According to the wire diameter and spacing of steel wire mesh, we manufactured two groups of specimens via conventional vacuum-assisted resin infusion. Further, the digital image correlation technique was applied to record the strain evolution. Based on the results, including impact response history, failure morphology, strain contour, the failure mechanism and effect of the parameters of steel wire mesh is revealed in detail. The results show that the embedding of wire mesh can improve the impact resistance and residual strength, with a more significant effect as both the increase of wire diameter and decrease of wire spacing. Compared with GFRP laminates, the peak force of specimens with the thickest and densest wire mesh increase by 105% and 141% under LVI tests and 254% and 141% in post-impact tensile tests, respectively.

To study the impact response and compression-after-impact (CAI) behavior of perforated sandwich panels comprised of foam core and glass fiber-reinforced epoxy hybrid facesheets, the hole diameter of specimens is changed in the fabrication via vacuum-assisted resin infusion. Furthermore, low-velocity-impact tests with various impact distances between the impact point and hole are carried out. With the help of the digital image correlation technique, CAI testing is conducted, and the strain evolution of specimens is monitored carefully. The mechanical response history, damage morphology, and compressive process are discussed in detail. The results show that the impact and CAI performance of specimens are weakened because of open holes. Compared with the non-perforated specimen, the maximum force of the specimen with a 6-mm hole and the 5-mm impact distance decreases by 41.21%, and its maximum displacement increases by 38.60%. During the CAI process, in comparison with the impact damage, more significant stress concentration and buckling around the hole are found.

This article aims to evaluate the effects of mesh size change on the mechanical properties of GFRP laminates, via low-velocity impact and compression-after-impact (CAI) test, and the failure mechanism was analyzed. Through vacuum-assisted resin infusion, wire meshes with different mesh numbers and wire diameters were incorporated into GFRP. Based on response history and failure morphology, the results show that the addition of wire mesh can disperse the incident energy from the impact center to the outer region, thereby improving the impact resistance of GFRP. It is worth noting that increasing the number of mesh could improve the stiffness of the panels and enhance their ability in CAI events compared with increasing the diameter of wires, their failure evolution was presented from the perspective of digital image correlation (DIC). For example, the maximum displacement of 0.50–40 J decreased by 10.6% from 2.5 to 2.26 mm compared with 20–60 J.

Landscape planning and design is an indispensable part of modern urban construction. In landscape design, rendering technology can transform designers' imagination into actual images, allowing people to better understand the design intent. In order to solve the problem of insufficient precision in image rendering in landscape design, this paper proposes a landscape design image rendering technology based on improved neural network technology. This technology combines stereo matching algorithms, which evaluate the corrected stereo images to calculate the differences between the real scene and the underlying model. The stereo matching algorithm is based on the basic model and obtains accurate depth information from a wide range image pair, making the rendered landscape image more realistic and precise. The experiment demonstrates the effectiveness of the landscape design image rendering system through two important aspects: processing speed and parallax accuracy. The development of image rendering technology in landscape design cannot be separated from the mutual promotion of theory and practice. The technology proposed in this article has certain practical value and hopes to make more positive contributions to urban construction and cultural inheritance.

Abstract Objective Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection. We aimed to evaluate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) for PJP. Methods A comprehensive electronic literature search of Web of Knowledge, PubMed, Cochrane Library, CNKI and Wanfang data was performed. Bivariate analysis was conducted to calculate the pooled sensitivity, specificity, diagnostic odds ratio (DOR), the area under the summary receiver operator characteristic (SROC) curve and the Q-point value (Q*). Results The literature search resulted in 9 studies with a total of 1343 patients, including 418 cases diagnosed with PJP and 925 controls. The pooled sensitivity of mNGS for diagnosis of PJP was 0.974 [95% confidence interval (CI), 0.953–0.987]. The pooled specificity was 0.943 (95% CI, 0.926–0.957), the DOR was 431.58 (95% CI, 186.77-997.27), the area under the SROC curve was 0.987, and the Q* was 0.951. The I 2 test indicated no heterogeneity between studies. The Deek funnel test suggested no potential publication bias. Subgroup analyses showed that the area under the SROC curve of mNGS for diagnosis of PJP in immunocompromised and non-HIV patients was 0.9852 and 0.979, respectively. Conclusions Current evidence indicates that mNGS exhibits excellent accuracy for the diagnosis of PJP. The mNGS is a promising tool for assessment of PJP in both immunocompromised and non-HIV patients.

Objectives Multiple myeloma (MM) is a malignant plasma cell disorder. The most widely accepted staging system for MM is the revised International Staging System based on cytogenetic and clinical biomarkers. The circulating clonal plasma cells (CPCs) were reported to have potential prognostic impact on MM. Among various diagnostic approaches, multiparametric flow cytometry (FCM) offers heightened sensitivity, minimal invasiveness and reproducibility. We conducted a meta-analysis to evaluate the prognostic value of quantifying CPCs via FCM in newly diagnosed symptomatic MM (NDMM) patients.Design Systematic review and meta-analysis.Data source PubMed, Web of Science, Embase and references of included studies.Eligibility criteria for selecting studies We included observational studies that evaluated the prognostic value of CPCs detected by FCM in NDMM.Data extraction and synthesis Data were screened and extracted independently by two investigators. The pooled results originated from random effects models. The primary endpoint was overall survival (OS). The secondary endpoint was progression-free survival (PFS). To evaluate the prognostic value of CPCs in NDMM, HRs and their 95% CI for both OS and PFS were derived using COX multivariable models. These values were then used to compute the pooled estimated effect.Results Our meta-analysis encompassed a total of 2704 NDMM patients from 11 studies up to 27 August 2022. The pooled HR for OS and PFS in CPC-positive (CPCs+) group and CPC-negative group were 1.95 (95% CI 1.24 to 3.07) and 2.07 (95% CI 1.79 to 2.39), respectively. The autologous stem cell transplantation (ASCT) failed to eliminate the adverse impact on OS and PFS. The heterogeneity may stem from the use of novel agents or traditional chemotherapy as initial treatment.Conclusion This meta-analysis indicates CPCs+ had an adverse impact on the prognosis of NDMM patients in the total population, and the adverse impact could not be eliminated by ASCT.PROSPERO registration number CRD42021272381.

Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.

With the help of bolted joints to assemble a complex structure, carbon fiber reinforced polymer composite (CFRP) is widely used in various fields. However, stress concentration around holes at the bolted joints leads to a decrease in bearing capacity. Composites often result in mechanical degradation subjected to a complex hydrothermal environment. Therefore, to study the tensile behavior of CFRP bolted joints subjected to hydrothermal aging, the tensile tests are conducted carefully. The influence of aging time and temperature on tensile strength is investigated based on the response history, strain contour, and failure morphology. The failure mechanism is revealed via digital image correlation technology. Finally, the experimental results demonstrate that the bearing capacity of the structure in hydrothermal aging decreases significantly. Compared with the unaged specimens, the peak force of the specimens aged for 6 weeks at 25°C and 65°C is reduced by 22.79% and 35.63%, respectively. Under both the unaged and aged, the same bearing failure is found in the tensile tests of CFRP single-bolt single-lap joints.

Abstract Spinal cord injury (SCI) can result in irreversible sensory and motor disability with no effective treatment currently. After SCI, infiltrated macrophages accumulate in epicenter through destructed blood-spinal cord barrier (BSCB). Further, great majority of macrophages are preferentially polarized to M1 phenotype, with only a few transient M2 phenotype. The purpose of this study was to explore roles of vascular endothelial cells in microglia/macrophages polarization and the underlying mechanism. Lipopolysaccharide (LPS) was used to pretreat BV2 microglia and RAW264.7 macrophages followed by administration of conditioned medium from microvascular endothelial cell line bEnd.3 cells (ECM). Analyses were then performed to determine the effects of exosomes on microglia/macrophages polarization and mitochondrial function. The findings demonstrated that administration of ECM shifted microglia/macrophages towards M2 polarization, ameliorated mitochondrial impairment, and reduced reactive oxygen species (ROS) production in vitro. Notably, administration of GW4869, an exosomal secretion inhibitor, significantly reversed these observed benefits. Further results revealed that exosomes derived from bEnd.3 cells (Exos) promote motor rehabilitation and M2 polarization of microglia/macrophages in vivo. Ubiquitin-specific protease 13 (USP13) was shown to be significantly enriched in BV2 microglia treated with Exos. USP13 binds to, deubiquitinates and stabilizes the NF-κB inhibitor alpha (IκBα), thus regulating microglia/macrophages polarization. Administration of the selective IκBα inhibitor betulinic acid (BA) inhibited the beneficial effect of Exos in vivo. These findings uncovered the potential mechanism underlying the communications between vascular endothelial cells and microglia/macrophages after SCI. In addition, this study indicates exosomes might be a promising therapeutic strategy for SCI treatment.

With increasing market competition and the arrival of technological innovation, the automobile-manufacturing industry faces great changes. In this situation, the quality of internal control becomes an important part that affects the growth and development of enterprises. According to the theories of internal control and enterprise growth, this paper selects data of Chinese listed-companies in the automobile manufacturing industry to analyse the relationship between the internal control index and enterprise growth. Further, it verifies the research conclusion using multiple regression analysis that the improvement of internal control quality can play a positive role in promoting the growth of automobile manufacturing enterprises.

The aim of this article is to investigate the failure and enhancement mechanism of bolt-strengthening glass fiber-reinforced polymer (GFRP) T-joints under quasi-static tension. One-step molding technology based on the vacuum-assisted resin infusion process is carried out to fabricate the GFRP T-joints structures. Then, a special fixture and constraint condition are set up to take the quasi-static tensile test with high reliability. Moreover, it is demonstrated that the T-joints structures may decrease their bearing capacity, resulting in interlaminar delamination at the corner region. Further, to strengthen the T-joints, the bolts are employed to effectively prevent the initiation and propagation of interlaminar delamination in the tensile loading. At the same time, as their enhancement and failure mechanisms are revealed deeply, the strengthening method is optimized as well.

Accumulating evidence suggests that liver injury can be induced by the over-expression of β1-adrenergic receptors (β1-ARs). High titers of autoantibodies specific to β1-adrenergic receptors (β1-AA) are detected in the sera of heart failure patients, potentially playing agonist-like roles. However, the role of β1-AA in liver function has not been characterized. In this study, we collect the sera of primary biliary cholangitis (PBC) patients, a condition which easily develops into liver fibrosis, and analyze the relationship between PBC and β1-AA. A passive immunization model is established to assess the effect of β1-AA on the liver. Subsequently, the effect of β1-AA on macrophages is investigated in vitro. Results show that PBC patients have a high titer and ratio of β1-AA, compared to controls. Liver injury and fibrosis are induced by β1-AA. In vitro experiments with ROS probe demonstrate that β1-AA induces macrophages to produce ROS and secrete TNFα. These effects can be partially reversed by metoprolol, a blocker for β1-AR. Results from the transwell and phagocytosis assays show that β1-AA promotes macrophage migration and phagocytosis. FCM tests suggest that β1-AA induces the alteration of M1 rather than M2 markers in macrophages. Finally, the Annexin V/PI assay indicates that macrophage culture supernatants stimulated by β1-AA cause hepatocyte apoptosis. Overall, these results suggest that β1-AA is involved in PBC. The β1-AA-induced activation, phagocytosis and phenotypic modification of macrophages may play an important role in the development of hepatic fibrosis and injury.

Abstract Background Spinal cord ischemia reperfusion injury (SCIRI) is a complication of aortic aneurysm repair or spinal cord surgery that is associated with permanent neurological deficits. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been shown to be potential therapeutic options for improving motor functions after SCIRI. Due to their easy access and multi-directional differentiation potential, adipose‐derived stem cells (ADSCs) are preferable for this application. However, the effects of ADSC-derived sEVs (ADSC-sEVs) on SCIRI have not been reported. Results We found that ADSC-sEVs inhibited SCIRI-induced neuronal apoptosis, degradation of tight junction proteins and suppressed endoplasmic reticulum (ER) stress. However, in the presence of the ER stress inducer, tunicamycin, its anti-apoptotic and blood–spinal cord barrier (BSCB) protective effects were significantly reversed. We found that ADSC-sEVs contain tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) whose overexpression inhibited ER stress in vivo by modulating the PI3K/AKT pathway. Conclusions ADSC-sEVs inhibit neuronal apoptosis and BSCB disruption in SCIRI by transmitting TSG-6, which suppresses ER stress by modulating the PI3K/AKT pathway.

COVID-19 induces acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and leads to severe immunological changes that threatens the lives of COVID-19 victims. Studies have shown that both the regulatory T cells and macrophages were deranged in COVID-19-induced ALI. Herbal drugs have long been utilized to adjust the immune microenvironment in ALI. However, the underlying mechanisms of herbal drug mediated ALI protection are largely unknown. This study aims to understand the cellular mechanism of a traditional Chinese medicine, Qi-Dong-Huo-Xue-Yin (QD), in protecting against LPS induced acute lung injury in mouse models. Our data showed that QD intrinsically promotes Foxp3 transcription via promoting acetylation of the Foxp3 promoter in CD4+ T cells and consequently facilitates CD4+CD25+Foxp3+ Tregs development. Extrinsically, QD stabilized β-catenin in macrophages to expedite CD4+CD25+Foxp3+ Tregs development and modulated peripheral blood cytokines. Taken together, our results illustrate that QD promotes CD4+CD25+Foxp3+ Tregs development via intrinsic and extrinsic pathways and balanced cytokines within the lungs to protect against LPS induced ALI. This study suggests a potential application of QD in ALI related diseases.

Abstract Background Increasing germline gene mutations have been discovered in haematological malignancies with the development of next-generation sequencing (NGS), which is critical for proper clinical management and long-term follow-up of affected individuals. Tet methylcytosine dioxygenase 2 (TET2) is one of the most common mutations in haematological neoplasms. We aimed to compare the clinical characteristics of patients with germline and somatic TET2 mutations in haematological diseases and to analyse whether germline TET2 mutations have a family aggregation and tumour predisposition. Methods Out of 612 patients who underwent NGS of 34 recurrently mutated genes in haematological diseases, 100 haematological patients with TET2 mutations were selected for further study. Somatic mutations were detected by NGS in bone marrow/peripheral blood genomic DNA (gDNA). Germline TET2 mutations were validated in nail/hair gDNA by Sanger sequencing. Digital data were extracted from the haematology department of the West China Hospital of Sichuan University. TET2 mutation results were analysed by referencing online public databases (COSMIC and ClinVar). Results One hundred patients were studied, including 33 patients with germline and 67 patients with somatic TET2 mutations. For germline TET2 mutations, the variant allele frequency (VAF) was more stable (50.58% [40.5–55], P

The effect of hydrothermal aging on the impact resistance of foam core sandwich panels is studied in this study. The sandwich panels with glass fiber-reinforced skins and polyurethane foam core were fabricated and then were treated with different hydrothermal aging conditions. The moisture absorption characteristic of the composite skins was evaluated. A modified Fickian formulation was proposed to predict the moisture absorption behavior of composite skins. The low-velocity impact resistance of the aged sandwich panels was determined at three different impact energies. The impact responses including contact force, deflection, and dissipated energy of the sandwich panels with and without hydrothermal aging were analyzed. The macroscopic and microscopic damage morphologies were observed by visual inspection and scanning electron microscope methods, respectively. The damage mechanism of the aged panels was revealed. Results indicate that the impact resistance of aged sandwich panels is degraded, and the performance degradation is larger with increasing aging temperature. Compared to the panel without hydrothermal aging, the reduction of the contact force is 35.69%, and the increase of the deflection is 71.43% for the aged panel at 70°C aging temperature. The fiber/matrix interfacial cohesive performance is degraded resulting from the hydrothermal aging.

Objectives Whether KMT2A-PTD has a prognostic impact on patients with acute myeloid leukaemia (AML) is controversial. Therefore, we conducted a meta-analysis to assess the prognostic value of KMT2A-PTD in patients with AML.Methods Eligibility criteria: we included studies concerning the prognostic value of KMT2A-PTD in patients with AML.Information sources: Eligible studies were identified from PubMed, Embase, Medline, Web of Science, Cochrane Library and Chinese Biomedical Database. The systematic search date was 19 December 2020.Risk of bias: Sensitivity analysis was used to evaluate the stability and reliability of the combined results. Begg’s and Egger’s tests were used to assess the publication biases of studies.Synthesis of results: We calculated the pooled HRs and their 95% CIs for overall survival (OS) and event-free survival (EFS) by Stata V.12 software.Results Included studies: 18 studies covering 6499 patients were included.Synthesis of results: KMT2A-PTD conferred shorter OS in total population (HR=1.30, 95% CI 1.09 to 1.51). In the subgroup analysis, KMT2A-PTD also resulted in shorter OS in karyotypically normal AML patients (HR=2.72, 95% CI 1.83 to 3.61) and old AML patients (HR=1.93, 95% CI 1.44 to 2.42). KMT2A-PTD indicated no prognostic impact on EFS in total population (HR=1.26, 95% CI 0.86 to 1.66). However, in the sensitivity analysis, KMT2A-PTD resulted in poor EFS (HR=1.34, 95% CI 1.04 to 1.64) when deleting the study with a relatively obvious effect on the combined HR. In the subgroup analysis, KMT2A-PTD was associated with poor EFS in old AML patients (HR=1.64, 95% CI 1.25 to 2.03).Conclusion The findings indicated that KMT2A-PTD had an adverse impact on the prognosis of patients with AML in the total population, and the conclusion can also be applied to some subgroups including karyotypically normal AML and old AML patients. KMT2A-PTD may be a promising genetic biomarker in patients with AML in the future.Trial registration number CRD42021227185.

Superelastic shape memory alloy (SMA) as an advanced smart material has been used to improve the impact performance of fiber-reinforced composites in recent decades. Due to the low impact toughness of the thin composite face-sheet and the poor strength of the foam core, sandwich panels are sensitive to the transverse loading. SMA fibers were embedded into the composite laminated to improve the impact resistance of the traditional foam core sandwich panel in this work. Five new types of SMA hybrid panels were prepared, and the testing panels with penetration failure were observed at the impact energy of 50 J. The impact mechanical responses and the damage morphology were analyzed, and the impact failure mechanism was also revealed. Results show that all sandwich panels were failed, the fiber breakage occurred at the impact region in the traditional panels, while part plies of the rear face-sheets split-off in the SMA hybrid panels. The impact performance of the SMA hybrid panels is improved when compared with the traditional panel, the reduction of the delamination area by 48.15% and the increase of the load-bearing threshold by 32.75% are acquired for the hybrid sandwich panel with two layers of SMA fibers in the rear face-sheet.

Patients with chronic myeloid leukemia (CML) show resistance to tyrosine kinase inhibitors (TKIs) targeting ABL1 due to the emergence of BCR::ABL1 mutants, especially compound mutants during the treatment, which brings great challenges to clinical practice. Combination therapy is an effective strategy for drug resistance. GMB-475, a proteolysis targeting chimera (PROTAC) targeting the myristoyl pocket of ABL1 in an allosteric manner, degrades the BCR::ABL1 through the ubiquitin–proteasome pathway. In this study, we combined GMB-475 with orthosteric TKIs targeting ABL1 to overcome resistance. We constructed Ba/F3 cells carrying BCR::ABL1 mutants by gene cloning technology and compared the effects of combination therapy with those of monotherapy on the biological characteristics and signaling pathways in CML cells. We found that the effects of ABL1 inhibitors, including imatinib, dasatinib, ponatinib, and ABL001, on growth inhibition and promoting apoptosis of Ba/F3 cells with BCR::ABL1 mutants, especially compound mutants, were weakened. GMB-475 combined with TKIs, especially dasatinib, synergistically inhibited growth, promoted apoptosis, and blocked the cell cycle of Ba/F3 cells carrying BCR::ABL1 mutants and synergistically blocked multiple molecules in the JAK-STAT pathway. In conclusion, dasatinib enhanced the antitumor effect of GMB-475; that is, the combination of PROTAC targeting ABL1 in an allosteric manner and orthosteric TKIs, especially dasatinib, provides a novel idea for the treatment of CML patients with BCR::ABL1 mutants in clinical practice.

Abstract Background Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM. Methods We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software. Results We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543–0.806), 0.317 (95%CI 0.221–0.454), and 0.479 (95%CI 0.328–0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584–1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284–3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41–2.344). Conclusions Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.

Abstract Background Spinal cord injury (SCI) is a severe traumatic disease which causes high disability and mortality rates. The molecular pathological features after spinal cord injury mainly involve the inflammatory response, microglial and neuronal apoptosis, abnormal proliferation of astrocytes, and the formation of glial scars. However, the microenvironmental changes after spinal cord injury are complex, and the interactions between glial cells and nerve cells remain unclear. Small extracellular vesicles (sEVs) may play a key role in cell communication by transporting RNA, proteins, and bioactive lipids between cells. Few studies have examined the intercellular communication of astrocytes through sEVs after SCI. The inflammatory signal released from astrocytes is known to initiate microglial activation, but its effects on neurons after SCI remain to be further clarified. Methods Electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting were applied to characterize sEVs. We examined microglial activation and neuronal apoptosis mediated by astrocyte activation in an experimental model of acute spinal cord injury and in cell culture in vitro. Results Our results indicated that astrocytes activated after spinal cord injury release CCL2, act on microglia and neuronal cells through the sEV pathway, and promote neuronal apoptosis and microglial activation after binding the CCR2. Subsequently, the activated microglia release IL-1β, which acts on neuronal cells, thereby further aggravating their apoptosis. Conclusion This study elucidates that astrocytes interact with microglia and neurons through the sEV pathway after SCI, enriching the mechanism of CCL2 in neuroinflammation and spinal neurodegeneration, and providing a new theoretical basis of CCL2 as a therapeutic target for SCI.

Abstract A large maxillary odontogenic cyst could intrude into the maxillary sinus. The traditional approach following surgery for such a cyst is the Caldwell–Luc procedure. However, the traditional CDL procedure is associated with more complications and damage of the sinus mucosa. The purpose of this study was to assess a new method with easier operation, which not only prevented postoperative infection but also caused less damage to the maxillary sinus mucosa. A large odontogenic cyst in the maxillary sinus of 40 patients was diagnosed through radiographic imaging and postoperative histopathology. Twenty patients were treated with maxillary sinus saline irrigation after surgery, while 20 patients underwent the traditional Caldwell–Luc procedure. The therapeutic efficacy was evaluated by clinical examination and radiographic imaging; the longest follow-up was 36 months. The postoperative reaction was evaluated. There was a statistically significant difference in facial swelling, visual analog scale (VAS) and temperature elevation between the 2 groups. Sinus irrigation following large odontogenic cyst surgery involving the maxillary sinus can serve as an alternative to standard CDL and has the advantages of fewer complications, reduced trauma, restoration of the mucosa and more satisfactory results.

Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.

Yue Zhou,1 Ai-Qing Nie,1 Shang Chen,2 Meng-Meng Wang,1 Rui Yin,1 Bo-Hao Tang,1 Yue-E Wu,1 Fan Yang,1 Bin Du,1 Hai-Yan Shi,3 Xin-Mei Yang,3 Guo-Xiang Hao,1 Xiu-Li Guo,4 Qiu-Ju Han,5 Yi Zheng,1,* Wei Zhao1,3,* 1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Institute of Biochemical and Biotechnological Drug, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 5Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zheng; Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhengyi@sdu.edu.cn; zhao4wei2@hotmail.comPurpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.Keywords: disease-induced pharmacokinetic change, renal transporters, inflammatory cytokines, clearance

Cyberspace strategic early-warning is a monitoring and warning system that is established by a country or group for early detection, tracking, identification, and notification of incoming major cyber attacks or the spreading destruction of powerful viruses. It’s an important component of a national security defense system. The implementation of the national cyber development strategy in China requires high attentions to the construction of a cyberspace strategic early-warning system. This study analyzes the major characteristics and basic requirements of strategic early-warning in cyberspace, and studies four major warning styles: security vulnerabilities, security threats, intrusion attacks, and abnormal behaviors warning. It also emphasizes four key projects, namely cyberspace surveying and mapping system, vulnerability collection and early-warning platform, threat intelligence perception and push system, as well as security monitoring and comprehensive early-warning system, after summarizing the construction of strategic early-warning and monitoring systems in cyberspace in China and abroad. Furthermore, we propose several countermeasures and suggestions, including strengthening high-level coordination, focusing on multi-source data integration, establishing professional earlywarning agencies, conducting regular security assessments, and implementing threat and early-warning grading mechanisms.

The aim of this paper is to study the effect of friction coefficient and impact angle on the failure behaviors of glass fiber reinforced aluminum laminates (GLARE) under the low-velocity impact (LVI) loading. A methodology is developed in commercial software ABAQUS/Explicit, and its accuracy is verified based on the results of comparison between simulation and experiment. In the simulation, Johnson–Cook flow stress model and surface-based cohesive behavior are carried out to simulate the damage evolution of aluminum alloy layers and delamination at the interface. Further, both the dynamic response history and damage mechanism characterization of these hybrid laminates are presented and compared carefully. Additionally, due to the advantage of simulation, it is accurate and easy to discuss on the evolution of the damage contour consisting of the damage degree of composite and metal layers as well as the interface between them. Finally, the influence rules of friction coefficient and angle on the failure behaviors of GLARE under LVI are drawn clearly.

m6A modification is the most common modification in eukaryotes. METTL3, as a core methyltransferase of m6A modification, plays a vital role in normal and malignant hematopoiesis. Recent studies have shown that METTL3 is required for normal and symmetric differentiation of hematopoietic stem/progenitor cells (HSPCs). Moreover, METTL3 strongly impacts the process and development of hematological neoplasms, including the differentiation, apoptosis, proliferation, chemoresistance, and risk of tumors. Novel inhibitors of METTL3 have been identified and studied in acute myeloid leukemia (AML) cells. STM2457, a selective inhibitor of METTL3, has been identified to block proliferation and promote differentiation and apoptosis of AML cells without impacting normal hematopoiesis. Therefore, in our present review, we focus on the structure of METTL3, the role of METTL3 in both normal and malignant hematopoiesis, and the potential of METTL3 for treating hematological neoplasms.

The adoption of zero-emission vehicles (ZEVs) offers multiple benefits for the climate, air quality, and public health by reducing tailpipe emissions. However, the environmental justice implications of the nonexhaust emissions from future ZEV fleets for near-roadway communities remain unclear. Here, we model the on-road fine particulate matter (PM2.5) emissions across all California counties and assess the near-roadway exposure disparities at the census block group level in the Los Angeles County in 2050, when almost all passenger vehicles are projected to be ZEVs. We found that promoting zero-emission heavy-duty trucks generates more air quality benefits for disadvantaged communities than light-duty passenger vehicles. Persistent disparities in near-roadway PM2.5 levels, however, exist due to the remaining brake and tire wear emissions and increased truck traffic in disadvantaged communities. We recommend implementing fleet-specific ZEV policies to address brake and tire wear emissions and optimizing freight structures to address these persistent environmental justice issues in California.

Qian Li,1,2,* Kai Wang,3,* Hai-Yan Shi,2 Yue-E Wu,1 Yue Zhou,1 Min Kan,1 Yi Zheng,1 Guo-Xiang Hao,1 Xin-Mei Yang,2 Yi-Lei Yang,2 Le-Qun Su,2 Xiao-Ling Wang,4 Evelyne Jacqz-Aigrain,5,6 Jun Zhou,7,* Wei Zhao1,2,* 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Respiratory Disease, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 5Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, AP-HP, Paris, France; 6University Paris Diderot, Sorbonne Paris-Cité, Paris, France; 7Clinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun ZhouClinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, 16766 Jing Shi Street, Jinan 250014, People’s Republic of ChinaTel/Fax +86 531 8237 3200Email zhoujun_jn@163.comWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 Culture West Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei@hotmail.comBackground: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients.Methods: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient’s clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.Results: Fifty patients (age range: 0.7–10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient’s weight was also found to be significantly corrected with montelukast clearance (p

Due to the properties of shape memory effect and super-elasticity, shape memory alloy (SMA) is added into glass fiber reinforced polymer (GFRP) face-sheets of foam core sandwich panels to improve the impact resistence performance by many researchers. This paper tries to discuss the failure mechanism of sandwich panels with GF/ epoxy face-sheets embedded with SMA wires and conventional 304 SS wire nets under low-velocity impact and compression after impact (CAI) tests. The histories of contact force, absorbed energy and deflection during the impact process are obtained by experiment. Besides, the failure modes of sandwich panels with different ply modes are compared by visual inspection and scanning electron microscopy (SEM). CAI tests are conducted with the help of digital image correlation (DIC) technology. Based on the results, the sandwich panels embedded with SMA wires can absorb more impact energy, and show relatively excellent CAI performance. This is because the SMA wires can absorb and transmit the energy to the outer region of GFRP face-sheet due to the super-elasticity-behavior. The failure process and mechanism of the CAI test is also discussed.

Aim: This study aimed to investigate the relationship between clinicopathological characteristics of atypical meningiomas (AM) and its post-operative recurrence.Materials and Methods: The clinicopathological characteristics and findings from follow up were retrospectively reviewed and compared between AM and benign meningioma (BM) patients. Univariate and multivariate analyses were employed to identify the factors related to the post-operative recurrence of AM.Results: More BM patients were females and received complete resection; the recurrence rate was significantly lower in BM patients as compared to AM patients. The progesterone receptor (PR), E-cadherin protein (E-Ca) and β-catenin positive rates and Ki67 labeling index were significantly different between two groups. Univariate analysis showed the age, tumor size, tumor invasiveness, E-Ca expression, and extent of resection were related to the post-operative recurrence of AM. However, multivariate analysis showed only the extent of resection and tumor invasiveness were the independent factors associated with the post-operative recurrence of AM.Conclusions: The extent of resection and tumor invasiveness are related to the post-operative recurrence of AM. To improve the surgical procedures to maximize the tumor resection is important to improve the prognosis of AM patients.

Sudden unexplained nocturnal death syndrome （SUNDS） is always a difficulty in forensic medicine researches. Although the development of molecular genetics promotes the etiologic study of SUNDS, the pathogenesis of most such cases is still unclear. Sleep apnea syndrome （SAS） is one of the common forms of sleep disorders, and obstructive sleep apnea hypopnea syndrome （OSAHS） is the most common. In recent years, some domestic and international researches show that OSAHS is related to the development of cardiovascular disease, which may cause cardiac arrhythmia, even sudden death. This article reviews the relationship between SUNDS and OSAHS and aims to provide new ideas for the pathogenesis of SUNDS.