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For the analysis of multivariate failure time data when the primary covariates are incomplete but the auxiliary covariates for them are available for the whole cohort subjects, an estimated quadratic inference function method is developed to improve the estimation efficiency under the marginal hazard model with common baseline hazard function. Both the auxiliary information and the intra-cluster correlation between the failure times are incorporated in the estimation procedure. The proposed estimator is shown to be consistent and asymptotically normal. Simulation studies demonstrate that when the intra-cluster correlation is strong or moderate, the proposed method gains noticeable efficiency compared to other existing methods. [ABSTRACT FROM AUTHOR]

We develop the quadratic inference function method to the parameter estimation of the marginal models with general relative risk form and common baseline hazard function for multivariate failure time data. The usual exponential relative risk form is relaxed to an non-negative twice differentiable form. The proposed estimator, under some regularity conditions, is shown to be consistent and asymptotically normal with a covariance matrix that can be consistently estimated. In addition, a test statistic based on the quadratic inference function for the parameter inference has been provided. The simulation results show that the proposed method taking the correlation between the failure times into the estimation procedure gains more efficiency than the method using the independent structure when the correlation cannot be ignored, and can easily deal with the situation when the cluster size is large. The proposed method is illustrated by analysis of a real data from the Diabetic Retinopathy Study. [ABSTRACT FROM AUTHOR]

An estimated quadratic inference function method is proposed for correlated failure time data with auxiliary covariates. The proposed method makes efficient use of the auxiliary information for the incomplete exposure covariates and preserves the property of the quadratic inference function method that requires the covariates to be completely observed. It can improve the estimation efficiency and easily deal with the situation when the cluster size is large. The proposed estimator which minimizes the estimated quadratic inference function is shown to be consistent and asymptotically normal. A chi‐squared test based on the estimated quadratic inference function is proposed to test hypotheses about the regression parameters. The small‐sample performance of the proposed method is investigated through extensive simulation studies. The proposed method is then applied to analyze the Study of Left Ventricular Dysfunction (SOLVD) data as an illustration. [ABSTRACT FROM AUTHOR]

In order to study the mechanical properties of ultra-high performance engineered cementitious composites (UHP-ECC) used for cable channel repair, orthogonal tests were carried out with four influencing factors, water binder ratio, silica fume, fly ash and mortar ratio, to obtain the optimum mix ratio of the cement paste. On this basis, the effects of ethylene-vinyl acetate (EVA) polymer and polyvinyl alcohol (PVA) fiber on the fluidity, flexural strength and compressive strength of UHP-ECC were studied, and the micromechanism was analyzed with SEM. The results show that the fluidity of UHP-ECC material prepared was 170–200 mm, which meets the requirements of working performance. The average compressive strength at 28 days reached 85.3 MPa, and the average flexural strength at 28 days reached 22.3 MPa. EVA polymer has a fast film forming rate in an alkaline environment. The formed polymer film wraps the fiber, enhances the bridging role between the fiber and the matrix and increases the viscosity of the material. Therefore, the early flexural strength is significantly improved. The 1-d flexural strength of UHP-ECC material mixed with 9-mm fiber is increased by 18%, and the 1-d flexural strength of 3-mm fiber is increased by 15%. Due to PVA fiber's high elastic modulus and tensile strength, it improved the flexural and tensile properties of the material after incorporation, especially in the later stages; the 28-d flexural strength of UHP-ECC material mixed with 9-mm fiber increased by 12%, and the 28-d flexural strength of 3-mm fiber increased by 7%. It was concluded that the effect of 9-mm PVA fiber is better than that of 3 mm PVA fiber. [ABSTRACT FROM AUTHOR]

Background: The triglyceride glucose (TyG) index, which is a new surrogate indicator of insulin resistance (IR), is thought to be associated with many diseases, such as cardiovascular disease, but its relationship with cerebrovascular disease is still controversial. Methods: The PubMed, EMBASE, Cochrane Library, Web of Science and Medline databases were searched until March 2022 to evaluate the association between the TyG index and cerebrovascular disease risk. A random‒effects model was used to calculate the effect estimates and 95% confidence intervals (CIs). Results: A total of 19 cohort studies and 10 case‒control/cross‒sectional studies were included in our study, which included 11,944,688 participants. Compared with a low TyG index, a higher TyG index increased the risk of cerebrovascular disease (RR/HR = 1.22, 95% CI [1.14, 1.30], P< 0.001; OR = 1.15, 95% CI [1.07, 1.23], P< 0.001). Furthermore, the results of the dose-response analysis of the cohort study demonstrated that the risk of cerebrovascular disease increased by 1.19 times per 1 mg/dl increment of the TyG index (relative risk = 1.19, 95% CI [1.13,1.25], P< 0.001). Conclusion: TyG index is related to cerebrovascular disease. More data and basic research are needed to confirm the association. [ABSTRACT FROM AUTHOR]

In this article, we develop a so‐called profile likelihood ratio test (PLRT) based on the estimated error density for the multiple linear regression model. Unlike the existing likelihood ratio test (LRT), our proposed PLRT does not require any specification on the error distribution. The asymptotic properties are developed and the Wilks phenomenon is studied. Simulation studies are conducted to examine the performance of the PLRT. It is observed that our proposed PLRT generally outperforms the existing LRT, empirical likelihood ratio test and the weighted profile likelihood ratio test in sense that (i) its type I error rates are closer to the prespecified nominal level; (ii) it generally has higher powers; (iii) it performs satisfactorily when moments of the error do not exist (eg, Cauchy distribution); and (iv) it has higher probability of correctly selecting the correct model in the multiple testing problem. A mammalian eye gene expression dataset and a concrete compressive strength dataset are analyzed to illustrate our methodologies. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the clinical efficacy of Andersson lesion (AL) treatments and prognostic factors using medium‐ to long‐term follow‐up data and discuss the clinical characteristics and treatment of AL. Forty‐eight consecutive AL cases at our center from June 2011 to March 2018 were retrospectively analyzed, including 13 cases treated conservatively and 35 treated surgically. Epidemiological characteristics, treatment modalities, clinical features and outcomes, and prognostic factors of the Japanese Orthopaedic Association (JOA) recovery rate were reviewed. Neurological functional recovery was evaluated by American Spinal Injury Association (ASIA) classification. Clinical efficacy was evaluated by JOA score, visual analog scale (VAS) score, and Cobb's angle. The mean overall follow‐up duration was 44.5±18.5 months (range, 27–85 months). There were 36 male and 12 female patients, with a mean age of 49.4±13.1 years (range, 26–72 years). The most common lesion location was the thoracolumbar region, i.e., T10‐L2 (n=33; 68.8%), followed by the thoracic (n=10) and lumbar (n=5) regions. Patients treated surgically showed significantly better JOA scores, VAS scores and Cobb's angles at the final follow‐up than did patients treated conservatively (P<.05). Univariate and binary logistic regression analyses identified two prognostic factors of the JOA score recovery rate: treatment modality (OR=0.157; 95%CI, 0.028–0.89; P=.036) and bone fusion (OR=9.965; 95%CI, 2.052–48.387; P=.004). Conservative treatment and bone nonunion predict worse JOA score recovery. Surgery remains the optimal treatment for AL in ankylosing spondylitis patients, with better clinical efficacy demonstrated by medium‐ to long‐term follow‐up data. [ABSTRACT FROM AUTHOR]

Fabrication of polymer films with superb mechanical properties is far from mature compared to that of fibers, hampering the further engineering applications of lightweight polymer materials. Herein, high density polyethylene (HDPE) films reinforced with re-dispersed or refined reduced graphene oxide (rGO) are prepared via a facile melt-stretching strategy. The incorporation of only 0.2 wt% rGO is demonstrated to endow the melt-stretched film (80× stretch ratio) with ultrahigh Young's modulus of 2.9 GPa and tensile strength of 162.2 MPa, which are comparable to many engineering plastics and also significantly superior to the existing HDPE/graphene composites. More importantly, these modulus and strength values are increased by 71 and 65% compared to the neat PE (80×), respectively, far more than the theoretical prediction with the mixing rule. Experimental characterizations indicate that the high-efficient mechanical enhancement is attributed to the strong synergy of melt stretching-driven crystallization and rGO re-dispersion or refinement in constructing the compact and robust shish-kebabs crystal network. Such microstructural characteristics greatly promote the load transfer along the covalently bonded molecular chains, and also from polymer to rigid fillers under loading. Furthermore, the excellent puncture resistance and thermo-mechanical properties of PE/rGO films have been demonstrated. This work provides a feasible way towards scalable manufacturing of high-performance polymer nanocomposite films from general plastics and carbonaceous nanomaterials. [Display omitted] • HDPE/rGO nanocomposite films are fabricated by a facile melt stretching process. • Superb mechanical performance of films is achieved at very low filler content. • Melt stretching-driven rGO re-dispersion or refinement is demonstrated. • rGO re-dispersion enhances the formation of robust shish-kebabs crystal network. • Good puncture resistance and thermo-mechanical properties of films are revealed. [ABSTRACT FROM AUTHOR]

In many industrial processes, polymer melt undergoes complex flow-cooling environments before being solidified into the final products. Investigating polymer crystallization under processing conditions is a necessary step to predict and customize the structures and properties of semicrystalline polymers. Herein, the crystallization behavior of high-density polyethylene (HDPE) under combined melt stretching and fast cooling fields was studied through a homemade extensional rheometer. A series of HDPE samples were prepared by cooling the stretched melt at different cooling rates (0.02–220 °C/s) immediately after flow, or after waiting for different times of isothermal crystallization at 128 °C. Microstructural characterizations confirm four different structural states related to the evolution of shish-kebabs after melt stretching, namely generation of shish precursors, shish crystal growth, kebab lamellar growth, and perfection of shish-kebabs, which diversify greatly the structures and morphologies of the final solidified samples. By prolonging the isothermal crystallization time at high temperature, the fast cooling-induced lamellae keep decreasing in thickness. This supports the occurrence of molecular segregation caused by shish-kebabs growth at high temperature, which reduces the molecular weight of the remaining un-crystallized melt. In addition, quantitative analysis of crystalline orientation manifests that the lamellar growth during isothermal process takes strictly the shish as a template and adopts a high orientation, while the fast cooling-induced lamellae are only related to the chains conformation of un-crystallized melt prior to cooling. This work would be essential to advance the in-depth understanding on the actual industrial processing of semicrystalline polymeric materials. [Display omitted] • Melt crystallization of HDPE under combined stretching and fast cooling fields was studied. • Four different structural states related to the evolution of shish-kebabs after flow were identified. • Molecular segregation caused by shish-kebabs growth at high temperature was suggested. • Isothermal and non-isothermal crystallization under flow presented different lamellar growth modes. [ABSTRACT FROM AUTHOR]

Gallic acid (GA) and lecithin showed important roles in antioxidant and drug delivery, respectively. A complex synthesized from GA and soybean lecithin (SL-GAC), significantly improved bioavailability of GA and pharmacological activities. However, the antioxidant activity of SL-GAC and its effect on iron-overload-induced liver injury remains unexplored. This study investigates the antioxidant properties of SL-GAC in vitro and in mice, and its remediating effects against liver injury by iron-overloaded. In vitro, free radical scavenging activity, lipid peroxidation inhibition, and ferric reducing power of SL-GAC were measured by absorbance photometry. In vivo, C57BL/6J mice were randomized into 4 groups: control, iron-overloaded, iron-overloaded + deferoxamine, and iron-overloaded + SL-GAC. Treatments with deferoxamine (150 mg/kg/intraperitioneally) and SL-GAC (200 mg/kg/orally) were given to the desired groups for 12 weeks, daily. Iron levels, oxidative stress, and biochemical parameters were determined by histopathological examination and molecular biological techniques. In vitro, SL-GAC showed DPPH and ABTS free radicals scavenging activity with IC50 values equal to 24.92 and 128.36 μg/mL, respectively. In C57BL/6J mice, SL-GAC significantly reduced the levels of serum iron (22.82%), liver iron (50.29%), aspartate transaminase (25.97%), alanine transaminase (38.07%), gamma glutamyl transferase (42.11%), malondialdehyde (19.82%), total cholesterol (45.96%), triglyceride (34.90%), ferritin light chain (18.51%) and transferrin receptor (27.39%), while up-regulated the levels of superoxide dismutase (24.69%), and glutathione (11.91%). These findings encourage the use of SL-GAC to treat liver injury induced by iron-overloaded. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine. [ABSTRACT FROM AUTHOR]

Keywords: COVID-19; venous thrombosis EN COVID-19 venous thrombosis 181 183 3 07/16/20 20200714 NES 200714 The coronavirus disease 2019 (COVID-19) pandemic has caused >4 million infections and 280 000 deaths worldwide (as of May 13, 2020). During the 2002 severe acute respiratory syndrome pandemic, the incidences of deep vein thrombosis (DVT) and pulmonary embolism were 20.5% and 11.4% in autopsy cases.[2] Whether thrombosis contributes to the high mortality of COVID-19 remains unclear. In terms of patient deaths, as of April 16, 2020, 2 patients (28.6%) in the no DVT group, 10 (27.8%) in the isolated distal DVT group, and 3 (60%) in the proximal DVT group died ( I P i =0.43). [Extracted from the article]

Background: Various trials have compared the efficacy and toxicity of liposomal doxorubicin-based chemotherapy with the conventional formulation of doxorubicin although arriving at inconsistent conclusions. To derive a conclusive assessment of the efficacy and cardiotoxicity associated with chemotherapy, we performed a meta-analysis by combining data from all eligible randomized controlled trials. Methods: We used the PubMed database to identify relevant studies published through December 28, 2014. Eligible studies included randomized controlled trials directly comparing the efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy with conventional doxorubicin in advanced breast cancer with adequate data. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the efficacy and cardiotoxicity in a fixed-effects or random-effects model. Results: Ten randomized controlled trials containing efficacy and data from a total of 2,889 advanced breast cancer patients were included in this report. Liposomal doxorubicin-based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity (OR = 0.46, 95% CI 0.23 to 0.92, p = 0.03) and a significant improvement in the overall response rate (ORR) (OR = 1.25, 95% CI 1.02 to 1.52, p=0.03) compared with conventional doxorubicin. An apparent improvement in progression-free survival (PFS) for patients treated with liposomal doxorubicin-based chemotherapy was noted; however, this difference was not significant (HR = 1.14, 95% CI 0.96 to 1.34, p = 0.12). In terms of overall survival (OS), no significant difference between the two chemotherapy regimens was noted (HR = 1.00, 95% CI 0.91 to 1.10, p = 0.93). Conclusion: The results of this meta-analysis suggest that liposomal doxorubicin-based chemotherapy is associated with a significant improvement in the ORR and a significant reduction in the risk of cardiotoxicity. [ABSTRACT FROM AUTHOR]

ATP-sensitive K(+) channels (K(ATP) channels) of pancreatic beta-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP(2)), stimulate K(ATP) channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of K(ATP) channels and hence of insulin secretion in beta-cells. Here, we tested this hypothesis by manipulating the interactions between K(ATP) channels and membrane phospholipids in a beta-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP(2) by overexpressing PIP(2)-insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP(2) by upregulating PIP(2) levels via overexpression of a lipid kinase, phosphatidylinositol 4-phosphate 5 kinase, decreases the ATP sensitivity of endogenous K(ATP) channels by approximately 26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and K(ATP) channels in regulating insulin secretion. [ABSTRACT FROM AUTHOR]

The pancreatic ATP-sensitive potassium (KATP) channel, a complex of four sulfonylurea receptor 1 (SUR1) and four potassium channel Kir6.2 subunits, regulates insulin secretion by linking metabolic changes to β-cell membrane potential. Sulfonylureas inhibit KATP channel activities by binding to SUR1 and are widely used to treat type II diabetes. We report here that sulfonylureas also function as chemical chaperones to rescue KATP channel trafficking defects caused by two SUR1 mutations, A116P and V187D, identified in patients with congenital hyperinsulinism. Sulfonylureas markedly increased cell surface expression of the A116P and V187D mutants by stabilizing the mutant SUR1 proteins and promoting their maturation. By contrast, diazoxide, a potassium channel opener that also binds SUR1, had no effect on surface expression of either mutant. Importantly, both mutant channels rescued to the cell surface have normal ATP, MgADP, and diazoxide sensitivities, demonstrating that SUR1 harboring either the A116P or the V187D mutation is capable of associating with Kir6.2 to form functional KATP channels. Thus, sulfonylureas may be used to treat congenital hyperinsulinism caused by certain KATP channel trafficking mutations. [ABSTRACT FROM AUTHOR]

The ideal tissue engineering scaffold should facilitate rapid cell infiltration and provide an optimal immune microenvironment during interactions with the host. Electrospinning can produce two-dimensional (2D) membranes mimicking the extracellular matrix. However, their dense structure hinders cell penetration, and their thin form restricts scaffold utility. In this study, latticed hydrogels were three-dimensional (3D) printed onto electrospun membranes. This technique allowed for layer-by-layer assembly of the membranes into 3D scaffolds, which maintained their resilience impressively under both dry and wet conditions. We assessed the cellular and host responses of these 3D nanofiber scaffolds by comparing random membranes and mesh-like membranes with three different mesh sizes (250, 500, and 750 μm). It was found that scaffolds with a mesh size of 500 μm were superior for M2 macrophage phenotype polarization, vascularization, and matrix deposition. Furthermore, it was confirmed by subsequent experiments such as RNA sequencing that the mesh-like topology may promote polarization to the M2 phenotype by affecting the PI3K/AKT pathway. In conclusion, our work offers a novel method for transforming 2D nanofiber membranes into 3D scaffolds. This method boasts flexibility, allowing for the use of varied electrospun membranes and hydrogels in terms of structure and composition. It has vast potential in tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

The treatment and repair of large bone defects remains a major therapeutic challenge in the clinical setting. Nanofiber scaffolds fabricated via the electrospinning technique have been developed as a universal method for bone regeneration due to their suitable properties. However, traditional two-dimensional (2D) nanofiber mats are usually too dense, which may prevent cell infiltration and growth, thereby restricting their application. Herein, a three-dimensional (3D) polycaprolactone nanofiber scaffold was developed, modified by biomineralization and silk fibroin coating. The scaffold possessed a parallel array of nanofiber surfaces, mimicking the parallel structure of fibrils in natural bone tissue. Furthermore, the fabricated radially or laterally interconnected macrochannels were investigated to elucidate the effect of the scaffold structure on bone regeneration. In vitro studies revealed that the scaffolds could guide cell arrangement and that the radially aligned scaffold demonstrated a stronger ability to promote cell proliferation. In vivo results showed that the radially aligned scaffold could guide tissue arrangement and remodeling and support a significantly faster regeneration rate of bone tissue. Therefore, 3D-mineralized polycaprolactone nanofiber scaffolds with radially interconnected macrochannels and aligned nanofibers are expected to be used in tissue engineering, including in the repair of bone defects, cartilage or other composite tissues. [ABSTRACT FROM AUTHOR]

Purpose: The sensitivity of advanced hepatocellular carcinoma (HCC) to Sorafenib is low. The purpose of this study was to investigate the effects of cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on the prognosis of HCC and the sensitivity of HCC cells to Sorafenib. Patients and methods: Streptavidin-perosidase (SP) staining was performed to determine the expression of CDKN2B in HCC tissues and adjacent tissues. The cell counting kit-8 (CCK-8) assay was carried out to determine cell viability. CDKN2B mRNA and protein were tested by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. CDKN2B gene was silenced or over-expressed in the cells by plasmid transfection technique. Flow cytometry was carried out to detect cell cycle and apoptosis. Results: SP staining results showed that CDKN2B was positive in adjacent tissues and in HCC tissues from partial response (PR) patients, CDKN2B was slightly positive in stable disease (SD) patients, but negative in progression disease (PD) patients. The survival rate of patients with low expression of CDKN2B was low. Up-regulation of CDKN2B expression could promote the pro-apoptotic effect of Sorafenib and cell arrest in G1 phase. When the CDKN2B gene expression was down-regulated, the cell apoptosis rate and the proportion of cells treated with Sorafenib in G1 phase decreased. Silencing CDKN2B reversed CDKN2B overexpression caused by Sorafenib. Conclusion: CDKN2B genes were lowly expressed in tumor tissues from HCC patients who were treated with Sorafenib and had a poor prognosis. Up-regulation of CDKN2B promoted sensitivity of HCC to Sorafenib, and similarly down-regulation of CDKN2B reduced the sensitivity. [ABSTRACT FROM AUTHOR]

Trivalent iron (Fe3+)-dependent anaerobic oxidation of methane (Fe-AOM), which is mediated by metal-reducing bacteria, is widely recognized as a major sink for the greenhouse gas methane (CH 4), and is a key driver of the carbon (C) biogeochemical cycle. However, the effect of Fe3+ addition on AOM in the present investigation is still ambiguous, and the mechanism is vague. In this study, we investigated the mechanism of changes in AOM response to Fe3+ input at different wetlands by using laboratory incubation methods combined with molecular biology techniques. Results indicated that Fe3+ input did not always lead to promoted AOM rates, which may be mediated by complex environmental factors, while lower soil total nitrogen (TN) had a positive effect on the response of AOM subjected to Fe3+ input. Notably, the promoted response of AOM was regulated by higher soil microbial diversity, of which the Shannon index was a key indicator leading to variation in the AOM response. Additionally, several biomarkers, including Planctomycetota and Burkholderiaceae , were key microorganisms responsible for alterations in AOM response. Our results suggest that the capacity of Fe3+ cycling-mediated AOM may gradually decrease in light of increasing anthropogenic N and Fe inputs to global estuarine wetlands, while its reaction processes will become more complex and more strongly coupled with multiple environmental factors. This finding contributes to the enhanced understanding and prediction of the wetland CH 4 -related C with Fe cycles, as well as provides theoretical support for the underlying mechanisms. [Display omitted] • The mechanism of the change in the response to Fe3+ input by AOM was investigated. • Fe3+ input did not necessarily contribute to the AOM rate. • Lower soil TN content positively influenced the response of AOM. • Higher Shannon index has a positive effect on the response of AOM. • Planctomycetota , Burkholderiaceae , etc. caused variation in the response of AOM. [ABSTRACT FROM AUTHOR]

BACKGROUND The present study aimed to evaluate the effects of heat stress and probiotic supplementation on protein functionality and oxidative stability of ground chicken leg during display storage. Two hundred and forty, 1-day-old male chicks (5 birds per pen) were subjected to four treatments in a 2 (thermoneutral condition at 21 °C and cyclic heat stress at 32-21-32 °C for 10 h day-1) × 2 (regular diet with 0 or 0.25 g kg-1 Bacillus subtilis) factorial design. Chickens were harvested at day 46, and pairs of whole legs were collected at 1 day postmortem. The chicken legs were deboned, ground, tray-packaged with oxygen-permeable film, and displayed for 3 days. RESULTS Heat stress and probiotic supplementation had no impact on pH, water-holding capacity, color, protein functionality, lipid lipolysis and lipid/protein oxidation stability ( P > 0.05). Display storage increased the pH and lipid oxidation of ground chicken legs ( P < 0.05). In addition, protein oxidation occurred during display storage, as determined via an increased carbonyl group ( P = 0.0109) and reduced thiol group ( P < 0.0001). CONCLUSION The results of the present study indicate that chronic heat stress and probiotic supplementation had no practical adverse impact on protein functionality and oxidative stability of ground chicken leg meat. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

The study was conducted to determine the effects of probiotic supplementation and fast freezing on quality attributes and oxidation stability of frozen/thawed chicken breast muscle. Broilers (n = 168) were fed with a basal diet or the basal diet plus 250 mg of Sporulin (three strains of Bacillus subtilis )/kg of basal diet for 45 days. Pairs of breasts were separated from chicken carcasses and randomly assigned to either slow (−30 °C) or fast freezing (−70 °C) and stored at −30 °C. After thawing at 2 °C for 24 h, half of the thawed breasts from each treatment were stored for an additional 48 h. Probiotic supplementation increased phospholipid content in breasts ( P < 0.05), but substantially delayed both primary and secondary lipid oxidation products shown by the results from peroxide value and 2-thiobarbituric acid reactive substances ( P < 0.05). Further, the breasts from probiotic chicken group had a significantly lower nonheme iron content than those from control chicken group. Fast freezing significantly reduced thaw/purge loss and minimized lipid oxidation ( P < 0.05). Our results suggest that oxidative deterioration and increased purge/thaw loss of frozen chicken breasts can be effectively minimized by probiotic supplementation coupled with fast freezing. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, it was found that miR-22 might be involved in the regulation of muscle tenderness and was an important miRNA that affects meat quality. In the present study, we demonstrated that miR-22 regulates the fatty acid composition and mitochondrial morphology of skeletal muscle cells by inhibiting ELOVL6 expression. This study presented the first systematical investigation on the miR-22 correlation with fatty acid composition and mitochondrial function in muscle cells. Our finding is important to help us to understand the function of miR-22 in skeletal muscle cells and the complicacy of muscle metabolism regulation. Recently, miR-22 has been suggested to be an important microRNA (miRNA) affecting meat quality. Studies have shown that muscle fatty acid composition and mitochondrial function are closely related to meat quality. The regulatory mechanism of miR-22 on skeletal muscle fatty acid composition and mitochondrial function is not well characterized. Therefore, we aimed to explore the effects of miR-22 on fatty acid composition and mitochondrial function in C2C12 cells. Here, it demonstrate that elevated expression of miR-22 significantly repressed fatty acid elongation and mitochondrial morphology in C2C12 myoblasts, while the knockdown of miR-22 showed opposite results. Furthermore, miR-22 targets the elongase of very long chain fatty acids 6 (ELOVL6) and represses its expression in muscle cells. Knockdown of ELOVL6 mimicked the effect of miR-22 on fatty acid composition and mitochondrial function, while overexpression of ELOVL6 restored the effects of miR-22. These findings indicate that miR-22 downregulates the elongation of fatty acids and mitochondrial morphology by inhibiting ELOVL6 expression in muscle cells, which may provide some useful information for controlling muscle lipid accumulation and mitochondrial function in livestock in the future. [ABSTRACT FROM AUTHOR]

• MFePCN@1-MT target tumor cells to alleviate side effects. • MFePCN@1-MT has GSHOx activity, CAT activity and sonic sensitivity. • MFePCN@1-MT induce ROS generation, ferroptosis, and responsive release of 1-MT. • The synergistic therapy amplifies the ICD effect and induces a robust immune response. The metastasis and recurrence of osteosarcoma (OS) are significant challenges in its clinical management. Tumor immunogenic cell death (ICD)-induced immunotherapy has been widely investigated to solve these problems. However, achieving sufficient ICD and a robust immune response is challenging for nanoparticle-based OS immunotherapy. Here, we report an ultrasound-responsive metal–organic framework-based nanosystem (MFePCN@1-MT) with sonodynamic therapy (SDT) and 1-methyltryptophan (1-MT) responsive release properties. Under ultrasound irradiation, the nanosystem induces reactive oxygen species (ROS) generation, ferroptosis, and the responsive release of 1-MT, which competitively inhibits indoleamine-2,3-dioxygenase (IDO), promotes further ROS accumulation, and amplifies ferroptosis. Notably, SDT/amplified ferroptosis/IDO blockade synergistically kills OS cells, maximizes the amplified ICD effect, activates dendritic cells (DCs) maturation, inhibits regulatory T lymphocytes (Tregs), and triggers CD4+ T-cell and CD8+ T-cell immune responses. Thus, this nanosystem synergistically inhibits K7M2 primary tumors via SDT/amplified ferroptosis/IDO blockade. In addition, the nanosystem enhances the ICD effect, modulates the immunosuppressive microenvironment, promotes immunity against solid tumors, and inhibits distant metastatic tumor growth. This study combines SDT/amplified ferroptosis/IDO blockade into a single nanomedicine and presents a new strategy for OS immunotherapy. [ABSTRACT FROM AUTHOR]

The thymus-derived lymphocytes of jawed vertebrates have four T-cell receptor (TCR) chains that play a significant role in immunity. As chickens have commercial value, their immune systems require a great deal of attention. Local chicken breeds are an essential part of poultry genetic resources in China. Here, we used high-throughput sequencing to analyze the TCRα and TCRβ repertoires and their relative expression levels in the native chicken breeds Baier Buff, Longyou Partridge, Xiaoshan, and Xianju. We found that TCR Vα and TCR Vβ were expressed and included 17, 19, 17, and six segments of the Vα2, Vα3, Vβ1, and Vβ2 subgroups, respectively. V-J pairing was biased; Jα11 was utilized by nearly all Vα segments and was the most commonly used. Breed-specific V segments and V-J pairings were detected as well. The results of the principal coordinate analysis (PCoA) as well as the V-J pairing and CDR3 diversity analyses suggested that the four local chicken breeds did not significantly differ in terms of TCR diversity. Hence, they expressed not significant differentiation, and they are rich genetic resources for the development and utilization of immune-related poultry breeding. • Both Vα subgroups and Vβ subgroups are expressed in chicken. • Various TCR diversity with V segments, V-J pairing, and CDR3 diversity. • No significant differentiation of TCR diversity parameters among local chicken breeds. [ABSTRACT FROM AUTHOR]

[Display omitted] • Propose a preparation method for 3D-printed bioceramics with immunomodulation, angiogenesis, and osteogenesis. • Finding that 3D-printed bioceramics have excellent mineralization properties. • Finding that 3D-printed bioceramic scaffolds can solve implant migration and ectopic osteogenesis of DBM. • 3D-printed bioceramics have excellent biosafety, immunomodulation, angiogenesis, and osteogenesis. Personalized repair of bone defects remains a tremendous clinical challenge. Developing 3D-printed bioceramics with excellent osteogenic potential is an effective therapeutic strategy to overcome this challenge. In this study, we prepared composite bioceramics (designated as CSC-DBM) with immunomodulatory, vascularization, and osteogenesis based on calcium silicate (CS) bioceramics, calcium sulfate (CSH), and decalcified bone matrix (DBM). CSC-DBM bioceramics has an unmatched biomineralization potential due to the synergistic promotion of CS and CSH. Meanwhile, CSC-DBM bioceramics could effectively modulate the immune response, induce M2 macrophage polarization, promote vascular regeneration, and further enhance new bone formation. In summary, this composite bioceramics made of CS bioceramics, CSH, and DBM can provide a new solution for bone defect repair in the clinic. [ABSTRACT FROM AUTHOR]

Wide bandgap (WBG) semiconductor devices are developing rapidly due to their superior performance compared to traditional silicon-based devices. However, the packaging technology of traditional devices has limited the application of WBG semiconductor devices because of the challenges in electrical insulation. The complex environment of high blocking voltage, high frequency, and high temperature is the major reason for insulation failure of encapsulation structure. Therefore, in this article, an epoxy resin composite with nonlinear conductivity is proposed to be used as a coating to improve the electric field distribution of high-voltage high-power IGBT modules. First, an electrical field simulation model was built considering the thermal stress. It was found that the electric field in high temperature was improved compared with that in room temperature due to the temperature-dependent conductivity of silicone gel. Nevertheless, the risk of insulation failure still exists. After the application of nonlinear conductivity materials (NCMs) coating, the maximum electric field at the triple junctions and the ratio of electric field distortion in high field areas were significantly decreased. Further analysis showed that the optimization ratio of electric field increased with the increase of the blocking voltages or power losses in the IGBT chip. The results have demonstrated that the NCMs can reduce the maximum electric field in the IGBT encapsulation structure by 73% under the operating conditions of 120 W 10 kV. Partial discharge (PD) tests show that the partial discharge initial voltage (PDIV) of the substrates with NCM coating is increased by 33% compared with the normal encapsulation structure and the coating significantly inhibits the growth of electric trees. The presented results indicate that the NCMs have the potential to improve the insulation performance of high-voltage high-power IGBT modules. [ABSTRACT FROM AUTHOR]

Background: Persistent synovial hyperplasia with inflammation in rheumatoid arthritis is one of the main pathogeneses of refractory rheumatoid arthritis (RRA). Photodynamic therapy (PDT) causes less trauma than steroid injections or arthroscopic synovectomy while providing stronger targeting and more durable curative effects. The aim of this trial was to evaluate the short-, medium-, and long-term clinical efficacy of PDT when applied as a treatment for RRA synovial hyperplasia and synovitis.Methods and Analysis: This protocol is for a single-center, randomized, double-blind, blank-controlled prospective trial. A sample of 126 RRA patients will be randomly divided into 3 groups: the control group, the "PDT once" group, and the "PDT twice" group, with 42 participants per group. The trial will be conducted by the Rheumatology and Immunology Department of the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. The Ultrasound Compound Score of Synovitis (UCSS) has been selected as the primary outcome measure. The secondary outcome measures include knee joint clinical assessments, ratio of relapse, duration of remission, Disease Activity Score in 28 joints (DAS28), inflammation indexes, serum concentrations of specific antibodies, and changes in articular structures as detected by X-ray scans in the 48th week. The improvement ratios of the UCSS at the 8th, 24th, and 48th weeks (compared with baseline) reflect short-, medium-, and long-term time frames, respectively.Ethics and Dissemination: The protocol was approved by the Medical Ethics Committee of the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, China (Approval No. granted by the ethics committee: NFZXYEC-2017-005) and then entered in the Chinese Clinical Trials Registry under registration number ChiCTR1800014918 (approval date: February 21, 2018). All procedures are in accordance with Chinese laws and regulations and with the Declaration of Helsinki by the World Medical Association (WMA). Any modifications of this protocol during execution will need additional approval from the Ethics Committee of our hospital.Trial Registration Number: ChiCTR1800014918 . [ABSTRACT FROM AUTHOR]

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. [ABSTRACT FROM AUTHOR]

The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients. [ABSTRACT FROM AUTHOR]

Due to poor management and the lack of environmental awareness, lots of masks (an emerging form of plastic pollution) are discarded into the environment during the COVID-19, thereby jeopardizing the health of humans and the environment. Our study introduces a novel perspective by examining the impact of physical damage on the microbial composition of masks in the water environment. We focus on the variations in biofilm formation on each layer of both damaged and undamaged masks, which allows us to understand more about the biofilm on each layer and the significant changes that occur when masks are physically damaged. Research has shown that the community structure of microorganisms on discarded masks can be altered in just ten days, showing an evolution from undifferentiated pioneer colonizing species ("non-picky") to adaptive dominant species ("picky"). Especially, considering that discarded masks were inevitably damaged, we found that the biomass on the damaged samples is 1.62–2.38 times higher than that of the undamaged samples, respectively. Moreover, the microbial community structure on it was also significantly different. Genes involved in biogeochemical cycles of nutrients are more enriched in damaged masks. When damaged, the colonization process and community structure in the middle layer significantly differ from those in the inner and outer layers and even enrich more pathogenic bacteria. Based on the above, it is evident that the environmental risk of masks cannot be assessed as a whole, and the middle layer carries a higher risk. [Display omitted] • Succession from undifferentiated pioneer colonized species to the adaptive dominant. • The biofilm on the middle layer was different from that on the other two layers. • When damaged, the middle layer enriched more pathogenic bacteria than the others. • The integrity of the masks plays a significant role in microbial colonization. • There is difference in biogeochemical cycling between damaged and undamaged masks. [ABSTRACT FROM AUTHOR]

Although various strategies have been utilized to accelerate bone regeneration in bone tissue engineering (BTE), the treatment and repair of large bone defects remains a clinical challenge worldwide. Inspired by the natural extracellular matrix of bone tissue, organic-inorganic composite scaffolds with three-dimensional (3D) porous structures, sufficient mechanical properties, excellent cytocompatibility, osteoconductivity, and osteogenic potential have received considerable attention within the field of bone engineering. In this work, a novel epichlorohydrin (ECH)-crosslinked hydroxyethyl cellulose (HEC)/soy protein isolate (SPI) porous bi-component scaffold (EHSS) with hydroxyapatite (HAp) functionalization (EHSS/HAp) was constructed for bone defect repair via the combination of lyophilization and in situ biomimetic mineralization. Systematic characterization experiments were performed to assess the morphology, HAp-forming properties, mechanical properties and degradation rate of the scaffold. The results indicated that the prepared scaffolds exhibited an interconnected porous structure, a biomimetic HAp coating on their surfaces, improved mechanical properties in compression and a controllable degradation rate. In particular, semiquantitative analysis showed that the calcium/phosphorus (Ca/P) ratio of EHSS/HAp with 70% SPI content (1.65) was similar to that of natural bone tissue (1.67) according to energy dispersive X-ray spectroscopy analysis. In vitro cell culture experiments indicated that the EHSS/HAp with 70% SPI content showed improved cytocompatibility and was suitable for MC3T3-E1 cell attachment, proliferation and growth. Consistently, in vitro osteogenic differentiation studies showed that EHSS/HAp with 70% SPI content can significantly accelerate the expression of osteogenesis-related genes (Col-1, Runx2, OPN, and OCN) during osteogenic differentiation of MC3T3-E1 cells. Furthermore, when applied to the repair of critical-sized cranial defects in a rat model, EHSS/HAp with 70% SPI was capable of significantly promoting tissue regeneration and integration with native bone tissue. Microscopic computed tomography (micro-CT) results demonstrated that the bone defect site was nearly occupied with newly formed bone at 12 weeks after implantation of EHSS/HAp with 70% SPI content into the defect. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of histological sections further confirmed that EHSS/HAp with 70% SPI markedly promoted new bone formation and maturation. Collectively, our results demonstrate the potential of EHSS/HAp scaffolds with 70% SPI for successful bone defect repair and regeneration. [ABSTRACT FROM AUTHOR]

According to the characteristics of an actual electromagnetic rail launcher (EMRL), this article points out defects in the traditional dynamic response model of EMRL, proposes an improved dynamic response model, and analyzes its dynamic and stopping response characteristics. On this basis, it presents a fast and accurate numerical calculation method for three-dimensional transient electromagnetic (EM) force of the EMRL and an order-reduced model of EMRL dynamic response. Furthermore, the second development of commercial software leads to the establishment of an interior ballistic simulation model with EM-structural coupling. The model is used to analyze the interior ballistic characteristics of the EMRL under sequential discharge and continuous firing. The finding is that the dynamic response of the first launching rail will cause a deformation in the second launching rail, in which a greater fluctuation happens. When the time interval between successive launches reaches 1.0 s, the deformation of the second launching rail will no longer be affected by the dynamic response of the first launching rail. [ABSTRACT FROM AUTHOR]

The difference in muscle fiber types is very important to the muscle development and meat quality of broilers. At present, the molecular regulation mechanisms of skeletal muscle fiber-type transformation in broilers are still unclear. In this study, differentially expressed genes between breast and leg muscles in broilers were analyzed using RNA-seq. A total of 767 DEGs were identified. Compared with leg muscle, there were 429 upregulated genes and 338 downregulated genes in breast muscle. Gene Ontology (GO) enrichment indicated that these DEGs were mainly involved in cellular processes, single organism processes, cells, and cellular components, as well as binding and catalytic activity. KEGG analysis shows that a total of 230 DEGs were mapped to 126 KEGG pathways and significantly enriched in the four pathways of glycolysis/gluconeogenesis, starch and sucrose metabolism, insulin signalling pathways, and the biosynthesis of amino acids. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to verify the differential expression of 7 selected DEGs, and the results were consistent with RNA-seq data. In addition, the expression profile of MyHC isoforms in chicken skeletal muscle cells showed that with the extension of differentiation time, the expression of fast fiber subunits (types IIA and IIB) gradually increased, while slow muscle fiber subunits (type I) showed a downward trend after 4 days of differentiation. The differential genes screened in this study will provide some new ideas for further understanding the molecular mechanism of skeletal muscle fiber transformation in broilers. [ABSTRACT FROM AUTHOR]

Functionally graded materials (FGMs) and functionally graded structures (FGSs) are special types of advanced composites with peculiar features and advantages. This article reviews the design criteria of functionally graded additive manufacturing (FGAM), which is capable of fabricating gradient components with versatile functional properties. Conventional geometrical‐based design concepts have limited potential for FGAM and multi‐scale design concepts (from geometrical patterning to microstructural design) are needed to develop gradient components with specific graded properties at different locations. FGMs and FGSs are of great interest to a larger range of industrial sectors and applications including aerospace, automotive, biomedical implants, optoelectronic devices, energy absorbing structures, geological models, and heat exchangers. This review presents an overview of various fabrication ideas and suggestions for future research in terms of design and creation of FGMs and FGSs, benefiting a wide variety of scientific fields. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of a system aiming to correct scoliosis called "electromagnetically controlled shape-memory alloy rods" (EC-SMAR) used in a rabbit model.Methods: We heat-treated shape-memory alloy (SMA) rods to achieve a transition temperature between 34 and 47 °C and a C-shape austenite phase. We then developed a water-cooled generator capable of generating an alternating magnetic field (100 kHz) for induction heating. We next studied the efficacy of this system in vitro and determined some parameters prior to proceeding with animal experiments. We then employed a rabbit model, in which we fixed a straight rod along the spinous processes intraoperatively, and conducted induction heating postoperatively every 4 days for 1 month, while performing periodic X-ray assessments.Results: Significant kyphotic deformations with Cobb angles of about 45° (p < 0.01) were created in five rabbits, and no complications occurred throughout the experiment. The rabbits are still very much alive and do not show any signs of discomfort.Conclusions: This is the first system that can modulate spinal deformation in a gradual, contactless, noninvasive manner through electromagnetic induction heating applied to SMA alloy rods. Although this study dealt with healthy spines, it provides promising evidence that this device also has the capacity to correct human kyphosis and even scoliosis in the future. These slides can be retrieved under Electronic Supplementary Material. [ABSTRACT FROM AUTHOR]

[Display omitted] • PLA/shellac-FA dimer NPs with tunable shape are designed and prepared to co-load and deliver PTX and CUR. • PTX + CUR-loaded snowman-like PLA/shellac-FA dimer NPs are able to enhance anti-tumor efficacy. • PTX + CUR-loaded snowman-like PLA/shellac-FA dimer NPs activate immune system and reverse immunosuppressive TME. Chemotherapy is indispensable for the systematic treatment of aggressive malignancies, such as pancreatic ductal adenocarcinoma (PDAC), while delivery vehicles are essential for improving delivery efficiency and enhancing anti-tumor therapy. Here, we design and synthesize snowman-like tumor-targeting PLA/shellac-FA dimer nanoparticles (NPs), which demonstrate improved delivery efficiency and enhanced anti-tumor therapy. Paclitaxel (PTX) and curcumin (CUR) are co-loaded in PLA/shellac-FA dimer NPs and their delivery performance is optimized by tuning the particle shape to be snowman-like. In vivo tests confirm that PTX + CUR-loaded snowman-like PLA/shellac-FA dimer NPs could effectively reduce the proportion of tumor-associated macrophages (TAMs) in lymphocytes and reshape the M1/M2 polarization into an anti-tumor type. Meanwhile, the dimer NPs could enhance the infiltration of cytotoxic T lymphocytes (CTLs), thus activating the immune response in the tumor microenvironment (TME). The results suggest that snowman-like PLA/shellac-FA dimer NPs with a sharp shape can effectively improve the delivery efficiency and enhance the anti-tumor therapy, being a promising system for clinical applications. [ABSTRACT FROM AUTHOR]

Background: Primary pulmonary enteric adenocarcinoma (PEAC) is an extremely rare variant of invasive lung cancer. It is highly heterogeneous while shares some common morphologic and immunohistochemical features with usual pulmonary adenocarcinoma (PAC) and colorectal adenocarcinoma (CRAC), making the differential diagnosis difficult. At present there are only limited studies about distinctive features of primary PEAC and the results are often inconsistent.Methods: We retrospectively analyzed total 129 primary PEACs and 50 CRACs that were published since 1991 or diagnosed in our centre. Among them eight typical samples of primary PEACs and usual PACs were detected by targeted exome sequencing.Results: The combination of CK7+/CDX2+ acquires high sensitivity (71.3%) and specificity (82%) in differential diagnosis of PEACs from CRAC. The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation. Moreover, compared with usual PACs, the primary PEACs have higher nonsynonymous tumor mutation burden and more frequent MMR mutation.Conclusions: The combination of CK7+/CDX2+ immunostaining and the distinctive genetic signatures, including low incidence of sensitivity genes mutations and high tumor mutation burden, is an important supplementary to the clinical differential diagnosis of primary PEACs. Our findings thus have significant implications for development of individualized treatment strategy in these patients. [ABSTRACT FROM AUTHOR]

OGG1 is the first enzyme in the base excision repair pathway (BER) responsible for repairing 8-oxoguanine DNA lesions. Recent studies found that OGG1 may also be involved in epigenetic regulation. In this study, we focused on the roles of OGG1 in histone modification. First, to study the effects of OGG1 on histone modification, the protein levels of symmetric dimethylation of histone H4 arginine-3 (H4R3me2s) were determined by western blot analysis following the knockdown or overexpression of OGG1. Second, the molecular mechanisms by which OGG1 regulates H4R3me2s were assessed by co-immunoprecipitation (CO-IP) assays in mouse embryonic fibroblast (MEF) wild-type (WT) and Ogg −/− cells. Finally, to verify the regulation of H4R3me2s by OGG1 on specific genes, chromatin immunoprecipitation (CHIP) was performed on MEF WT and Ogg −/− cells. We found that OGG1 affects PRMT5 binding on histone H4 and the formation of H4R3me2s via PRMT5. The methylation level of H4R3me2s was dramatically decreased in MEF Ogg −/− cells compared to WT cells. Knockdown of OGG1 by siRNA led to a decrease in H4R3me2s, while overexpression of OGG1 increased the level of H4R3me2s. OGG1 also interacted with PRMT5 and histone H4, and the interaction between PRMT5 and histone H4 was reduced in MEF Ogg −/− cells. Our data not only illustrate the important roles of OGG1 in histone modification, but also reveal the mechanism by which OGG1 affects PRMT5 binding on H4R3 resulting in the symmetrical dimethylation of histone H4 arginine-3. [ABSTRACT FROM AUTHOR]

Background Although FGF 19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF 19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma ( LSCC) and FGF 19 amplification as a potential therapeutic target for LSCC are not well understood. Methods Fluorescence in situ hybridization analysis and quantitative real-time- PCR was used to detect FGF 19 genetic amplification and FGF 19 messenger RNA expression in LSCC tumor and paired adjacent samples. Small interfering RNA and short hairpin RNA were used to knockdown FGF19 in vitro and in vivo. Results FGF 19 amplification was identified in a subset of LSCC patients (37.5%, 15/40), and upregulation of FGF 19 expression was found in 60% (24/40) of tumor tissues compared to adjacent non-tumorous tissues. Correlation analysis with clinicopathologic parameters showed that FGF 19 upregulation was significantly associated with heavy smoking. Small interfering RNA knockdown of FGF 19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF 19 gene, but these effects was not observed in non-amplified LSCC cells. Interfering FGF 19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF 19 in tumor cells. Conclusion Our results suggested that FGF 19 signaling activation is required for cell growth and survival of FGF 19 amplified LSCC cells, both in vitro and in vivo. Intervention of FGF 19 activation could be a potential therapeutic strategy for LSCC patients with FGF 19 amplification. [ABSTRACT FROM AUTHOR]

[Display omitted] • Propose a high porosity bioglass preparation method. • Finding bioglass enhances mild magnetothermal therapy. • The mechanism relies on calcium ions during glass degradation. • The composite scaffold has superior biosafety and osteogenic effect. Bone defects and tumor cell residues after bone tumor resection have always been a challenge. We tried to investigate a kind of bioglass with both bone repair and tumor killing capability to achieve two birds with one stone. We used a Sol-Gel method to prepare the high porous magnetic bioglass (MBG) and then compounded the MBG with calcium sulfate (CS) bone cement to form the composite scaffold (CS-MBG). We found that the CS-MBG could reach about 43 °C under the condition of magnetic field in vitro. Under this condition, CS-MBG would release Ca2+ resulting in the cell death of calcium overload. Meanwhile, the suitable pH and osteogenic activity of CS-MBG can promote the postoperative bone repair and inhibit the growth of bone tumors. Our work has innovatively designed a magnetic bioglass and verified its mechanism of synergistic hyperthermia against tumor, providing a new idea for the treatment of tumor bone defects with magnetic bioglass. [ABSTRACT FROM AUTHOR]

WD repeat domain 5 (WDR5) is a prominent target for pharmacological inhibition in cancer through its scaffolding role with various oncogenic partners such as MLL and MYC. WDR5-related drug discovery efforts center on blocking these binding interfaces or degradation have been devoted to developing small-molecule inhibitors or degraders of WDR5 for cancer treatment. Nevertheless, the precise role of WDR5 in these cancer cells has not been well elucidated genetically. Here, by using an MLL-AF9 murine leukemia model, we found that genetically deletion of Wdr5 impairs cell growth and colony forming ability of MLL-AF9 leukemia cells in vitro or ex vivo and attenuates the leukemogenesis in vivo as well, which acts through direct regulation of ribosomal genes. Pharmacological inhibition of Wdr5 recapitulates genetic study results in the same model. In conclusion, our current study demonstrated the first genetic evidence for the indispensable role of Wdr5 in MLL-r leukemogenesis in vivo , which supports therapeutically targeting WDR5 in MLL-rearranged leukemia by strengthening its disease linkage genetically and deepening insights into its mechanism of action. [Display omitted] • Wdr5 conditional knockout mice were generated utilizing CRISPR/Cas9 KI approach. • Genetically loss of Wdr5 impairs MLL-r leukemogenesis in vitro and in vivo. • Wdr5 regulates MLL-r leukemia via cell-cycle, apoptosis, and cell differentiation. • Wdr5 functions through direct regulation of ribosomal genes. • Wdr5 inhibitor recapitulates the effect by loss of Wdr5 in MLL-r leukemia. [ABSTRACT FROM AUTHOR]

Bone regeneration requires the interaction of osteogenesis, osteolysis, and angiogenesis as well as an appropriate immune microenvironment. Recombinant human parathyroid hormone (PTH1-34) is approved for clinical anti-osteoporosis treatment because of its good osteogenic activity, osteoclastosis, and angiogenesis. However, the phenomenon of net bone resorption limits its use in local bone repair. Our group provides an effective strategy for multifunctional calcium phosphate (CaP) ceramics with modulating M1 macrophage pro-inflammatory effects, and bone regeneration. CaP ceramic scaffold is functionalized with parathyroid hormone related peptide-1 (PTHrP-1) for bone defect repair. First, peptide-functionalized true bone ceramic (TBC) scaffold exhibit limited M1 macrophage pro-inflammatory effects to improve the osteogenic microenvironment. Second, PTHrP-1 retains the osteogenic activity and angiogenic properties of PTH1-34 while downregulating osteoclast activity to induce favorable bone formation. Third, the peptide modified by tri-continuous aspartic acids (D3) and serine phosphorylation (PSer) has high affinity to the natural CaP matrix, achieving a slow release of PTHrP-1 in the TBC scaffold. Fourth, the carboxyl group of aspartate combined with calcium effectively promotes hydroxyapatite (HAP) nucleation and completes self-assembled mineralization. which is beneficial for bone regeneration. The results show that PTHrP-1-TBC is more suitable for bone regeneration than TBC scaffold and unmodified peptide alone. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. CCA has become a global health problem with rising incidence and mortality that threatens the health of human beings. The immune microenvironment of CCA is characterized by abundant cancer-associated fibroblast and suppressive immune components. The increasing body of knowledge and recent developments in transcriptomic studies have given insight into the immune landscape of CCA, paving the way for better application of immunotherapy. Immunotherapy mainly applies in a limited subset of CCA with deficient mismatch and high microsatellite instability. With limited response rates and treatment efficacy, researchers are looking into novel strategies on combination strategies and alternatives, such as immune vaccines and adoptive cell therapy. Biomarker identification is also critical for patient selection. We present an up-to-date summary of the current research on immunotherapy for CCA patients, covering pre-clinical and clinical exploration beyond immune checkpoint inhibitors, immune vaccines, and adoptive cell therapy. In addition, we review the promising biomarkers for CCA immunotherapy and discuss recent development. [ABSTRACT FROM AUTHOR]

The laying performance of geese is mainly determined by follicular development and atresia, while follicular status is regulated by photoperiod. To understand the effect of photoperiod on the development of goose follicles, artificial light was used to change the photoperiod. In this study, ten healthy 220-day-old Zhedong white geese (Anser Cygnoides) with similar body weights and similar reproductive start times were reared for 60 days under long photoperiod (15 L:9 D) and short photoperiod (9 L:15 D) artificial light with the intensity controlled at 30 lux, and follicles were collected. Follicle development was analyzed by observing the morphology of follicle tissue, the localization of autophagosomes and autolysosomes, and the expression levels of apoptosis-related protein factors. Small white follicles (SWFs) were selected for RNA sequencing and bioinformatics analysis of the transcriptome. Under a long photoperiod, microtubule-associated protein 1 light chain 3 (LC3) and Caspase-3 were expressed in the granulosa cell layer and oocytes, respectively. LC3 and Caspase-3 protein expression was increased in SWF and large white follicles (LWFs), and there were more autophagosomes and autolysosomes in granulosa cells. RNA-seq found 93 differentially expressed genes (DEGs) in the short-photoperiod group, including 55 upregulated DEGs and 38 downregulated DEGs, distributed in 37 gene ontology categories. Kyoto Encyclopedia of Genes and Genomes-enriched signaling pathways revealed 5 pathways enriched in upregulated DEGs, including protein digestion and absorption, ECM-receptor interaction and regulation of lipolysis in adipocytes, and 4 pathways enriched in downregulated DEGs, such as fatty acid biosynthesis. Ten differentially expressed genes related to extracellular matrix and fatty acid metabolism (THBS2, COL12A1, MRC2, TUBA, COL1A1, COL11A1, HSPG2, FABP, MGLL , and OLAH) may be involved in the photoperiod regulation of follicle development in Zhedong white geese. The differentially expressed genes screened in this study will provide new ideas to further understand the molecular mechanism underlying photoperiod-mediated regulation of follicle development in Zhedong white geese. [ABSTRACT FROM AUTHOR]

Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway. However, the regulatory role of PHGDH in muscle development is unclear. We report that the expression of PHGDH increased significantly during proliferation of chicken skeletal muscle satellite cells. Knockdown of PHGDH by an siRNA suppressed myoblast proliferation, whereas overexpression of PHGDH enhanced muscle cell proliferation. Furthermore, PHGDH promoted the expression of Forkhead box protein M1 (FoxM1). Knockdown of FoxM1 by an siRNA attenuated the proliferation of chicken muscle cells, whereas its overexpression significantly promoted proliferation. Additionally, siRNA-PHGDH inhibited pcDNA3.1-FoxM1-induced FoxM1 expression in chicken muscle cells. Moreover, PHGDH inhibition overcame the stimulation by pcDNA3.1-FoxM1 of cell cycle-related gene expression. We propose that PHGDH accelerates chicken muscle cell proliferation by increasing FoxM1 expression. [ABSTRACT FROM AUTHOR]