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Abstract Background Grilled Nux Vomica (GNV) is a promising traditional Chinese medicine to treat myasthenia gravis (MG), but its effects and mechanisms need further exploration. Methods Experimental autoimmune MG (EAMG) model was established by muscle-specific kinase (MuSK) induction on C57BL/6 J mice. Mice were treated with GNV and/or ruxolitinib (JAK2 inhibitor) or AG490 (STAT3 inhibitor) for 30 days via gavage after modeling and randomized into 7 groups: control, model, low-dose GNV, middle-dose GNV, high-dose GNV, GNV + ruxolitinib, GNV + AG490. Body weight, muscle strength, clinical score, MuSK level, neuromuscular junction integrity (agrin and acetylcholine receptor [AChR] levels), inflammatory factors (IL-2 and IL-6), and the activation of the JAK2/STAT3 pathway were measured and compared between groups. Results GNV significantly improved body weight and muscle strength, as well as reduced clinical scores, MuSK levels, and inflammatory markers (IL-2 and IL-6) levels compared with untreated EAMG mice. GNV also protected the neuromuscular junction and increased agrin and AChR co-expression in a dose-dependent manner. In addition, GNV attenuated the levels of p-JAK2 and p-STAT3, which are aberrantly upregulated in EAMG mice. After co-treatment with ruxolitinib or AG490, the effect of GNV on body weight, muscle strength, clinical score, MuSK level, neuromuscular junction integrity, levels of inflammatory factors, and JAK2/STAT3 pathway was further amplified in EAMG mice. Conclusions GNV improves MG by inhibiting the JAK2/STAT3 pathway, which might be an effective therapeutic strategy for MG.

ObjectiveThis study investigated the association between social anxiety and sleep quality and further explored the potential mediating role of internet addiction in depressed adolescents.MethodsThis study included 440 Chinese depressed adolescents (mean age = 15.0 years, SD = 2.0). Participants completed questionnaires, including Social Avoidance and Social Distress Scale, Internet Addiction Test, and Pittsburgh Sleep Quality Index. A structural equation model was used to analyze the association between social anxiety and sleep quality, with internet addiction as a mediator. Gender differences were examined by multi-group analysis.ResultsAmong participants, 61.8% reported poor sleep quality. The sleep quality was significantly different on the level of gender (p = 0.016), education level (p = 0.043), and family history (p = 0.002). Sleep quality was positively associated with social anxiety (p < 0.001) and internet addiction (p < 0.001). Furthermore, internet addiction partially mediated the relationship between social anxiety and sleep quality, and the mediation effect ratio was 16.1% (p < 0.001). Finally, no significant differences were found in this mechanism.ConclusionWe concluded that both social anxiety and internet addiction were risk factors for depressed adolescents’ poor sleep quality. Social anxiety further affected sleep quality through internet addiction.

Summary: Cancer cells with mitochondrial dysfunction can be rescued by cells in the tumor microenvironment. Using human adenoid cystic carcinoma cell lines and fibroblasts, we find that mitochondrial transfer occurs not only between human cells but also between human and mouse cells both in vitro and in vivo. Intriguingly, spontaneous cell fusion between cancer cells and fibroblasts could also emerge; specific chromosome loss might be essential for nucleus reorganization and the post-hybrid selection process. Both mitochondrial transfer through tunneling nanotubes (TNTs) and cell fusion “selectively” revive cancer cells, with mitochondrial dysfunction as a key motivator. Beyond mitochondrial transfer, cell fusion significantly enhances cancer malignancy and promotes epithelial-mesenchymal transition. Mechanistically, mitochondrial dysfunction in cancer cells causes L-lactate secretion to attract fibroblasts to extend TNTs and TMEM16F-mediated phosphatidylserine externalization, facilitating TNT formation and cell-membrane fusion. Our findings offer insights into mitochondrial transfer and cell fusion, highlighting potential cancer therapy targets.

Organophosphate flame retardants 2-ethylhexyldiphenyl phosphate (EHDPP) and cadmium (Cd) are ubiquitous in environmental matrices, and dermal absorption is a major human exposure pathway. However, their detrimental effects on the human epidermis remain largely unknown. In this study, human keratinocytes (HaCaT cells) were employed to examine the toxicity and underlying mechanisms of co-exposure to EHDPP and Cd. Their influence on cell morphology and viability, oxidative damage, apoptosis, and tight junction were determined. The results showed that co-exposure decreased cell viability by >40 %, induced a higher level of oxidative damage by increasing the generation of reactive oxygen species (1.3 folds) and inhibited CAT (79 %) and GPX (90 %) activities. Moreover, Cd exacerbated EHDPP-induced mitochondrial disorder and cellular apoptosis, which was evidenced by a reduction in mitochondrial membrane potential and an elevation of cyt-c and Caspase-3 mRNA expression. In addition, greater loss of ZO-1 immunoreactivity at cellular boundaries was observed after co-exposure, indicating skin epithelial barrier function disruption, which may increase the human bioavailability of contaminants via the dermal absorption pathway. Taken together, oxidative damage, cell apoptosis, and tight junction disruption played a crucial role in EHDPP + Cd triggered cytotoxicity in HaCaT cells. The detrimental effects of EHDPP + Cd co-exposure were greater than individual exposure, suggesting the current health risk assessment or adverse effects evaluation of individual exposure may underestimate their perniciousness. Our data imply the importance of considering the combined exposure to accurately assess their health implication.

Abstract Jiarong Tibetan is a regional group with distinctive regional characteristics and possess precious traditional village resources. Studying the spatial distribution and influencing factors of traditional villages is of vital significance for the protection and renewal of villages and the revitalization of cultural heritage. Nevertheless, due to the fact that the Jiarong Tibetan inhabited area has not been clearly defined for a long time, there is a lack of holistic discussion on the distribution features and driving mechanisms of traditional villages in this region. In order to fill this research gap, the paper is the first to break away from the existing county administrative divisions to define the study area. Moreover, the analysis is carried out by using the nearest neighbor index, kernel density, GoeDa and Geodetector, etc. for traditional villages at national-level and provincial-level. The results show that the spatial distribution of the traditional villages of Jiarong Tibetan is characterized by typical aggregation, with the core intensive area in Danba County and the sub-core intensive area in the central and northern parts. The results of factor detection show that the spatial distribution pattern of the traditional villages is the consequence of the synergistic effect of multiple factors, and the interaction effect is significantly enhanced. The economic level and climatic conditions play a controlling role, and population, elevation, intangible cultural heritage and rivers also have notable effects. The findings of study can offer scientific guidance and suggestions for the inheritance and development of traditional villages in Jiarong Tibetan settlement area.

Global warming, as the main feature of the climate problem, is gradually coming into our field of vision. Under this background, Poisson jump is applied to describe the arrival of natural disasters caused by global warming. Households and firms can dynamically update their beliefs about the arrival rate of disasters. In order to mitigate global warming, firms pay a share of the cost to reduce the carbon emissions in the process of production. In this paper, we discuss the social planner equilibrium and the competitive equilibrium, respectively, and obtain the Hamilton-Jacobi-Bellman (HJB) equations of value function in both contexts. Then, the equations are numerically simulated, leading to the following conclusions: under the same level of pessimism, investments and values of firms, as well as household consumption, all decrease as the emission abatement rate increases, and the social welfare is almost unchanged compared to the situation without the cost of emission reduction. Furthermore, in order to deal with the short-term adverse effects on the economy caused by emission reductions, the government subsidy is introduced into the model. The results show that, under the same level of pessimism, the government subsidy drives the growth of investment and consumption. The value of the firms that pay the emission abatement has been boosted, and economic growth rate has risen to a certain degree, while social welfare remains almost the same.

Buddhism and Taoism have enjoyed a flourishing development in Chengdu with many famous Buddhist and Taoist temples. This research takes typical Buddhist temple buildings and Taoist temple buildings in Chengdu as the research object. Through architectural surveying and mapping, the height and area data of temple buildings are quantized and counted, and their components and axial spatial plane and vertical layout characteristics are analyzed and compared. The results show that both Buddhist temples and Taoist temples are composed of two elements, including figure worship and non-figure worship. In the plane layout, they are mostly used in the south and straight line layout. The hierarchy of the halls in Buddhist temples is clear, while Taoist temples are more open. By clarifying their respective characteristics, the study achieved a comprehensive and systematic understanding of the spatial layout of Buddhist and Taoist temples in Chengdu, which is of great significance to enrich the connotation of religious architecture culture and improve the local culture of Sichuan.

Based on Conservation of Resources Theory, this study tries to reveal the mechanism of action of work connectivity behavior after-hours triggering employees’ time banditry behavior. By using Mplus7.4 software the analysis of 429 leader-employee paired data collected in three stages reveals that work connectivity behavior after-hours has a positive effect on work alienation and psychological distress. Work alienation and psychological distress mediates the relationship between work connectivity behavior after-hours and employees’ time banditry behavior, respectively. In addition, organization-based self-esteem mitigates the positive effects of work connectivity behavior after-hours on work alienation and psychological distress, which in turn also moderates the indirect effects of work connectivity behavior after-hours on employees’ time banditry behavior through work alienation and psychological distress, respectively. This study provides practical guidance for organizations to reduce employee time banditry behavior and human resource management practices in the new technological environment.

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

Augmented Reality (AR) is rapidly advancing, with a new focus on broadening accessibility beyond the visually dominant interfaces. This study explores the integration of audio-based non-visual interfaces within AR, aiming to cater to a diverse audience, including users with visual impairments. The objective was to develop a prototype that leverages audio feedback to facilitate interaction with the AR environment, enhancing spatial awareness and mental imagery for all users without relying on visual cues. Employing a user-centered design approach, we conducted a comprehensive evaluation with university students to assess the prototype’s usability and immersive potential compared to traditional touchscreen interfaces. The findings highlighted a pronounced preference for the Audio-Based Natural Interface, emphasizing its capacity to provide an intuitive and immersive AR experience through sound alone. These results underline the potential of audio feedback in creating more inclusive AR experiences, suggesting a paradigm shift towards developing AR technologies that are accessible to a wider user base. Our study concludes that audio-based non-visual interfaces represent a viable and innovative direction for AR development, advocating for their further exploration to ensure AR’s universality and inclusivity.

Abstract Retraction: [Kaiyi Qiu, Xin Liu, Jie Liu, Hongbo Ma, Jingya Li, Zhengchao Zhang, Guangliang Chen, Li Cai, Research on tridimensional monitoring and defence technology of substation, IET Circuits, Devices & Systems 2022 (https://doi.org/10.1049/cds2.12129)]. The above article from IET Circuits, Devices & Systems, published online on 14 September 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Editor‐in‐Chief, Harry E. Ruda, the Institution of Engineering and Technology (the IET) and John Wiley and Sons Ltd. This article was published as part of a Guest Edited special issue. Following an investigation, the IET and the journal have determined that the article was not reviewed in line with the journal’s peer review standards and there is evidence that the peer review process of the special issue underwent systematic manipulation. Accordingly, we cannot vouch for the integrity or reliability of the content. As such we have taken the decision to retract the article. The authors have been informed of the decision to retract.

Largemouth bass ranavirus (LMBRaV), a double-stranded DNA (dsDNA) virus, leads to considerable mortality and significant economic impacts in the largemouth bass (Micropterus salmoides) aquaculture sector. This study evaluated and screened compounds from Chinese herbs for their activity against LMBRaV. Esculin exhibited the highest rate (73 %) of inhibition on LMBRaV major capsid protein (MCP) gene expression at a concentration of 60 mg/L in a cellular environment. It also significantly reduced the cytopathic effect (CPE), protecting infected cells from LMBRaV-induced nuclear damage and hindering LMBRaV infection by modulating viral entry mechanisms. For in vivo study, esculin increased the survival rate of LMBRaV-infected largemouth bass by 60.0 % and 53.3 %, in prevention experiment and treatment experiment, respectively. Concurrently, esculin significantly reduced viral loads and induced the upregulation of antiviral-associated genes, indicating its potential for immunoregulation. In summary, esculin holds potential for both preventing and treating LMBRaV infections in the aquaculture context.

Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered 18a, a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that 18a prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of 18a-induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by 18a via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound 18a and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems.

A widely used organophosphate flame retardant (OPFR), triphenyl phosphate (TPP), is frequently detected in various environmental media and humans. However, there is little known on the human corneal epithelium of health risk when exposed to TPP. In this study, human normal corneal epithelial cells (HCECs) were used to investigate the cell viability, morphology, apoptosis, and mitochondrial membrane potential after they were exposed to TPP, as well as their underlying molecular mechanisms. We found that TPP decreased cell viability in a concentration-dependent manner, with a half maximal inhibitory concentration (IC50) of 220 μM. Furthermore, TPP significantly induced HCEC apoptosis, decreased mitochondrial membrane potential in a dose-dependent manner, and changed the mRNA levels of the apoptosis biomarker genes (Cyt c, Caspase-9, Caspase-3, Bcl-2, and Bax). The results showed that TPP induced cytotoxicity in HCECs, eventually leading to apoptosis and changes in mitochondrial membrane potential. In addition, the caspase-dependent mitochondrial pathways may be involved in TPP-induced HCEC apoptosis. This study provides a reference for the human corneal toxicity of TPP, indicating that the risks of OPFR to human health cannot be ignored.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE−/− mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Ultrashort terahertz (THz) beam is often affected by spatio-temporal distortion due to its long wavelength, and this spatio-temporal coupling will degrade the focusing effect. Here, we develop a numerical model for calculating the vector focusing of ultrashort pulses with arbitrary spatial and temporal distribution, which adopt the vector diffraction integral and coherent spectrum superposition methods. Leveraging it, the focusing of a broadband pulse can be characterized together with its vector characteristics and we explore the influences of multifarious spatio-temporal couplings on the focusing of ultrashort THz pulses. In addition, the possibility of focusing the ultrashort THz radiation from an undulator to 1 GV/m is also discussed. This will provide further guidance for the non-equilibrium state of matter induced by ultrashort strong-field THz pulses.

The ultrafast electron beam diffraction technology, which involves an electron beam at the level of several megaelectron volts, is crucial for studying ultrafast dynamic processes at the atomic level. To discern these processes at a temporal resolution of a few femtoseconds, the demand to focus on electron beams with femtosecond or even subfemtosecond width and time jitter is increasing. In this paper, we investigate the dynamics of electron beams as they interact with lasers, present an explanation of the mechanism that results in time jitter, and propose a method to mitigate or possibly eliminate the time jitter by inducing a specific energy chirp in the electron beam through the use of X-band photocathode rf gun. The feasibility of this method is confirmed by implementing bunch compression with two radially polarized laser pulses. Simulation results demonstrate that the time jitter can be reduced to less than 1 fs when the amplitude jitter of the rf gun is within ±0.05% and the phase jitter is within ±0.5°. Based on our findings, we anticipate that this approach will substantially advance the field of ultrafast science and technology.

Augmented Reality serious games have become an emerging solution to positively influence the learning experience for children born in the digital age. However, systematic and empirically tested design guidelines for AR serious games remain largely unexplored. In this study, we investigated the design guidelines by designing and developing four AR serious games with different mechanics inspired by the psychological needs within Self-determination Theory, following with four user studies respectively. In the first study, we explored the AR game concepts by conducting participatory design sessions. In the second study, we investigated how children react to different types of interactions and feedback mechanics in AR serious games with 32 participants. Then, we scrutinized the effect of social interactions in AR serious games on children with 24 participants. Lastly, we designed an AR game with four different versions, tested pathways to immerse children to explore and play in an AR fantasy world with 81 participants. Generally, this research explored the concepts, prototypes, and results of incorporating AR with serious games for children. We realized multiple AR prototypes inspired by SDT and generalized a set of design guidelines, which are intended to help future related designs in AR serious games.

BackgroundGiven the high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children, non-invasive markers of disease to date are still limited and worth exploring.ObjectiveThis study aimed to evaluate the association between inflammatory markers and NAFLD in obese children.MethodsWe performed a case-control study in Hunan Children's Hospital from September 2020 to September 2021. Study participants were children with obesity diagnosed with NAFLD by abdominal ultrasound examination. Mean platelet volume (MPV), platelet distribution width (PDW), neutrophil, lymphocyte, monocyte, and platelet counts were extracted from medical records and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was performed to evaluate the association between inflammatory markers and NAFLD. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory cytokines for NAFLD.ResultsTwo hundred and sixty-seven obese children were enrolled, including 176 NAFLD patients and 91 simple obesity controls. Multivariable logistic model indicated that increased interleukin (IL)-1β [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.04–1.27], IL-6 (OR = 1.28, 95% CI: 1.07–1.53), and IL-17 (OR = 1.04, 95% CI: 1.02–1.07) levels were significantly associated with NAFLD. In contrast, we observed non-significant associations for IL-8, IL-12, IL-21, IL-32, tumor necrosis factor-α (TNF-α), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), mean platelet volume (MPV), and platelet distribution width (PDW) with NAFLD. The area under the curves (AUCs) of IL-1β, IL-6, and IL-17 to discriminate obese children with or without NAFLD were 0.94, 0.94, and 0.97, respectively.ConclusionsOur results indicated that IL-1β, IL-6, and IL-17 levels were significantly associated with NAFLD. These inflammatory cytokines may serve as non-invasive markers to determine the development of NAFLD and potentially identify additional avenues for therapeutic intervention.

Employee-based brand equity plays a crucial role in building organizations' brand equity, and organizations strive to maintain it because of its stimulating effect on competitive achievement. Based on psychological contract and stress theory, this study developed a model that points out the antecedents which can play an adverse role in the EBBE building process. This study explores the role of employee loneliness, job uncertainty, and psychological distress on employee-based brand equity. This study also explores the mediating role of emotional exhaustion in these relationships. For the empirical analyses of the model, this study gathered data based on a 459 sample size under a time-lag approach from the employees of clothing brands in China. This study analyzed the data through partial least square structural equation modeling (PLS-SEM). For this purpose, SmartPLS software was used. The outcomes revealed that employee loneliness has no direct relationship with employee-based brand equity; however, job uncertainty and psychological distress negatively influence employee-based brand equity, such as job uncertainty and psychological distress reduce employee-brand-based equity. Moreover, emotional exhaustion mediates the relationship between employee loneliness and employee-based brand equity and job uncertainty and employee-based brand equity; however, emotional exhaustion does not mediate the relationship between psychological distress and employee-based brand equity. Finally, practical implications, limitations, and future directions are discussed in this study.

Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (β) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating β cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of β cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of β cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in β cells, possibly improving β cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of β cells. We also reveal some of the underlying mechanisms of luteolin’s cytoprotective function.

Objective: To demonstrate that the kallikrein-kinin system (KKS) is upstream of angiogenic signaling pathway, and to determine the role of the kinin B1 and B2 receptors in myocardial angiogenesis induced by exercise training. Methods: Forty Wistar rats were randomly assigned to an exercise control (EC) group, a B1 receptor antagonist (B1Ant) group, a B2 receptor antagonist (B2Ant) group, and a double receptor antagonist ((B1+ B2)Ant) group. A myocardial infarction model was employed. Animals in all groups received 30 min of exercise training for 4 weeks. The expression of VEGF and eNOS, capillary supply, and apoptosis rate were evaluated. Results: The mRNA and protein expression of VEGF and eNOS showed similar trends in all groups, and were lowest in the (B1+ B2) Ant group, and highest in the EC group. Levels of VEGF and eNOS mRNA were significantly lower in the B1Ant group than in the B2Ant group (p

Abstract Background C-Myc aberrations confer a more aggressive clinic behavior in diffuse large B-cell lymphoma (DLBCL). Matrine is an alkaloid extracted from Sophora flavescens Ait. It possesses anti-cancer property through inhibiting the cell proliferation and inducing the apoptosis. The present study aimed to explore the underlying mechanisms of matrine in suppressing the cell growth of DLBCL. Methods The influence of matrine on the viability of cultured DLBCL cell lines SU-DHL-16 and OCI-LY3 cells were determined by CCK-8. Apoptosis and cell cycle were measured by flow cytometry after matrine exposure. Western blot was taken to investigate the expression of activated Caspase-3, cleaved PARP, c-Myc, phospho-c-Myc (Ser62), CaMKIIγ, phospho-CaMKIIγ (Thr287), CDK4 and CDK6 after matrine treatment. Cycloheximide chase analysis was used to determine the c-Myc protein half-lives before and after matrine treatment. Growth salvage analysis was taken by ectopic expression of c-Myc. Results In cultured DLBCL cells, matrine suppressed cell viability in a concentration and time dependent fashion. Matrine treated SU-DHL-16 and OCI-LY3 cells for 48 h with IC50 value of 1.76 mM and 4.1 mM, respectively. Matrine induced apoptosis through a caspase-independent pathway and caused G0/G1 cell cycle arrest in a concentration dependent manner in DLBCL cells. The protein expression of c-Myc was inhibited while the transcription of c-Myc was not reduced by matrine. c-Myc protein half-lives were decreased from 30.4, 69.4 min to 16.6, 15.9 min after matrine treatment in SU-DHL-16 and OCI-LY3, respectively. As a critical protein kinase of c-Myc, CaMKIIγ phosphorylation at Thr287 was found to be down-regulated and c-Myc phosphorylation at Ser62 was reduced together after matrine treatment in DLBCL. The growth suppression of SU-DHL-16 cells induced by matrine was rescued by over-expression of c-Myc achieved by recombinant adenovirus infection. The decreased expression of CDK6, not CDK4, induced by matrine was rescued by ectopic expression of c-Myc protein. Conclusions This study has shown for the first time that matrine suppresses cell growth of DLBCL via inhibiting CaMKIIγ/c-Myc/CDK6 signaling pathway.

The cartilage has poor ability to mount a sufficient healing response. Herein, kartogenin (KGN), an emerging stable non-protein compound with the ability to recruit bone marrow mesenchyme stem cells (BMSCs) to promote chondrogenic differentiation, was grafted onto dopamine-Fe(III) chelating nanoparticles, followed by involving a gelatin- and dextran-based injectable hydrogel to mimic the extracellular matrix to promote cartilage repair. The in vitro results demonstrated that KGN underwent long-term sustained release behavior and availably promoted the deep migration of BMSC cells in yielding hydrogels. Furthermore, in vivo New Zealand white rabbits’ cartilage defect model repairing results showed that cartilage defect obtained significant regeneration post operation in the 12th week, and the defect edge almost disappeared compared to adjacent normal cartilage tissue. Meanwhile, the T2-weighted magnetic resonance imaging (MRI) property resulting from dissociative Fe (III) can significantly monitor the degradation degree of the implanted hydrogels in the defect site. This integrated diagnosis and treatment system gives insight into cartilage regeneration.

PurposeBased on Social Exchange Theory, this paper constructs and evaluates the mediation model of servant leadership on employees’ voice behavior through psychological security and error learning ability and discusses the moderation role of work autonomy in the model.DesignThis research used 424 employees and their direct superiors as the research objects and then conducted a paired survey at three points. Mplus7.4 software analyzed the empirical data.FindingsThe results are shown servant leadership is positively correlated with employees’ voice behavior, but psychological security and error learning ability play a partial mediation role in the positive impact of servant leadership on employees’ voice behavior. while psychological security and error learning ability play a chain mediation role in the positive impact of servant leadership on employees’ voice behavior. Besides, work autonomy moderates the chain mediation path by enhancing the positive impact of servant leadership on psychological security. the higher the employees’ work autonomy is, the stronger the positive impact of servant leadership on psychological security will be, and the stronger the chain mediation effect of psychological security and error learning ability between servant leadership and employees’ voice behavior.Practical ImplicationsManagers should abandon the traditional “command and control” management mode, focus on the servant leadership style and improve employees’ psychological security through a comfortable and independent working environment. Besides, managers should set up a suitable error learning atmosphere mechanism, appropriately allow employees to work, give them a specific work autonomy, increase employees’ work flexibility, and encourage employees to provide a cheerful voice for the development and progress of the organization.Origin/valueFrom the perspective of Social Exchange, this study more comprehensively discusses the internal action path of the impact of servant leadership on employees’ voice behavior, enriches the antecedent variables of employees’ voice behavior, expands the existing research on the mediation mechanism of servant leadership, deepens the understanding of the efficiency mechanism of servant leadership, and has enlightenment significance for managers to stimulate employees’ voice better.

3-Azabicyclo[3.1.0]hexanes are common structural components in natural products and bioactive compounds. Traditionally, the metal-mediated cyclopropanation domino reaction of chain enzymes is the most commonly used strategy for the construction of this type of aza[3.1.0]bicycle derivative. In this study, a base-promoted intramolecular addition of alkenes used to deliver conformationally restricted highly substituted aza[3.1.0]bicycles is reported. This reaction was tailor-made for saturated aza[3.1.0] bicycle-containing fused bicyclic compounds that may be applied in the development of concise and divergent total syntheses of bioactive compounds.

BackgroundInflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive.ObjectiveThis study aimed to evaluate the association between inflammatory cytokines and NAFLD.MethodsPubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out.ResultsThe search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis.ConclusionsOur results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.

AimTo investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the regulating mechanism.MethodsNASH mice were induced by high-fat and high-fructose diets (HFFD). In the fifth week, mice in the YBT group were orally administrated YBT (22.12g·kg-1·d-1) daily for 12 weeks. Fresh stool of mice was collected at the 16th week for fecal 16S rDNA analysis. Hepatic pathology and biochemical indicators were used to reflect the improvement of YBT on hepatic inflammation and lipid metabolism in NASH mice. Quantitative real-time PCR (qRT-PCR) was used to verify the results of PICRUSt analysis.ResultsResults of the pathological and biochemical index showed that YBT could improve NASH mice. Compared with improving inflammation and hepatocyte damage, YBT may be more focused on enhancing metabolic disorders in mice, such as increasing HDL-c level. The diversity and richness of the gut microbiota of NASH mice induced by HFFD are significantly different from the normal control (NC) group. After YBT treatment, the diversity and richness of the mice microbiota will be increased to similar NC mice. Intestinimonas, Acetatifactor, Alistipes, Intestinimonas, Acetatifactor, and Alistipes have the most significant changes in the class level. PICRUSt analysis was performed to predict genomic functions based on the 16S rDNA results and reference sequencing. The efficacy of YBT in the treatment of NASH can be achieved by regulating the diversity and richness of gut microbiota. PICRUSt analysis results showed that the most relevant function of the microbiota construction variations is α- Linolenic acid (ALA) metabolism. Results of qRT-PCR showed significant differences between groups in the expression of Fatty acid desaturase 1 (FADS1), Fatty acid desaturase 2 (FADS2), Acyl-CoA Oxidase 1 (ACOX1), and Acyl-CoA Oxidase 2 (ACOX2) related to ALA metabolism. The expression of the above genes will be inhibited in the liver and small intestine of the HFFD group mice, and the expression can be restored after YBT treatment.ConclusionYBT could treat NASH mice by improving the diversity and richness of gut microbiota and further the improvement of ALA metabolism.

BackgroundSymptomatic intracranial hemorrhage (sICH) is a devastating complication of endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) and is associated with high risk of disability and mortality. This study intended to evaluate the predictors of sICH after EVT in patients with large vessel occlusion (LVO)-induced AIS.MethodsWe conducted a retrospective review on consecutive AIS patients who underwent EVT in our University hospital between January 2019 and August 2020. The patients were classified into two groups based upon the occurrence of sICH. The main outcomes were the occurrence of sICH using the Heidelberg Bleeding Classification and functional condition at 90 days. Multivariate logistic regression analysis and receiver operating characteristics (ROC) curves were used to identify independent predictors of sICH after EVT.ResultsThree hundred and 69 patients were enrolled in the study, of which 16.8% (n = 62) developed sICH. Favorable neurological outcome was lower in patients with sICH than in patients without sICH (6.5 vs. 43.3%; P < 0.001), with the overall mortality being 112 (30.4%) at 90 days post- EVT. Results from univariate analysis showed significant differences between the two groups in the prevalence of diabetes, initial Alberta Stroke Program Early CT Score (ASPECTS) score, National Institutes of Health Stroke Scale (NIHSS) score after operation, the levels of fasting blood glucose (FBG), neutrophil to lymphocyte ratio (NLR), platelets (PLT), and thrombin time (TT) at admission. Multivariate logistic regression analysis showed that FBG ≥ 7.54 mmol/L (OR: 2.765; 95% confidence interval [CI]: 1.513–5.054), NLR ≥ 5.48 (OR: 2.711; 95% CI: 1.433–5.128), TT at admission ≥ 16.25 s (OR: 2.022; 95% CI: 1.115–3.667), and NIHSS score within 24 h after the operation ≥ 10 (OR: 3.728; 95% CI: 1.516–9.170) were independent predictors of sICH. The combination of NLR ≥ 5.48, FBG ≥ 7.54 mmol/L, TT at admission ≥ 16.25 s, and NIHSS score within 24 h after the operation ≥ 10 generated an optimal prediction model (AUC: 0.723).ConclusionHigher levels of FDG, NLR, TT at admission, and NIHSS score after operation were associated with sICH after EVT in patients with LVO-induced AIS.

Abstract. Inner ear hair cells are important for maintaining hearing. Irreversible damage to hair cells is an important cause of sensorineural deafness. Electromagnetic radiation, especially high-power microwave, is an important threat to human health in modern society and war. However, it is not clear whether high-power microwave has an effect on cochlea hair cells. This study aimed to assess the effects of high-power microwave on cochlear hair cells in guinea pigs, and investigate the potential protection of these cells against high-power microwave-induced damage by recombinant adenovirus A20. Based on experimental results, a 65 W/cm2 irradiation density applied to guinea pigs in this study to establish a high-power microwave inner ear injury model. In addition, pAdEeay-1/A20 was injected via a round window into experimental guinea pig cochlea, whereas artificial perilymph was injected into the control group. Auditory function was assessed by testing the auditory brainstem response threshold, and damage to cochlear hair cells was investigated by cell counting and scanning electron microscopy observations of the basilar membrane. Inner ear injury was observed 6hours after 65 W/cm2 of irradiation and the auditory brainstem response threshold was significantly higher in the irradiation group (P

Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders.

Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease.

Background/Aim: Lymph node density is a parameter used to more accurately predict tumor recurrence and patient survival. However, its association with surgical outcome in pyriform sinus carcinoma remains unclear. The purpose of this study was to assess the prognostic value of lymph node density in advanced pyriform sinus carcinoma. Patients and Methods: A total of 87 patients with pyriform sinus carcinoma treated between 2008 and 2015 were enrolled. Then, 5-year overall survival, 5-year disease-specific survival, 5-year disease-free survival, and 5-year regional recurrence-free survival were utilized to assess the prognostic significance of lymph node density. Results: With a median follow-up period of 31.8 months, 5-year overall survival, disease-specific survival, disease-free survival, and regional recurrence-free survival were 37.9%, 46.0%, 41.4%, and 54.0%, respectively. Univariate analysis revealed that lymph node density ≥ 0.093 was a significant predictor of poor 5-year overall survival ( P = .005), disease-specific survival ( P = .008), disease-free survival ( P = .0013), and regional recurrence-free survival ( P = .003). Furthermore, multivariate analysis demonstrated that lymph node density was negatively associated with adverse 5-year overall survival (hazard ratio = 1.62, 95% CI: 1.15-2.29, P = .006), disease-specific survival (hazard ratio = 1.86, 95% CI: 1.24-2.80, P = .003), disease-free survival (hazard ratio = 0.45, 95% CI: 0.24-0.85, P = .014), and regional recurrence-free survival (hazard ratio = 2.97, 95% CI: 1.43-6.17, P = .004). Conclusion: Taken together, these results reveal that lymph node density is a powerful prognostic factor for patients with T3 and T4 pyriform sinus carcinoma, and the median lymph node density cutoff values ≥ 0.093 are associated with a greater risk of recurrence and poorer survival.

Tonotopic differences in the structure and physiological function, e.g., synapse number, membrane properties, Ca2+ channels, Ca2+ dependence of exocytosis and vesicle pool replenishment of inner hair cells (IHCs) along the longitudinal cochlear axis have recently been discovered, suggesting different gene expression patterns of IHCs. To determine whether IHCs present different gene expression patterns along the longitudinal cochlear axis, apical and basal IHCs were collected separately using the suction pipette technique from adult mouse cochleae for RNA-seq and genome-wide transcriptome analysis. We found 689 annotated genes showed more than 2-fold increase in expression. Interestingly, 93.4% of the differentially expressed genes (DEGs) was upregulated in apical IHCs. Although a subset of genes that related to IHC machinery and deafness were found to be differentially expressed, a gradient of gene expression was indeed detected in Ocm, Pvalb, Prkd1, Fbxo32, Nme2, and Sncg, which may play putative roles in the Ca2+ buffering and survival regulation. The expression of these genes was validated by real-time quantitative PCR (RT-qPCR) or immunostaining. We conclude that IHCs from different mouse cochlear longitudinal position have different gene expression profiles. Our data might serve as a valuable resource for exploring the molecular mechanisms underlying different biological properties as well as the survival regulation of IHCs.

The cutting power consumption of milling has direct influence on the economic benefits of manufacturing particle boards. The influence of the milling parameters on the cutting power were investigated in this study. Experiments and data analyses were conducted based on the response surface methodology. The results show that the input parameters had significant effects on the cutting power. The high rake angle reduced the cutting force. Thus, the cutting power decreased with the increase in the rake angle and the cutting energy consumption was also reduced. The cutting power increased with the rotation speed of the main shaft and the depth of milling induced the impact resistance between the milling tool and particle board and the material removal rate. The p-values of the created models and input parameters were less than 0.05, which meant they were significant for cutting power and power efficiency. The depth of milling was the most important factor, followed by the rotation speed of the main shaft and then the rake angle. Due to the high values of R2 of 0.9926 and 0.9946, the quadratic models were chosen for creating the relationship between the input parameters and response parameters. The predicted values of cutting power and power efficiency were close to the actual values, which meant the models could perform good predictions. To minimize the cutting power and maximize the power efficiency for the particle board, the optimized parameters obtained via the response surface methodology were 2°, 6991.7 rpm, 1.36 mm for rake angle, rotation speed of the main shaft and depth of milling, respectively. The model further predicted that the optimized parameters combination would achieve cutting power and power efficiency values of 52.4 W and 11.9%, respectively, with the desirability of 0.732. In this study, the influence of the input parameters on the cutting power and power efficiency are revealed and the created models were useful for selecting the milling parameters for particle boards, to reduce the cutting power.

Abstract Background Low concentration NaHCO3 (ca. 12 mM) had been demonstrated to be an excellent carbon source for industrially important green alga Chlorella vulgaris and high concentration NaHCO3 (e.g. 160 mM) had been shown to be capable of controlling protozoa and stimulating lipid accumulation of another green alga, i.e., Neochloris oleoabundans. Furthermore, little was known about the mechanisms of the effects of NaHCO3 on microalgae. Thorough studies on the effects of high NaHCO3 on C. vulgaris and their mechanisms were therefore warranted. Methods We systematically compared the cell growth, lipid production, and cell morphology of the industrially important C. vulgaris in 160 mM NaHCO3 or 160 mM NaCl media at different pH levels. These data allowed us to analyze the effects of total dissolved inorganic carbon (DIC) and individual DIC species on C. vulgaris. Cell growth of C. vulgaris at a range of concentrations at 160 mM or lower was also studied. Results Cellular lipid cell content of 494 mg g−1 and lipid productivity of 44.5 mg L−1 day−1 were obtained at 160 mM NaHCO3 and pH 9.5. High concentration NaHCO3 (e.g. 160 mM) was inhibitive to cell growth but stimulating to lipid accumulation and caused unicellular C. vulgaris to transfer to colonial cells. Increasing pH in the range of 7.5–9.5 caused increasing inhibition to cell growth in 160 mM NaCl. Whereas the optimal pH for cell growth was 8.5 for 160 mM NaHCO3 cultures. Comparative experiments with 0–160 mM NaHCO3 indicate that 10 mM was the optimal concentration and increasing NaHCO3 from 10 to 160 mM caused increasing inhibition to cell growth. Conclusions High concentration DIC was inhibitor to cell growth but stimulator to lipid accumulation of C. vulgaris. It caused unicellular C. vulgaris to transform to colonial cells. Results suggest that high concentration of a particular DIC species, i.e., dCO2, was the primary stress responsible for cell growth inhibition. Where CO3 2− was likely the DIC species responsible for lipid stimulation of C. vulgaris. Furthermore, we propose that the colony formation at high DIC conditions was employed by C. vulgaris to mitigate the stress by minimizing cell exposure to unfavorable environment.

Abstract The Initiation-Response-Feedback (IRF) cycle (teachers’ initiation, students’ response and teachers’ feedback) has been a key focus in studies of second language classroom interaction and participation. This paper aims to examine the influence of the first language (L1) in the Initiation-Response-Feedback (IRF) cycle commonly appearing in teacher-fronted classroom interaction. Previous studies have come to different conclusions about the role and value of L1 in the IRF cycle. The direct method underpinning the avoidance of L1 has been adopted since 1880s. The use of L1 is not discussed in language pedagogy in the last decade or two and some researchers consider the occurrence of the L1 as a problem. On the other hand, recent studies show that L1 can be used as a mediating language to create effective learning context for second language acquisition. However, these arguments are discussed either from a theoretical position or in a general classroom context and pay less attention to what is happening in micro interactions. This paper addresses the effect of using L1 in English as a foreign language classroom through an examination of the micro IRF cycle in English language classrooms in China. The data was collected through video recordings in a senior high school in China and analysed through conversation analysis. The analysis suggests that L1 used in the IRF cycle can function as a key to open up dialogue and bring more target language into the conversation. I argue that L1 in the IRF cycle can be used as a mediating tool and promote acquisition of the target language. This study will provide new insights into the role of L1 in teaching and learning interactions.

Crocins are highly valuable natural compounds for treating human disorders, and they are also high-end spices and colorants in the food industry. Due to the limitation of obtaining this type of highly polar compound, the commercial prices of crocins I and II are expensive. In this study, macroporous resin column chromatography combined with high-speed counter-current chromatography (HSCCC) was used to purify crocins I and II from natural sources. With only two chromatographic steps, both compounds were simultaneously isolated from the dry fruit of Gardenia jasminoides, which is a cheap herbal medicine distributed in a number of countries. In an effort to shorten the isolation time and reduce solvent usage, forward and reverse rotations were successively utilized in the HSCCC isolation procedure. Crocins I and II were simultaneously obtained from a herbal resource with high recoveries of 0.5% and 0.1%, respectively, and high purities of 98.7% and 99.1%, respectively, by HPLC analysis. The optimized preparation method was proven to be highly efficient, convenient, and cost-effective. Crocins I and II exhibited inhibitory activity against ATP citrate lyase, and their IC50 values were determined to be 36.3 ± 6.24 and 29.7 ± 7.41 μM, respectively.

Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

The primary aim of the current study was to assess the effects of oropharingeal muscle exercises in obstruction severity on stroke patients with OSAS. The secondary aims were to evaluate the effects of the exercises on rehabilitation of neurological function, sleeping, and morphology change of upper airway. An open-label, single-blind, parallel-group, randomized, controlled trial was designed. Fifty post-stroke patients with moderate OSAS were randomly assigned into 2 groups (25 in each group). For the therapy group, oropharyngeal muscle exercise was performed during the daytime for 20 min, twice a day, for 6 weeks. The control group was subjected to sham therapy of deep breathing. Primary outcomes were the obstruction severity by polysomnography. Secondary outcomes included recovery of motor and neurocognitive function, personal activities of daily living assessment (ADL), sleep quality and sleepiness scale. It also included upper airway magnetic resonance imaging (MRI) measurements. Assessments were made at baseline and after 6-week exercise. Finally, 49 patients completed the study. The apnea–hypopnea index, snore index, arousal index, and minimum oxygen saturation improved after exercise (P < 0.05). Oropharyngeal muscle exercises improved subjective measurements of sleep quality (P = 0.017), daily sleepiness (P = 0.005), and performance (both P < 0.05) except for neurocognition (P = 0.741). The changes in obstruction improvement, sleep characteristics and performance scale were also associated with training time, as detected by Pearson's correlation analysis. The anatomic structural remodeling of the pharyngeal airway was measured using MRI, including the lager retropalatal distance (P = 0.018) and shorter length of soft palate (P = 0.044) compared with the baseline. Hence, oropharyngeal muscle exercise is a promising alternative treatment strategy for stroke patients with moderate OSAS.Clinical Trial Registration:http://www.chictr.org.cn. Unique identifier: ChiCTR-IPR-16009970

The clinical application of dipeptidyl peptidase IV inhibitors (DPP4i) increasing active glucagon-like peptide-1 (AGLP-1) levels has been linked to pancreatitis, pancreatic tumors, and cardiovascular events. However, DPP4 mutations in humans or the long-term outcomes of high glucagon-like peptide-1 (GLP-1) level exposure have not been reported. A trio family with a proband showing an extremely high AGLP-1 level [defined here as hyperglipemia (hyper-glucagon-like peptide-1-emia)] were conducted whole-exome sequencing for potential pathogenic genetic defects. One novel DPP4 mutation, p.V486M (c.1456 G>A), was identified in the proband and showed damaged enzymatic activity of DPP4. Ex vivo functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight DPP4 variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. Of note, the levels of glucose, lipids, and tumor markers (especially for CA15-3 and CA125), increased gradually in the proband during a 4-year follow-up period, although no abnormal physical symptoms or imaging results were observed at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs.

Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic “brown-like” cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue-specific AMPK α1/α2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a β3-adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKα induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively, whereas chronic AMPK activation by A-769662 promoted WAT browning in inguinal WAT and protected against HFD-induced obesity and related metabolic dysfunction. These findings reveal a vital role for adipocyte AMPK in regulating the browning process in inguinal WAT and in maintaining energy homeostasis, which suggests that the targeted activation of adipocyte AMPK may be a promising strategy for anti-obesity therapy.

Today’s sensor networks need robustness, security and efficiency with a high level of assurance. Error correction is an effective communicational technique that plays a critical role in maintaining robustness in informational transmission. The general way to tackle this problem is by using forward error correction (FEC) between two communication parties. However, by applying zero-error coding one can assure information fidelity while signals are transmitted in sensor networks. In this study, we investigate zero-error coding via both classical and quantum channels, which consist of n obfuscated symbols such as Shannon’s zero-error communication. As a contrast to the standard classical zero-error coding, which has a computational complexity of O ( 2 n ) , a general approach is proposed herein to find zero-error codewords in the case of quantum channel. This method is based on a n-symbol obfuscation model and the matrix’s linear transformation, whose complexity dramatically decreases to O ( n 2 ) . According to a comparison with classical zero-error coding, the quantum zero-error capacity of the proposed method has obvious advantages over its classical counterpart, as the zero-error capacity equals the rank of the quantum coefficient matrix. In particular, the channel capacity can reach n when the rank of coefficient matrix is full in the n-symbol multilateral obfuscation quantum channel, which cannot be reached in the classical case. Considering previous methods such as low density parity check code (LDPC), our work can provide a means of error-free communication through some typical channels. Especially in the quantum case, zero-error coding can reach both a high coding efficiency and large channel capacity, which can improve the robustness of communication in sensor networks.

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC50 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague–Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes.

A small library of 6-aminoquinoxalines has been prepared by nucleophilic substitution of 6-fluoroquinoxaline with amines and nitrogen-containing heterocycles under computer-controlled microwave irradiation. Some compounds were found to be potent inhibitors of JNK Stimulatory Phosphatase-1 (JSP-1) in an in vitro biological assay.

BMS309403 is a biphenyl azole inhibitor against fatty acid binding protein 4 (FABP4) and regarded as a lead compound for effective treatment of obesity related cardio-metabolic diseases. Here we discovered an off-target activity of BMS309403 in that it stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs. Further analysis indicated that BMS309403 activates AMPK through increasing the ratio of intracellular AMP:ATP while decreasing mitochondrial membrane potential. These findings provide mechanistic insights on the action of BMS309403.

The concept of Cooperated Multipoint (CoMP) transmission is proposed for LTE-Advanced, which is in a form of distributed networks. In this background, a novel CoMP architecture is proposed in this paper, based on Group Cell concept in China FuTURE 4G TDD systems. Moreover, four actual scenarios are also concluded in CoMP, which, respectively, are single user in intracell, multiple users in intracell, single user in intercell and slide handover in intercell. In addition, a joint subcarrier optimization method is proposed to mitigate the intercell interference and improve performance under CoMP architecture; the method includes two aspects, which, respectively, are subcarrier allocation with maximum gain to interference plus noise ratio (GINR) and power allocation based on balanced signal to interference plus noise ratio (SINR). On this basis, three combined schemes are presented in simulation. Compared with traditional scheme, the proposed scheme improves throughputs and reduces blocking probability. Moreover, the average data rates in cell edge are also raised.