Competing Charge Transfer and Screening Effects in Two-Dimensional Ferroelectric Capacitors.

Two-dimensional (2D) ferroelectrics promise ultrathin flexible nanoelectronics, typically utilizing a metal-ferroelectric-metal sandwich structure. Electrodes can either contribute free carriers to screen the depolarization field, enhancing nanoscale ferroelectricity, or induce charge doping, disrupting the long-range crystalline order. We explore electrodes' dual roles in 2D ferroelectric capacitors, supported by first-principles calculations covering a range of electrode work functions. Our results reveal volcano-type relationships between ferroelectric-electrode binding affinity and work function, which are further unified by a quadratic scaling between the binding energy and the transferred interfacial charge. At the monolayer limit, charge transfer dictates the ferroelectric stability and switching properties. This general characteristic is confirmed in various 2D ferroelectrics including α-In2Se3, CuInP2S6, and SnTe. As the ferroelectric layer's thickness increases, the capacitor stability evolves from a charge-transfer-dominated state to a screening-dominated state. The delicate interplay between these two effects has important implications for 2D ferroelectric capacitor applications.

Sirt1 alleviates osteoarthritis via promoting FoxO1 nucleo-cytoplasm shuttling to facilitate autophagy.

This study aims to investigate the role and underlying mechanisms of Sirt1 in the pathophysiological process of OA. Safranine O and HE staining were utilized to identify pathological changes in the cartilage tissue. Immunohistochemistry was employed to evaluate the expression levels of proteins. IL-1ß treatment and TamCartSirt1flox/flox mice were utilized to induce OA model both in vitro and in vivo. Key autophagy-related transcription factors, autophagy-related genes, and chondrocyte extracellular matrix (ECM) breakdown enzyme markers were examined using multi assays. Immunofluorescence staining revealed subcellular localization and gene expression patterns. ChIP assay and Co-immunoprecipitation assay were conducted to investigate the interactions between FoxO1 and the promoter regions of Atg7 and Sirt1. Our results demonstrate that Sirt1 deficiency exhibited inhibitory effects on ECM synthesis and autophagy, as well as exacerbated angiogenesis. Moreover, Atg7, Foxo1, and Sirt1 could form a protein complex. Sirt1 was observed to facilitate nuclear translocation of FoxO1, enhancing its transcriptional activity. Furthermore, FoxO1 was found to bind to the promoter regions of Atg7 and Sirt1, potentially regulating their expression. This study provides valuable insights into the involvement of Sirt1-Atg7-FoxO1 loop in OA, opening new avenues for targeted therapeutic interventions aiming to mitigate cartilage degradation and restore joint function.

Perturbation diversity certificates robust generalization.

Whilst adversarial training has been proven to be one most effective defending method against adversarial attacks for deep neural networks, it suffers from over-fitting on training adversarial data and thus may not guarantee the robust generalization. This may result from the fact that the conventional adversarial training methods generate adversarial perturbations usually in a supervised way so that the resulting adversarial examples are highly biased towards the decision boundary, leading to an inhomogeneous data distribution. To mitigate this limitation, we propose to generate adversarial examples from a perturbation diversity perspective. Specifically, the generated perturbed samples are not only adversarial but also diverse so as to certify robust generalization and significant robustness improvement through a homogeneous data distribution. We provide theoretical and empirical analysis, establishing a foundation to support the proposed method. As a major contribution, we prove that promoting perturbations diversity can lead to a better robust generalization bound. To verify our methods' effectiveness, we conduct extensive experiments over different datasets (e.g., CIFAR-10, CIFAR-100, SVHN) with different adversarial attacks (e.g., PGD, CW). Experimental results show that our method outperforms other state-of-the-art (e.g., PGD and Feature Scattering) in robust generalization performance.

Inhibition of MEG3 ameliorates cardiomyocyte apoptosis and autophagy by regulating the expression of miRNA-129-5p in a mouse model of heart failure.

The long non-coding RNA, maternally expressed gene 3 (MEG3), are involved in myocardial fibrosis and compensatory hypertrophy, but its role on cardiomyocyte apoptosis and autophagy in heart failure (HF) remains unclear. The aim of this study was to investigate the effect of MEG3 on cardiomyocyte apoptosis and autophagy and the underlying mechanism. A mouse model of HF was established by subcutaneous injection of isoproterenol (ISO) for 14 days, and an in vitro oxidative stress injury model was replicated with H2O2 for 6 h. SiRNA-MEG3 was administered in mice and in vitro cardiomyocytes to knock down MEG3 expression. Our results showed that cardiac silencing of MEG3 can significantly ameliorate ISO-induced cardiac dysfunction, hypertrophy, oxidative stress, apoptosis, excessive autophagy and fibrosis induced by ISO. In addition, inhibition of MEG3 attenuated H2O2-induced cardiomyocyte oxidative stress, apoptosis and autophagy in vitro. Downregulation of MEG3 significantly inhibited excessive cardiomyocyte apoptosis and autophagy induced by ISO and H2O2 through miRNA-129-5p/ATG14/Akt signaling pathways, and reduced H2O2-induced cardiomyocyte apoptosis by inhibiting autophagy. In conclusion, inhibition of MEG3 ameliorates the maladaptive cardiac remodeling induced by ISO, probably by targeting the miRNA-129-5p/ATG14/Akt signaling pathway and may provide a tool for pharmaceutical intervention.

Automated design of freeform imaging systems for automotive heads-up display applications.

The freeform imaging system is playing a significant role in developing an optical system for the automotive heads-up display (HUD), which is a typical application of augmented reality (AR) technology. There exists a strong necessity to develop automated design algorithms for automotive HUDs due to its high complexity of multi-configuration caused by movable eyeballs as well as various drivers' heights, correcting additional aberrations introduced by the windshield, variable structure constraints originated from automobile types, which, however, is lacking in current research community. In this paper, we propose an automated design method for the automotive AR-HUD optical systems with two freeform surfaces as well as an arbitrary type of windshield. With optical specifications of sagittal and tangential focal lengths, and required structure constraints, our given design method can generate initial structures with different optical structures with high image quality automatically for adjusting the mechanical constructions of different types of cars. And then the final system can be realized by our proposed iterative optimization algorithms with superior performances due to the extraordinary starting point. We first present the design of a common two-mirror HUD system with longitudinal and lateral structures with high optical performances. Moreover, several typical double mirror off-axis layouts for HUDs were analyzed from the aspects of imaging performances and volumes. The most suitable layout scheme for a future two-mirror HUD is selected. The optical performance of all the proposed AR-HUD designs for an eye-box of 130 mm × 50 mm and a field of view of 13° × 5° is superior, demonstrating the feasibility and superiority of the proposed design framework. The flexibility of the proposed work for generating different optical configurations can largely reduce the efforts for the HUD design of different automotive types.

A Genetic Variant of FAM46A is Associated With the Development of Adolescent Idiopathic Scoliosis in the Chinese Population.

STUDY DESIGN: A genetic case-control study. OBJECTIVE: To replicate recently reported genetic loci associated with adolescent idiopathic scoliosis (AIS) in the Chinese Han population, and to determine the relationship between gene expression and the clinical features of the patients. SUMMARY OF BACKGROUND DATA: A recent study conducted in the Japanese population identified several novel susceptible loci, which might provide new insights into the etiology of AIS. However, the association of these genes with AIS in other populations remains unclear. MATERIALS AND METHODS: A total of 1210 AIS and 2500 healthy controls were recruited for the genotyping of 12 susceptibility loci. Paraspinal muscles used for gene expression analysis were obtained from 36 AIS and 36 patients with congenital scoliosis. The difference regarding genotype and allele frequency between patients and controls was analyzed by χ 2 analysis. The t test was performed to compare the target gene expression level between controls and AIS patients. Correlation analysis was performed between gene expression and phenotypic data, including Cobb angle, bone mineral density, lean mass, height, and body mass index. RESULTS: Four SNPs, including rs141903557, rs2467146, rs658839, and rs482012, were successfully validated. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of single nucleotide polymorphism rs482012 showed significantly higher frequency in patients. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of rs482012 could notably increase the risk of AIS patients, with an odds ratio of 1.49, 1.16, 1.11, and 1.25, respectively. Moreover, tissue expression of FAM46A was significantly lower in AIS patients as compared with controls. Moreover, FAM46A expression was remarkably correlated with bone mineral density of patients. CONCLUSION: Four SNPs were successfully validated as novel susceptibility loci associated with AIS in the Chinese population. Moreover, FAM46A expression was associated with the phenotype of AIS patients.

Towards the high-quality development of City Region Food Systems: Emerging approaches in China.

The outbreak of COVID-19 has underscored the vulnerability of our current food systems. In China, following a series of strategies in guaranteeing food security in the past decades, the pandemic has further highlighted the necessity to strengthen urban-rural linkages and facilitate the sustainable development of local agri-food systems. The study for the first time introduced the City Region Food Systems (CRFS) approach to Chinese cities and attempted to holistically structure, analyze and promote the sustainability of local food systems in China. Taking Chengdu as an example, the study first took stock of existing concepts and policies in China and the city, and defined the high-quality development goals of CRFS for Chengdu. An indicator framework was then developed to serve as a CRFS assessment tool for identifying existing challenges and potentials of local food systems. Further, a rapid CRFS scan using the framework was conducted in Chengdu Metropolitan Area, providing concrete evidence for potential policy interventions and practice improvement in the area. The study has explored new paradigm of analysis for food related issues in China and provided supporting tools for evidence-based food planning in cities, which collectively contribute to the food system transformation in a post-pandemic scenario.

Cartilage-specific deficiency of clock gene Bmal1 accelerated articular cartilage degeneration in osteoarthritis by up-regulation of mTORC1 signaling.

Although a growing body of studies recently demonstrated that circadian clock gene Bmal1 plays an important role in cartilage development and homeostasis, evidence regarding the contribution of Bmal1 in articular cartilage of OA progression is still unclear. In the present study, we investigated the direct role of Bmal1 in articular cartilage homeostasis during OA progression using tamoxifen-induced cartilage-specific knockout mice. We found that the expression of BMAL1 was decreased in OA-damaged and aging cartilage tissues. Cartilage-specific deletion of Bmal1 promoted cartilage degradation and chondrocyte apoptosis, and inhibited chondrocyte anabolism in OA mice, leading to acceleration of articular cartilage degeneration and osteophyte formation during OA progression. Mechanistic study indicated that loss of Bmal1 resulted in hyperactivation of mammalian target of rapamycin complex 1(mTORC1) signaling in OA cartilage, and pharmacological inhibition of mTORC1 signaling pathway by rapamycin alleviated partially Bmal1 ablation-induced cartilage degradation and chondrocyte apoptosis in ex vivo OA model. Therefore, our results provide the evidence of a vital role for Bmal1 in cartilage degradation in post-traumatic OA by partially regulating the mTORC1 signaling.

Blocking circadian clock factor Rev-erbα inhibits growth plate chondrogenesis via up-regulating MAPK-ERK1/2 pathway.

Emerging evidence indicated circadian clock gene Rev-erbα was involved in cartilage metabolism, however the contribution of Rev-erbα to growth plate chondrogenesis remains unknown. Here, we found that Rev-erbα exhibited the spatiotemporal expression model in growth plate. Moreover, Rev-erbα antagonist SR8278 inhibited longitudinal elongation of metatarsal bone ex vivo. And morphological analysis exhibited SR8278 led to the reduced height of growth plate and hypertrophic zone. Furthermore, blocking Rev-erbα suppressed the proliferation and hypertrophic differentiation of chondrocytes in growth plate. Similarly, knock-down Rev-erbα inhibited the proliferation and differentiation of primary chondrocytes in vitro. The mechanistic study indicated that knock-down Rev-erbα up-regulated MAPK-ERK1/2 pathway in chondrocytes. However, restraint of MAPK-ERK1/2 pathway alleviated partially SR8278-inhibited longitudinal elongation of metatarsal bone and growth plate development. Therefore, our results provide evidence of the vital role of Rev-erbα on growth plate chondrogenesis.

Study on essential medicine system from the perspective of coordinated with centralized volume-based procurement policy / 中国药房

OBJECTIVE To provide a reference for further improvement of the essential medicine system. METHODS Statistical analysis method and comparative analysis method were used to explain the necessity of coordination between the two systems from the direct correlation and indirect impact of centralized volume-based procurement on the essential medicine system at the present stage. The relevant suggestions were put forward for the development of the essential medicine system in the new era from the perspective of improving institutional synergy. RESULTS & CONCLUSIONS There was a direct correlation between the policy of centralized procurement and the essential medicine system in terms of policy objectives and medicines selection. However， it also indirectly affects the use of essential medicines in medical institutions through production and supply， coincidence degree between the essential medicine list and the selected variety， and the consistency evaluation of generic drugs. It is suggested that in the selection of essential medicine list in the future， priority should be given to the selection of varieties through centralized procurement， and improve the drug supply guarantee capacity under the dual policy linkage； at the same time， incentive assessments for the allocation and use of essential medicines by various entities should be further strengthened to promote the further improvement and development of the essential medicine system.

Synthesis and Biological Evaluation of PEGylated MWO4 Nanoparticles as Sonodynamic AID Inhibitors in Treating Diffuse Large B-Cell Lymphoma.

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its ability to overcome critical limitations, including low tissue-penetration depth and phototoxicity in photodynamic therapy (PDT). Biogenic metal oxide nanoparticles (NPs) have been used as anti-cancer drugs due to their biocompatibility properties with most biological systems. Here, sonosensitizer MWO4-PEG NPs (M = Fe Mn Co Ni) were synthesized as inhibitors to activation-induced cytidine deaminase (AID), thus neutralizing the extensive carcinogenesis of AID in diffuse large B-cell lymphoma (DLBCL). The physiological properties of these nanomaterials were examined using transmission electron microscopy (TEM). The inhibition of NPs to AID was primarily identified by the affinity interaction prediction between reactive oxygen species (ROS) and AID through molecular dynamics and molecular docking technology. The cell apoptosis and ROS generation in US-triggered NPs treated DLBCL cells (with high levels of AID) were also detected to indicate the sonosensitivity and toxicity of MWO4-PEG NPs to DLBCL cells. The anti-lymphoma studies using DLBCL and AID-deficient DLBCL cell lines indicated a concentration-dependent profile. The synthesized MWO4-PEG NPs in this study manifested good sonodynamic inhibitory effects to AID and well treatment for AID-positive hematopoietic cancers.

Relook into the Risk Factors of Proximal Junctional Kyphosis in Early Onset Scoliosis Patients: Does the Location of Upper Instrumented Vertebra in Relation to the Sagittal Apex Matter?

OBJECTIVE: Growing rods surgery is the mainstay of treatment for early-onset scoliosis (EOS) while proximal junctional kyphosis (PJK) is one of the most commonly reported postoperative complications. We sought to investigate the impact of the location of upper instrumented vertebra (UIV) in relation to the sagittal apex on proximal junctional kyphosis in EOS after traditional growing rods (GRs) treatment. METHODS: A total of 102 EOS patients who received traditional growing rods treatment with a follow-up of at least 2 years between 2009 and 2020 were retrospectively reviewed. Radiographic measurements were performed before and after the index surgery and at the latest follow-up. We investigated the coronal Cobb angle and spinopelvic parameters of the whole spine. The location of the UIV, apex, lower instrumented vertebra (LIV), inflection vertebra (IV), the number and distance of UIV-apex, LIV-apex and IV-apex were also recorded. Risk factors for PJK were analyzed by logistic regression analysis. RESULTS: PJK was observed in 21 patients (20.6%) during the follow-up period. The PJK group showed a younger age at the index surgery (5.9 vs. 7.1 years, P = 0.042), more lengthening procedure times (5.0 vs. 4.0, P = 0.032), larger preoperative coronal Cobb angle (82.0 vs. 75.6°, P = 0.038), higher correction rate (51.2% vs. 44.4%, P = 0.047) and larger postoperative proximal junctional angle (PJA) (13.9 vs. 5.5°, P < 0.001) than the non-PJK group. The ratio of the number and distance from UIV-apex to IV-apex also differed significantly between the two groups. The logistic regression revealed that age at the index surgery ≤ 7 years, the ratio of the number from UIV- apex to IV- apex ≤ 0.6 and the ratio of the distance from UIV- apex to IV- apex ≤ 0.6 were independent risk factors for postoperative PJK. CONCLUSION: Besides younger age, a closer location of UIV relative to the sagittal apex is identified to be an independent risk factor of postoperative PJK. Selection of UIV at a relatively farther location away from the sagittal apex might help prevent occurrence of PJK.

Galectin-3 Enhances Osteogenic Differentiation of Precursor Cells From Patients With Diffuse Idiopathic Skeletal Hyperostosis via Wnt/ß-Catenin Signaling.

Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory skeletal disease characterized by the progressive ectopic ossification and calcification of ligaments and enthuses. However, specific pathogenesis remains unknown. Bone marrow mesenchymal stem cells (BMSCs) are a major source of osteoblasts and play vital roles in bone metabolism and ectopic osteogenesis. However, it is unclear whether BMSCs are involved in ectopic calcification and ossification in DISH. The current study aimed to explore the osteogenic differentiation abilities of BMSCs from DISH patients (DISH-BMSCs). Our results showed that DISH-BMSCs exhibited stronger osteogenic differentiation abilities than normal control (NC)-BMSCs. Human cytokine array kit analysis showed significantly increased secretion of Galectin-3 in DISH-BMSCs. Furthermore, Galectin-3 downregulation inhibited the increased osteogenic differentiation ability of DISH-BMSCs, whereas exogenous Galectin-3 significantly enhanced the osteogenic differentiation ability of NC-BMSCs. Notably, the increased Galectin-3 in DISH-BMSCs enhanced the expression of ß-catenin as well as TCF-4, whereas attenuation of Wnt/ß-catenin signaling partially alleviated Galectin-3-induced osteogenic differentiation and activity in DISH-BMSCs. In addition, our results noted that Galectin-3 interacted with ß-catenin and enhanced its nuclear accumulation. Further in vivo studies showed that exogenous Galectin-3 enhanced ectopic bone formation in the Achilles tendon in trauma-induced rats by activating Wnt/ß-catenin signaling. The current study indicated that enhanced osteogenic differentiation of DISH-BMSCs was mainly attributed to the increased secretion of Galectin-3 by DISH-BMSCs, which enhanced ß-catenin expression and its nuclear accumulation. Our study helps illuminate the mechanisms of pathological osteogenesis and sheds light on the possible development of potential therapeutic strategies for DISH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).

Differences of endoscopic features between undifferentiated-typed early gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma / 中华消化内镜杂志

Objective:To analyze and compare the features of undifferentiated-typed early gastric cancer (UD-EGC) and gastric mucosa-associated lymphoid tissue(MALT) lymphoma under white light endoscopy (WLE) and magnifying endoscopy-narrow band imaging (ME-NBI).Methods:Data of patients with complete endoscopic images of WLE and ME-NBI in Shanghai General Hospital, Shanghai Jiao Tong University from March 2015 to July 2019 were retrospectively analyzed.Twenty-six UD-EGC patients and seven gastric MALT lymphoma patients in ⅠE1 stage were included, and the characteristics of the two diseases under WLE and ME-NBI were compared and summarized.Results:There were no significant differences in age, sex or infiltration depth of lesions between the two groups.Under WLE, UD-EGC was often manifested as a single lesion located in the lower part of the stomach, with unclear lesion boundaries. While MALT lymphoma lesions were mostly multifocal with clear boundaries, located in the middle of the stomach. Under ME-NBI, the microsurface pattern of UD-EGC showed dilation or disappearance of areas between the recesses, and the spiral microvascular pattern. However, the microsurface pattern of MALT lymphomas were characterized by " cross-road traffic sign" , " pebble sign" , and the presentation of residual glandular duct at the lesion was similar to that of Helicobacter pylori ( HP)-related gastritis. Furthermore, the microvascular pattern of MALT lymphomas often showed " tree like appearance (TLA)" . After HP eradication therapy, the morphology of microsurface pattern and microvascular pattern in the original lesion area gradually returned to normal. Conclusion:UD-EGC and gastric MALT lymphoma showed particular features in the number, site and boundary under WLE, and they showed significantly different microsurface pattern and microvascular pattern under ME-NBI. Differentiation of the two diseases will help reduce the risk of missed diagnosis and misdiagnosis.

Epigenetic regulation of chondrocyte hypertrophy and apoptosis through Sirt1/P53/P21 pathway in surgery-induced osteoarthritis.

Sirt1 involved in cellular aging and aging-related diseases, including osteoarthritis (OA). Our previous study showed Sirt1 played a role in the pathogenesis of OA, however, the underlying mechanisms are still poorly elicited. In this study, we investigated the role of Sirt1 in epigenetically regulating P53/P21 pathway in a Sirt1 loss model. Sirt1 deletion male mice (n = 10) with destabilization of the medial meniscus (DMM) were used to observe its role on OA development. Then, the relationships between SIRT1 and P53 were detected by Coimmunoprecipitation (CoIP), and the gain-off function of P53 gene was indicated by P53 activators and inhibitors in vitro. Finally, human cartilage samples from patients with OA were collected. Sirt1 deletion mice displayed a spontaneous OA development, manifesting severe chondrocytes hypertrophy markers MMP13 and ADAMTS5, highly expressed P53 and P21. Strikingly, surgery-induced meniscus injury promoted the OA pathogenesis and apoptosis in Sirt1 deficient mice. Ultimately, our CoIP data demonstrated that Sirt1 directly interacted with P53 in vitro. However inhibition of P53 alleviated OA progression. We also observed that chondrocyte apoptosis and P53 increased in osteoarthritis (OA) progression with a declining expression of Sirt1 in human cartilage. Loss of Sirt1 in cartilage led to accelerated OA pathogenesis via aberrant activation of p53/p21 mediated senescence associated secretory phenotype, hypertrophy and apoptosis.

Postnatal Conditional Deletion of Bmal1 in Osteoblasts Enhances Trabecular Bone Formation Via Increased BMP2 Signals.

A large number of studies in recent years indicated the involvement of peripheral circadian clock in varied pathologies. However, evidence regarding how peripheral clocks regulate bone metabolism is still very limited. The present study aimed to investigate the direct role of Bmal1 (the key activator of peripheral circadian clock system) in vivo during bone developmental and remodeling stages using inducible osteoblast-specific Bmal1 knockout mice. Unexpectedly, the removal of Bmal1 in osteoblasts caused multiple abnormalities of bone metabolism, including a progressive increase in trabecular bone mass in as early as 8 weeks, manifested by an 82.3% increase in bone mineral density and 2.8-fold increase in bone volume per tissue volume. As mice age, an increase in trabecular bone mass persists while cortical bone mass decreases by about 33.7%, concomitant with kyphoscoliosis and malformed intervertebral disk. The increased trabecular bone mass is attributed to increased osteoblast number and osteoblast activity coupled with decreased osteoclastogenesis. Remarkably, the ablation of Bmal1 in osteoblasts promoted the expression level of Bmp2 and phosphorylation of SMAD1, whereas the attenuation of BMP2/SMAD1 signaling partially alleviated the effects of Bmal1 deficiency on osteoblast differentiation and activity. The results revealed that Bmal1 was a transcriptional silencer of Bmp2 by targeting the Bmp2 promoter. The peripheral clock gene Bmal1 in osteoblasts was crucial to coordinate differential effects on trabecular and cortical bones through regulating BMP2/SMAD1 during bone development, thus providing novel insights into a key role of osteoblast Bmal1 in homeostasis and integrity of adult bones. © 2020 American Society for Bone and Mineral Research.

Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R.

Neuropeptide Y (NPY) is known to regulate bone homeostasis; however, its functional role as a risk factor during osteoarthritis (OA) remains elusive. In this study, we aim to investigate the direct effect of NPY on degradation of cartilage and progression of OA and explore the molecular events involved. NPY was overexpressed in human OA cartilage accompanied with increased expression of NPY1 receptor (NPY1R) and NPY2 receptor (NPY2R). Stressors such as cold exposure resulted in the peripheral release of NPY from sympathetic nerves, which in turn promoted upregulation of NPY and NPY2R in articular cartilage in vivo. Intra-articular administration of NPY significantly promoted chondrocyte hypertrophy and cartilage matrix degradation, with a higher OARSI score than that of control mice, whereas inhibition of NPY2R but not NPY1R with its specific antagonist remarkably ameliorated NPY-mediated effects. Moreover, NPY activated mTORC1 pathway in articular chondrocytes, whereas the administration of rapamycin (an mTORC1 inhibitor) in vitro abrogated NPY-mediated effects. Mechanistically, mTORC1 downstream kinase S6K1 interacted with and phosphorylated SMAD1/5/8 and promoted SMAD4 nuclear translocation, resulting in upregulation of Runx2 expression to promote chondrocyte hypertrophy and cartilage degradation. In conclusion, our findings provided the direct evidence and the crucial role of NPY in cartilage homeostasis. © 2020 American Society for Bone and Mineral Research.

PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance.

Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inflammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracellular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-α (TNF-α). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor κB (NF-κB) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-a expression, whereas NF-κB inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-κB activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-κB dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.

Characteristic Analysis and Hepatic Transcriptomics of High-fat Diet-induced Cholesterol Gallstone Model in Mice / 胃肠病学

Background: The mouse model of high-fat diet-induced cholesterol gallstone is widely used in researches of pathogenesis, prevention and treatment of gallstones. Aims: To investigate the characteristics and hepatic transcriptomics of the mouse model of high-fat diet-induced cholesterol gallstone. Methods: Twenty male C57BL/6J mice were randomly allocated into chow diet (control) group and lithogenic diet (LD) group. After 8 weeks, the occurrence of gallstone was observed; the serum lipids and gallbladder bile lipids were detected; and the differentially expressed hepatic genes between the two groups were identified with Illumina NovaSeq sequencing systems. The enrichment analysis was mapped in GO and KEGG pathway databases. Real-time PCR was used to detect the expressions of genes related to bile acid synthesis in the liver. Results: The cholesterol gallstone formation rate was 100% in LD group, whereas no gallstone was observed in control group. Hepatomegaly and steatosis were obvious in mice of LD group. The serum levels of total cholesterol and triacylglycerol, as well as the cholesterol content and cholesterol saturation index of the gallbladder bile in LD group were significantly higher than those in control group (P<0.05). A total of 1 330 differentially expressed genes were identified by high-throughput sequencing and bioinformatics analysis. KEGG analysis showed that the differentially expressed genes were mainly enriched in lipid metabolism, bile secretion, and insulin secretion pathways. GO analysis showed that fatty acid metabolic process-related pathways were significantly enriched. Both hepatic transcriptomics analysis and real-time PCR showed that the expression levels of genes related to bile acid synthesis, including CYP7A1, CYP8B1 and CYP7B1 decreased significantly in the liver of LD group as compared with those of control group (P<0.05). Conclusions: The metabolism of cholesterol, bile acids and fatty acids is significantly disordered in mice with cholesterol gallstone. Transcriptomics analysis can screen out the differentially expressed genes that play roles in the formation of cholesterol gallstone, so as to provide references for studies focusing on these topics.

Analysis of Spatial Distribution and Association Network of Pharmaceutical Industry in the Yangtze River Economic Belt from the Perspective of Social Network Analysis / 中国药房

ABSTRACT OBJECTIVE：To analyze spatial distribution characteristics of pharmaceutical industry in the Yangtze RiverEconomic Belt，and to provide reference for regional pharmaceutical industry planning. METHODS：Based on the central analysis，agglomerated sub group analysis and secondary assignment program analysis of social network analysis，the industrial relevancebetween regional pharmaceutical industry and regional cities were studied（using the image matrix of agglomerated sub group），using regional pharmaceutical enterprises in the Yangtze River Economic Belt as the research object. RESULTS &CONCLUSIONS：The study involved 111 listed pharmaceutical companies in 82 regional cities，and 82 urban nodes formed aregional pharmaceutical industry distribution network，which could generate 8 urban cohesion subgroups，represented by Shanghai，Chengdu and Chongqing；Shanghai and Hangzhou in the Yangtze River Delta，Chengdu and Chongqing in the Chengdu and Chongqing economic circle have more advanced position in network centrality. The centrality of Shanghai was the highest（25.926），followed by Chongqing and Chengdu（both were 19.753）. It shows that the spatial distribution of the pharmaceuticalindustry in the Yangtze River Economic Belt shows a distribution pattern dominated by the Yangtze River Delta urbanagglomeration. At the same time，the Chengdu-Chongqing urban agglomeration also shows a greater influence. The regional citiesplay different roles in industrial development. Chongqing and Taizhou have shown stronger industrial radiation capabilities，while?Shanghai and Hangzhou have shown stronger industrial absorption capacity.