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Lin Zheng,1,* Yusi Yang,2,* Jie Liu,3 Tianliang Zhao,3 Xin Zhang,3 Lihua Chen3 1Department of Vascular Surgery, the Second Hospital, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Department of Cardiology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China; 3Department of Cardiac Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lihua Chen, The Second Hospital of Hebei Medical University, 215 Hepingxi Street, Shijiazhuang, 050000, People’s Republic of China, Tel +86 188 4679 1714, Fax +86 0311-87045297, Email lin0928@fjmu.edu.cnPurpose: Immune microenvironment plays an important role in aortic dissection (AD). Therefore, novel immune biomarkers may facilitate AD prevention, diagnosis, and treatment. This study aimed at mining key immune-related genes and relevant mechanisms involved in AD pathogenesis.Patients and Methods: Key immune cells in AD were identified by ssGESA algorithm. Next, genes associated with key immune cells were screened by weighted gene coexpression network analysis (WGCNA). Then hub immune genes were picked from protein-protein interaction network of overlapped genes from differential expression and WGCNA analyses by cytohubba plug-in. Their diagnostic potential was evaluated in two independent cohorts from GEO database. In addition, the expressions of hub immune genes were determined by quantitative RT-PCR, immunohistochemistry, and Western blotting in dissected and normal aortic tissues.Results: Activated B cells, CD56dim natural killer cells, eosinophils, gamma delta T cells, immature B cells, natural killer cells and type 17 T helper cells were identified as key immune cells in AD. Thereafter, a gene module significantly correlated with key immune cells we

Histoplasmosis is a systemic mycosis caused by the dimorphic fungus in the genus Histoplasma. Histoplasmosis is overlooked in China. This study aims to provide an epidemiological and clinical update on histoplasmosis in China by literature review. We reviewed cases of histoplasmosis reported in recent 11 years and described a case of histoplasmosis-triggered hemophagocytic lymphohistiocytosis (HLH) in an immunocompetent patient. A total of 225 cases of histoplasmosis diagnosed in China between 2012 and 2022 were involved in this study, compared with 300 cases reviewed from 1990 to 2011, an increasing number of cases of histoplasmosis have been diagnosed in the last 11 years. The majority of cases of histoplasmosis were autochthonous cases, mainly from provinces Sichuan (56/225, 24.9%), Hunan (50/225, 22.2%), Guangdong (31/225, 13.8%), and Yunnan (24/225, 10.7%). Higher incidence (52.5%, 53/99) of histoplasmosis occurred in immunocompetent patients which is similar to those from the previous 21 years, and the prevalence of the disease did not vary highly over time. Of note, the number of histoplasmosis cases is increasing, and the geographic distribution is shifting southwards over time. Improved awareness is critically important for informing clinical practice in China.

In this paper, the LCV2 modular method is proposed for the Grounded Visual Question Answering task in the vision-language multimodal domain. This approach relies on a frozen large language model (LLM) as intermediate mediator between the off-the-shelf VQA model and the off-the-shelf visual grounding (VG) model, where the LLM transforms and conveys textual information between the two modules based on a designed prompt. LCV2 establish an integrated plug-and-play framework without the need for any pre-training process. This framework can be deployed for VQA Grounding tasks under low computational resources. The modularized model within the framework allows application with various state-of-the-art pre-trained models, exhibiting significant potential to be advance with the times. Experimental implementations were conducted under constrained computational and memory resources, evaluating the proposed method's performance on benchmark datasets including GQA, CLEVR, and VizWiz-VQA-Grounding. Comparative analyses with baseline methods demonstrate the robust competitiveness of LCV2., Comment: 21 pages,9 figures

Immunocharacteristics-based typing strategies can be used to reflect the similar status of tumors. Therefore, we aimed to demonstrate whether the immune subtypes of GBM have independent prognostic efficacy and whether these subtypes can be used as clinical guidance for predicting the progression of GBM and determining drug sensitivity. In this study, we found that patients with GBM were divided into three conserved immune-related subtypes based on the infiltration level of immune cells, including immunosuppressed, moderate immunoactivity, and high immunoactivity. Regarding the relevant clinical significance, the high immunoactivity in GBM indicates the worst survival, which exhibited the highest levels of oncogenic activity, including angiogenesis, tumor-associated macrophages and tumor-associated fibroblasts, indicated worst survival. The immunosuppressive subtype of GBM was more likely to carry epidermal growth factor receptor mutations and MGMT methylation, and belong to the classical and proneural subtypes; however, but the high immunoactivity subtype was not. The immune subtype-specific transcription factors (TFs) regulatory network indicates that specific TFs drive the construction of each immune subtype, and that these subtype-specific TFs are more prone to internal TFs regulation. Furthermore, the immunosuppressed and moderate immunoactivity subtypes were significantly correlated with the drugs sensitivity, whereas the high immunoactivity subtype was not, indicating that GBMs with high immunoactivity were refractory. We also found that obatoclax mesylate, NPK76-II-72-1, gemcitabine, TAK-715 are potential drugs for the treatment of refractory GBM based on drug sensitivity models of different immune subtypes. Therefore, we demonstrated that the immune subtypes of GBM have independent prognostic efficacy and can be used as clinical guidance for predicting the progression of GBM and drug sensitivity. Most importantly, this study is expected to provide a pathway

The origin of calcium production in the first stars (Pop III stars), which formed out of the primordial matter of the Big Bang, and their fates, remain most fascinating mysteries in astrophysics. Advanced nuclear burning and supernovae were thought to be the dominant source of the Ca production seen in all stars. Here we report on a qualitatively different path to Ca production through break-out from the "warm" carbon-nitrogen-oxygen (CNO) cycle. We extend direct measurement of the $^{19}$F($p$, $\gamma$)$^{20}$Ne break-out reaction down to an unprecedentedly low energy point of 186 keV and discover a key resonance at 225 keV. In the domain of astrophysical interest, at around 0.1 giga kelvin, this thermonuclear $^{19}$F($p$,$\gamma$)$^{20}$Ne rate is up to a factor of 7.4 larger than the previous recommended rate. Our stellar models show a stronger break-out during stellar hydrogen burning than thought before, and may reveal the nature of Ca production in Pop III stars imprinted on the oldest known ultra-iron poor star, SMSS0313-6708. This result from the China Jinping Underground Laboratory, the deepest laboratory in the world, offering an environment with extremely low cosmic-ray induced background, has far-reaching implications on our understanding of how the first stars evolve and die. Our rate showcases the impact that faint Pop III star supernovae can have on the nucleosynthesis observed in the oldest known stars and first galaxies, key mission targets of the James Webb Space Telescope., Comment: 32 pages, 8 figures, 6 tables

Jiacheng Sun,1,2,* Guoping Cai,1,2,* Jinlong Shen,1,2 Pu Cheng,1,2 Jiapeng Zhang,1,2 Dengteng Jiang,1,2 Xianquan Xu,1,2 Fangying Lu,1,2 Lihua Chen,1,2 Haixiao Chen1,2 1Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, People’s Republic of China; 2Bone Development and Metabolism Research Center of Taizhou Hospital, Linhai, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haixiao Chen; Lihua Chen, Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, N.150 Ximen Road of Linhai City, Taizhou, Zhejiang Province, People’s Republic of China, Tel +86 15268400288, +86 13757624851, Email sun846231221@163.com; lhchen2008@126.comBackground: Osteoporosis is a metabolic bone disease. Osteoclasts are significantly involved in the pathogenesis of osteoporosis. AS-605240 (AS) is a small molecule PI3K-γ inhibitor and is less toxic compared to pan-PI3K inhibitors. AS also exerts multiple biological effects including anti-inflammatory, anti-tumor, and myocardial remodeling promotion. However, the involvement of AS in the differentiation and functions of osteoclasts and the effect of AS in treating patients with osteoporosis is still unclear.Purpose: This study aimed to investigate if AS inhibits the differentiation of osteoclasts and resorption of the bones induced by M-CSF and RANKL. Next, we evaluated the therapeutic effects of AS on bone loss in ovariectomy (OVX)-induced osteoporosis mice models.Methods: We stimulated bone marrow-derived macrophages with an osteoclast differentiation medium containing different AS concentrations for 6 days or 5μM AS at different times. Next, we performed tartrate-resistant acid phosphatase (TRAP) staining, bone resorption assay, F-actin ring fluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting (WB). Next, MC3T3-E1s (pre-os

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67(+)glucagon(+) and Ki67(+)insulin(+)) while apoptosis was reduced (caspase3(+)glucagon(+) and caspase3(+)insulin(+)). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism., Funding Agencies|AstraZeneca ABAstraZeneca

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67(+)glucagon(+) and Ki67(+)insulin(+)) while apoptosis was reduced (caspase3(+)glucagon(+) and caspase3(+)insulin(+)). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism., Funding Agencies|AstraZeneca ABAstraZeneca

Lihua chen,1,2,* Yuxuan Huang,3,4,* Binhua Dong,3,4 Yu Gu,1,2 Ye Li,3,4 Wei Cang,1,2 Pengming Sun,3,4 Yang Xiang1,2 1Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 3Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 4Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fuzhou, People’s Republic of China*These authors contributed equally to workCorrespondence: Yang Xiang, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuai Fu Yuan Wang Fu Jing, Dong Cheng District, Beijing, 100730, People’s Republic of China, Tel +86-1065296068, Fax +86-1065296218, Email xiangy@pumch.cn Pengming Sun, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-591-87558732 ; +86-591-97279671, Fax +86-591-87551247, Email sunfemy@hotmail.comIntroduction: The FMS-related tyrosine kinase 3 (FLT3) ligand (FLT3LG), a growth factor, binds to FLT3 on dendritic cell (DCs) to enhance their differentiation and expansion. It has shown great potential as an immunotherapy target for cancers. However, the expression and function of FLT3LG in cervical cancer remain largely unknown.Materials and Methods: In this study, we obtained the expression of FLT3LG, the clinical prognosis in cervical cancer, via multiple databases, in

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67(+)glucagon(+) and Ki67(+)insulin(+)) while apoptosis was reduced (caspase3(+)glucagon(+) and caspase3(+)insulin(+)). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism., Funding Agencies|AstraZeneca ABAstraZeneca

Although a variety of methods have been proposed for sequential recommendation, it is still far from being well solved partly due to two challenges. First, the existing methods often lack the simultaneous consideration of the global stability and local fluctuation of user preference, which might degrade the learning of a user's current preference. Second, the existing methods often use a scalar based weighting schema to fuse the long-term and short-term preferences, which is too coarse to learn an expressive embedding of current preference. To address the two challenges, we propose a novel model called Time Lag aware Sequential Recommendation (TLSRec), which integrates a hierarchical modeling of user preference and a time lag sensitive fine-grained fusion of the long-term and short-term preferences. TLSRec employs a hierarchical self-attention network to learn users' preference at both global and local time scales, and a neural time gate to adaptively regulate the contributions of the long-term and short-term preferences for the learning of a user's current preference at the aspect level and based on the lag between the current time and the time of the last behavior of a user. The extensive experiments conducted on real datasets verify the effectiveness of TLSRec., Comment: This paper has been accepted by CIKM 2022

Renming Chen, Qin Huang, Lihua Chen Department of Nephropathy and Rheumatology,The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of ChinaCorrespondence: Lihua Chen, Department of Nephropathy and Rheumatology,The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, 158 Wuyang County Street, Enshi, Hubei, People’s Republic of China, Tel +86 0718-8263471, Email clh133374920762022@163.comObjective: Fracture is a critical unfavorable prognostic factor in patients with rheumatoid arthritis(RA) and osteoporosis. At present, models involving clinical indices that accurately predict fracture are still uncommon. We addressed this gap by developing machine learning (ML)-based predictive models to individualize the risk of fracture in elderly patients with RA and osteoporosis and to identify a high-risk group for fracture.Methods: 487 patients diagnosed with RA and osteoporosis at the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture were randomly divided into a training cohort (used for building the model) and a validation cohort (used for validating the model). Five ML-assisted models were developed from candidate clinical features using two-step estimation methods. The receiver operating characteristic curve (ROC), decision curve analysis (DCA), and clinical impact curve (CIC) were performed to evaluate the robustness and clinical practicability of each model.Results: A total of twenty-two candidate variables were included, and the prediction model was established by an ML-based algorithm. The areas under the ROC curve (AUCs) of the random forest classifier (RFC) model, artificial neural network (ANN), support vector machine (SVM), eXtreme gradient boosting (XGBoost), decision tree (DT), probability of major osteoporotic fractures (PMOF), and probability of hip fracture (PHF) ranged from 0.695 to 0.878. Among them, RFC obtained the optimal prediction efficiency via adding serum selenium and clinic

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67(+)glucagon(+) and Ki67(+)insulin(+)) while apoptosis was reduced (caspase3(+)glucagon(+) and caspase3(+)insulin(+)). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism., Funding Agencies|AstraZeneca ABAstraZeneca

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67(+)glucagon(+) and Ki67(+)insulin(+)) while apoptosis was reduced (caspase3(+)glucagon(+) and caspase3(+)insulin(+)). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism., Funding Agencies|AstraZeneca ABAstraZeneca

Xinhui Wu,1,2,* Kangxian Zhao,1,2,* Xiaoxin Fang,3,4 Feng Lu,3,4 Weikang Zhang,1,2 Xiaoting Song,1,2 Lihua Chen,5 Jiacheng Sun,1,2 Haixiao Chen1,2,4 1Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China; 3Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, People’s Republic of China; 5Enze Medical Research Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haixiao ChenDepartment of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, People’s Republic of ChinaEmail drchx@126.comBackground: Osteolytic diseases such as osteoporosis are featured with accelerated osteoclast differentiation and strong bone resorption. Considering the complications and other limitations of current drug treatments, it is necessary to develop a safer and more reliable drug to deal with osteoclast-related diseases. Saikosaponin D (SSD) is the active extract of Bupleurum, which has anti-inflammation, anti-tumor and liver protection functions. However, the role of SSD in regulating the differentiation and function of osteoclasts is not clear.Purpose: To explore whether SSD could prevent osteoclast differentiation and bone resorption induced by M-CSF and RANKL, and further evaluate the potential therapeutic properties of SSD in LPS-induced inflammatory bone loss mouse models.Methods: BMMs were cultured in complete medium stimulated by RANKL with different concentrations of SSD. TRAP staining, bone resorption determination, qRT-PCR, immunofluorescence and Western blotting were performed. A mouse model of LPS-induced calvarial bo

Lihua Chen,1,2,* Binhua Dong,2,3,* Hangjing Gao,2,3 Huifeng Xue,4 Diling Pan,5 Pengming Sun1– 3 1Department of Gynecology, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Provincial Key Laboratory of Women and Children Major Disease, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 3Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 4Medical Center of Cervical Disease and Colposcopy, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 5Department of Pathology, Fujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pengming SunFujian Provincial Maternity and Child Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou 350001, Fujian, People’s Republic of ChinaTel +86-591-87558732 (Lab Office)Fax +86-591-87551247Email sunfemy@hotmail.comPurpose: Human papillomavirus-16 (HPV-16) is the most carcinogenic HPV genotype. This study aimed to evaluate the clinical value of POU5F1B and HPV-16-E2/E6 by cervical cytology specimens to predict the cervical intraepithelial neoplasia two grade and more (CIN2+).Methods: Finally, 248 patients with HPV-16 single infection were enrolled. Using cytology specimen by real-time quantitative PCR (qPCR), POU5F1B mRNA and HPV-16-E2/E6 were detected. The relationship of POU5F1B, HPV-16-E2/E6 and CIN2+ were analyzed, and the optimal cut-off values of POU5F1B and HPV-16-E2/E6 to predict CIN2+ were calculated.Results: The mean HPV

The design/discovery of new materials is highly non-trivial owing to the near-infinite possibilities of material candidates, and multiple required property/performance objectives. Thus, machine learning tools are now commonly employed to virtually screen material candidates with desired properties by learning a theoretical mapping from material-to-property space, referred to as the \emph{forward} problem. However, this approach is inefficient, and severely constrained by the candidates that human imagination can conceive. Thus, in this work on polymers, we tackle the materials discovery challenge by solving the \emph{inverse} problem: directly generating candidates that satisfy desired property/performance objectives. We utilize syntax-directed variational autoencoders (VAE) in tandem with Gaussian process regression (GPR) models to discover polymers expected to be robust under three extreme conditions: (1) high temperatures, (2) high electric field, and (3) high temperature \emph{and} high electric field, useful for critical structural, electrical and energy storage applications. This approach to learn from (and augment) human ingenuity is general, and can be extended to discover polymers with other targeted properties and performance measures.

Artificial intelligence (AI) based approaches are beginning to impact several domains of human life, science and technology. Polymer informatics is one such domain where AI and machine learning (ML) tools are being used in the efficient development, design and discovery of polymers. Surrogate models are trained on available polymer data for instant property prediction, allowing screening of promising polymer candidates with specific target property requirements. Questions regarding synthesizability, and potential (retro)synthesis steps to create a target polymer, are being explored using statistical means. Data-driven strategies to tackle unique challenges resulting from the extraordinary chemical and physical diversity of polymers at small and large scales are being explored. Other major hurdles for polymer informatics are the lack of widespread availability of curated and organized data, and approaches to create machine-readable representations that capture not just the structure of complex polymeric situations but also synthesis and processing conditions. Methods to solve inverse problems, wherein polymer recommendations are made using advanced AI algorithms that meet application targets, are being investigated. As various parts of the burgeoning polymer informatics ecosystem mature and become integrated, efficiency improvements, accelerated discoveries and increased productivity can result. Here, we review emergent components of this polymer informatics ecosystem and discuss imminent challenges and opportunities.

Modern data-driven tools are transforming application-specific polymer development cycles. Surrogate models that can be trained to predict the properties of new polymers are becoming commonplace. Nevertheless, these models do not utilize the full breadth of the knowledge available in datasets, which are oftentimes sparse; inherent correlations between different property datasets are disregarded. Here, we demonstrate the potency of multi-task learning approaches that exploit such inherent correlations effectively, particularly when some property dataset sizes are small. Data pertaining to 36 different properties of over $13, 000$ polymers (corresponding to over $23,000$ data points) are coalesced and supplied to deep-learning multi-task architectures. Compared to conventional single-task learning models (that are trained on individual property datasets independently), the multi-task approach is accurate, efficient, scalable, and amenable to transfer learning as more data on the same or different properties become available. Moreover, these models are interpretable. Chemical rules, that explain how certain features control trends in specific property values, emerge from the present work, paving the way for the rational design of application specific polymers meeting desired property or performance objectives.

Wenyu Lin,1,2,* Liqing Lin,3,* Binhua Dong,2,4 Lihua Chen,1 Huifang Lei,1,2 Yuqin Gao,1,2 Yaojia Chen,1,2 Pengming Sun1,2,4 1Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 3Department of Women’s Health Care, Quanzhou Women’s and Children’s Hospital, Quanzhou, 362000, People’s Republic of China; 4Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pengming SunDirector of Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, No. 18 Daoshan Road, Fuzhou, Fujian 350001, People’s Republic of ChinaEmail sunfemy@hotmail.comBackground: The diagnosis of postpartum pelvic organ prolapse (POP) relies on symptoms combined with pelvic organ prolapse-quantification (POP-Q) and lacks serological indicators. The objective of this study was to assess serum elastin, type I collagen, miRNA-30d, and miRNA-181a in the early postpartum period to identify hematologic predictors of POP.Material and Methods: The study included 1013 42- to 60-day-postpartum women who had delivered at Quanzhou Women’s and Children’s Hospital from October 1, 2016, to October 31, 2017. This study was performed in accordance with the Declaration of Helsinki. The pregnancy and childbirth characteristics and pelvic floor function were evaluated. Forty cases with and without POP were matched, and serum elastin a

Chang Yu,1 Lihua Chen,1 Guanyu Ruan,1,2 Jian An,1 Pengming Sun1,2 1Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Key Laboratory of Fujian Maternal and Pediatric Major Disease Research, Fujian Provincial Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaCorrespondence: Pengming SunKey Laboratory of Fujian Maternal and Pediatric Major Disease Research, Fujian Provincial Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaTel +86 591 8755 8732Fax +86 591 8755 1247Email sunfemy@hotmail.comPurpose: To evaluate the level of human papilloma virus (HPV)-related knowledge and vaccination willingness of people in Fujian Province, and to explore the factors influencing doctors’ recommendation of HPV vaccine.Methods: We conducted two cross-sectional surveys in Fujian Province. The study cohort included 248 medical staff and medical students and 1001 community members. Descriptive statistics were used to identify the general demographics of the participants, along with their knowledge and attitudes regarding HPV and vaccination. Analyses were conducted to identify factors associated with willingness to vaccinate and willingness to recommend vaccination.Results: The level of HPV knowledge in Fujian province was found to be low, but more than 80% of participants would like to accept HPV vaccine. Medical staff had a higher willingness to recommend HPV vaccine than students (OR= 4.696, CI: 2.698-8.175), which may be related to work experience and acceptance of vaccine price but not to knowledge level. Conclusion: Knowledge of HPV in our community population appears to be lower than that in other regions in China. We suggest that a lack of knowledge may

AIMS/HYPOTHESIS: Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting.METHODS: We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets.RESULTS: Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells.CONCLUSIONS/INTERPRETATION: Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects.

Jinjin Wang,1,2,* Fanhui Meng,3,* Wen Song,3,* Jingyi Jin,2 Qianli Ma,2 Dongdong Fei,1 Liang Fang,2 Lihua Chen,2 Qintao Wang,1 Yumei Zhang3 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 2Department of Immunology, School of Basic Medicine, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 3State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China *These authors contributed equally to this work Introduction: Fabricating nanostructured surface topography represents the mainstream approach to induce osteogenesis for the next-generation bone implant. In the past, the bone implant was designed to minimize host repulsive reactions in order to acquire biocompatibility. However, increasing reports indicate that the absence of an appropriate immune response cannot acquire adequate osseointegration after implantation in vivo. Materials and methods: We prepared different topographies on the surface of titanium (Ti) specimens by grinding, etching and anodizing, and they were marked as polished specimen (P), specimen with nanotubes (NTs) in small diameters (NT-30) and specimen with NTs in large diameters (NT-100). We evaluated the ability of different topographies of the specimen to induce osteogenic differentiation of mice bone marrow mesenchymal stem cells (BMSCs) in vitro and to induce osseointegration in vivo. Furthermore, we investigated the effect of different topographies on the polarization and secretion of macrophages, and the

Jinjin Wang,1,2,* Fanhui Meng,3,* Wen Song,3,* Jingyi Jin,2 Qianli Ma,2 Dongdong Fei,1 Liang Fang,2 Lihua Chen,2 Qintao Wang,1 Yumei Zhang3 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 2Department of Immunology, School of Basic Medicine, The Fourth Military Medical University, Xi’an, Shannxi Province, China; 3State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shannxi Province, China *These authors contributed equally to this work Introduction: Fabricating nanostructured surface topography represents the mainstream approach to induce osteogenesis for the next-generation bone implant. In the past, the bone implant was designed to minimize host repulsive reactions in order to acquire biocompatibility. However, increasing reports indicate that the absence of an appropriate immune response cannot acquire adequate osseointegration after implantation in vivo. Materials and methods: We prepared different topographies on the surface of titanium (Ti) specimens by grinding, etching and anodizing, and they were marked as polished specimen (P), specimen with nanotubes (NTs) in small diameters (NT-30) and specimen with NTs in large diameters (NT-100). We evaluated the ability of different topographies of the specimen to induce osteogenic differentiation of mice bone marrow mesenchymal stem cells (BMSCs) in vitro and to induce osseointegration in vivo. Furthermore, we investigated the effect of different topographies on the polarization and secretion of macrophages, and the

Deep learning holds great promise in the reconstruction of undersampled Magnetic Resonance Imaging (MRI) data, providing new opportunities to escalate the performance of rapid MRI. In existing deep learning-based reconstruction methods, supervised training is performed using artifact-free reference images and their corresponding undersampled pairs. The undersampled images are generated by a fixed undersampling pattern in the training, and the trained network is then applied to reconstruct new images acquired with the same pattern in the inference. While such a training strategy can maintain a favorable reconstruction for a pre-selected undersampling pattern, the robustness of the trained network against any discrepancy of undersampling schemes is typically poor. We developed a novel deep learning-based reconstruction framework called SANTIS for efficient MR image reconstruction with improved robustness against sampling pattern discrepancy. SANTIS uses a data cycle-consistent adversarial network combining efficient end-to-end convolutional neural network mapping, data fidelity enforcement and adversarial training for reconstructing accelerated MR images more faithfully. A training strategy employing sampling augmentation with extensive variation of undersampling patterns was further introduced to promote the robustness of the trained network. Compared to conventional reconstruction and standard deep learning methods, SANTIS achieved consistent better reconstruction performance, with lower errors, greater image sharpness and higher similarity with respect to the reference regardless of the undersampling patterns during inference. This novel concept behind SANTIS can particularly be useful towards improving the robustness of deep learning-based image reconstruction against discrepancy between training and evaluation, which is currently an important but less studied open question.

Xiaodan Mao,1 Guanyu Ruan,1 Binhua Dong,1 Lihua Chen,1 Shuxia Xu,2 Fen Lin,1 Pengming Sun1,31Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; 2Department of Pathology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; 3Department of Gynecology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, ChinaPurpose: To estimate the high-risk human papillomavirus (HR-HPV) prevalence in a hospital-based population using the Cervista® and to determine the clinical value and significance of Cervista for cervical cancer screening in Fujian Province, China.Patients and methods: In a hospital-based population, a total of 10,771 women from the Fujian Province were screened for cervical cancer and precancerous lesions using the thinprep cytologic test (TCT) and/or the Cervista. Women with HR-HPV infection and/or abnormal TCT were referred for colposcopy and biopsy. Pathological diagnosis was used as the gold standard.Results: The overall HR-HPV prevalence was 16.57%. Among 10,229 cases, 976 had abnormal cytology results, of which, the HR-HPV positivity rate was 60.35% in this opportunistic screening population. The most common HR-HPV infection style was a simple infection. The most common species was A9 which was also the most prevalent species in all age. The women with CIN2+ (high-grade squamous intraepithelial lesion [HSIL]), especially cancer, were mostly concentrated in the age from 51 to 60 years old. The peak of CIN1 (low-grade squamous intraepithelial lesion, LSIL) prevalence was in the women aged 31–40. When using CIN1+, CIN2+ and CIN3+ as observed endpoints, the sensitivities were 86.07%, 92.73%, and 93.30% and negative likelihood ratio (NPV) were 99.15%, 99.75% and 99.83%

Hongzhi Qiao,1,2,* Lihua Chen,3,* Tianqi Rui,1,2 Jingxian Wang,1,2 Ting Chen,1,2 Tingming Fu,1,2 Junsong Li,1,2 Liuqing Di1,2 1College of Pharmacy, Nanjing University of Chinese Medicine, 2Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing, 3Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China *These authors contributed equally to this work Abstract: Andrographolide (ADG) is a diterpenoid isolated from Andrographis paniculata with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box–Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability (Papp) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (P<0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure wit

Hongzhi Qiao,1,2,* Lihua Chen,3,* Tianqi Rui,1,2 Jingxian Wang,1,2 Ting Chen,1,2 Tingming Fu,1,2 Junsong Li,1,2 Liuqing Di1,2 1College of Pharmacy, Nanjing University of Chinese Medicine, 2Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing, 3Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China *These authors contributed equally to this work Abstract: Andrographolide (ADG) is a diterpenoid isolated from Andrographis paniculata with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box–Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability (Papp) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (P<0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure wit

ObjectiveTo perform a meta-analysis exploring the correlation between the apparent diffusion coefficient (ADC) and tumor cellularity in patients.Materials and methodsWe searched medical and scientific literature databases for studies discussing the correlation between the ADC and tumor cellularity in patients. Only studies that were published in English or Chinese prior to November 2012 were considered for inclusion. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Sensitivity and subgroup analyses were performed to investigate potential heterogeneity.ResultsOf 189 studies, 28 were included in the meta-analysis, comprising 729 patients. The pooled r for all studies was -0.57 (95% CI: -0.62, -0.52), indicating notable heterogeneity (P<0.001). After the sensitivity analysis, two studies were excluded, and the pooled r was -0.61 (95% CI: -0.66, -0.56) and was not significantly heterogeneous (P = 0.127). Regarding tumor type subgroup analysis, there were sufficient data to support a strong negative correlation between the ADC and cellularity for brain tumors. There was no notable evidence of publication bias.ConclusionsThere is a strong negative correlation between the ADC and tumor cellularity in patients, particularly in the brain. However, larger, prospective studies are warranted to validate these findings in other cancer types.

ObjectiveTo perform a meta-analysis exploring the correlation between the apparent diffusion coefficient (ADC) and tumor cellularity in patients.Materials and methodsWe searched medical and scientific literature databases for studies discussing the correlation between the ADC and tumor cellularity in patients. Only studies that were published in English or Chinese prior to November 2012 were considered for inclusion. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Sensitivity and subgroup analyses were performed to investigate potential heterogeneity.ResultsOf 189 studies, 28 were included in the meta-analysis, comprising 729 patients. The pooled r for all studies was -0.57 (95% CI: -0.62, -0.52), indicating notable heterogeneity (P<0.001). After the sensitivity analysis, two studies were excluded, and the pooled r was -0.61 (95% CI: -0.66, -0.56) and was not significantly heterogeneous (P = 0.127). Regarding tumor type subgroup analysis, there were sufficient data to support a strong negative correlation between the ADC and cellularity for brain tumors. There was no notable evidence of publication bias.ConclusionsThere is a strong negative correlation between the ADC and tumor cellularity in patients, particularly in the brain. However, larger, prospective studies are warranted to validate these findings in other cancer types.

胰腺內的胰島具有極其重要的功能，通過產生并分泌一系列的胰島荷爾蒙，特別是能控制機體葡萄糖利用的胰島素，來調節體內血糖穩態。胰島素的分泌受到多種因素或信號通路的調節。据信，在臨床上表現出來明顯的高血糖症的時候，胰島細胞的分泌功能已經出現典型性的缺陷。由此，大量的研究證據指出，2 型糖尿病表現出來的代謝型缺陷主要為胰島功能紊亂，而并不是周圍組織胰島素抵抗。這表明，胰島素功能缺陷是早於高血糖症的發生的。另一方面，大量證據表明長期性的高血糖會導致胰島 細胞功能紊亂。鑒於此，揭示胰島功能調節的潛在機理并闡明胰島功能与高血糖症之間的關係變得尤為重要。, 在臨床上表現出能調節胰島功能和血糖控制的相關因子正與日俱增。其中極具研究價值的是一種多肽，稱作胰高血糖素様肽（GLP-1），其作用表現在通過增強胰島素分泌和胰島素敏感性來增強胰島 細胞的功能和增值。GLP-1 在體內的降解能被DPP-4 的抑製劑所延阻。同時，通過對一種名為SGLT2 的葡萄糖轉運蛋白的抑制，機體內的血糖水平能被顯著降低。這一作用是通過阻止腎臟對葡萄糖的重吸收來實現的，並且是不依賴于胰島素的。由於DPP-4 抑制所表現的最終生理作用需要通過胰島素的信號通路來實現，但SGLT2 的抑制卻不依賴於胰島素，由此不難想象，對SGLT2 和DPP-4 的聯合抑制在2 型糖尿病的血糖控制方面具有潛在的協同效應。即通過對SGLT2 的抑制來顯著降低血糖水平，從而促進GLP-1 在體內的作用效應。因此，本研究的第一部分研究SGLT2 和DPP-4 的單一或聯合抑制（利用SGLT2 抑製劑BI-38335 和DPP-4 抑製劑linagliptin）在二型糖尿病動物模型db/db老鼠種對胰島功能和體內葡萄糖穩態的作用。在此研究中，我們比較了SGLT2 和DPP-4 單一抑制或聯合抑制對db/db 老鼠胰島功能的影嚮。研究發現，所有的實驗組都能顯著降低血糖以及糖化血紅蛋白（HbA1c）的水平，而且聯合抑制組表現出更叫顯著的效應。聯合抑制組增強了胰島細胞的胰島素分泌功能，改善葡萄糖耐受并增加胰島素的敏感性。於此一致的是，聯合抑制組降低了β細胞凋亡和胰島免疫細胞標記物，並且抑制了与TLR2 信號通路相關的一系列炎症分子，通過則一系列作用實現對胰島的保護。上述研究表明，對SGLT2 和DPP-4 的聯合抑制在對胰島功能和胰島形態學上的保護至少能夠表現出加性效應，從而更好實現對血糖的調控。, 在第一部分的工作中，我們利用的動物模型db/db 老鼠是一類較嚴重的糖尿病動物模型，它表現出及其嚴重的高血糖症，糖耐受失調同β細胞缺陷。我們集中于研究SGLT2 和DPP-4 的抑制對這類嚴重糖尿病的胰島功能的調節，具體表現在對胰島β細胞功能的正向調節，包括胰島素分泌功能的增強和β細胞質量的增加。廣為接受的一點是，胰島素抵抗和胰島素分泌功能的缺失最能表徵從正常葡萄糖耐受發展到2 型糖尿病的這一進程。這一進程的早期主要表現為由肥胖或衰老而引起的代償性的胰島素抵抗，此時伴有正常或受損的葡萄糖耐受以及正常的胰島素分泌功能。此時，任何能影響胰島功能的因素都會減緩或加速2 型糖尿病的發生。鑒於此，研究此类因素從而到达阻止2 型糖尿病的发生就显得尤为重要。因此，在本研究的第二部分，我们研究利用高脂飼料诱导的肥胖老鼠模型和老化的老鼠模型来分别研究煙酸（niacin 或 nicotinic acid）对胰岛功能的影響。煙酸是一種臨床上廣汎使用的降血脂藥物，但近年來的研究發現長期或高劑量的使用會導致高血糖症和血糖控制失調的出現，然而這一現象產生的具體機製並不清楚。因此，我們第二部分的研究集中於揭示煙酸引起的高血糖症是否歸因於其對胰島功能的破壞，以及潛在的分子機制。我們的研究發現，在肥胖老鼠和老齡鼠中，煙酸能夠引起高血糖症，破壞葡萄糖體內穩態並且降低胰島素分泌能力；另一方面，煙酸增加饑餓血清胰島素水平並且引起葡萄糖耐受實驗中第一期胰島素分泌缺陷。體內和體外實驗還發現煙酸誘導煙酸受體GPR109a，UCP2 和PPARγ的表達增加以及SIRT1 的表達和NAD,NAD/NADH 降低。通過基因沉默技術降低GPR109a 在β細胞中的表達，我們發現煙酸的上述作用都被極大的減弱，從而揭示了煙酸引起的胰島功能降低是由其受體GPR109a 介導的。, 總闊來說，我們的研究揭示了DPP-4 同SGLT2 的聯合抑制在增強胰島功能和胰島形態學上的保護以及改善胰島素抵抗等方面能夠表現出加性效應，從而更好實現對血糖的調控。另一方面，我們的研究闡述了煙酸通過它的受體GPR109a 以及其下游信號通路如PPARγ和SIRT1 來損害胰島細胞功能。綜上所述，我們當前的研究證實了一系列因素對胰島功能的調控，從而充實并擴展了我們對胰島功能和血糖控制以及2 型糖尿病之間關係的認識。, Pancreatic islets are of great importance to govern glucose homeostasis through production and secretion of islet peptide hormones, notably insulin, which functions as a master regulator to control glucose disposal in the body. Insulin secretion is regulated by various factors and signaling pathways. It is well known that islet insulin secretory function is typically lost by the time when signs of hyperglycemia that becomes clinically apparent. Thus, it has been pointed out that islet dysfunction, rather than peripheral insulin resistance, is the primary defect of type 2 diabetes mellitus (T2DM), indicating that deficiencies in islet function are prior to the onset of hyperglycemia. On the other hand, it is also widely accepted that chronic hyperglycemia results in islet β cells dysfunction. In this regard, it is of great importance to unravel the underlying mechanisms by which islet function is regulated, thus elucidating the relationship between hyperglycemia and islet function., There are ever increasing candidates of clinically relevant factors identified as criticalregulators for islet function and glycemic control. Of great interest is the glucagon-like peptide 1 (GLP-1) that improves β cell function and proliferation and its degradation can be delayed by dipeptidyl peptidase-4 (DPP-4) inhibition. Meanwhile, plasma glucose levels can be remarkably lowered by inhibition of sodium-glucose co-transporter 2 (SGLT2), through blockade of renal glucose reabsorption. In this regard, since the mode of action of SGLT2 inhibition is independent of insulin but the efficacy of DPP-4 inhibition relies on the insulin signalling, it is plausible to hypothesize that sustained lowering of plasma glucose by SGLT2 inhibition can facilitate the actions of GLP-1 from DPP-4 inhibition, thus leading to a potential synergistic effect on islet function and glycemic control. Accordingly, the first part of this study was to investigate the combination effects of SGLT2 and DPP-4 blockade on islet function and glucose homeostasis using an animal model of T2DM, the db/db mice. We compared the effects of either DPP-4 inhibition (by a DPP-4 inhibitor, linagliptin) or SGLT2 inhibition (by an SGLT2 inhibitor, BI-38335) individually and in combination on islet function and glycemic control in db/db mice. Active treatments markedly enhanced islet function, improved glycemic control and reduced islet and peripheral tissue inflammation, with the combined treatment showing the greater effects. These data indicate that combined SGLT2 inhibition with DPP-4 inhibition work additively to exhibit benefits to islet function, inflammation and insulin resistance, thus improving glycemic control., In the first part, we investigated a positive regulation of islet function in overt diabetic mice, in which there are severe hyperglycemia and β cell failure. It is widely accepted that the progression from normal glucose tolerance to T2DM is characterized by dual defects that include insulin resistance and an insulin secretory defect caused by β cell dysfunction. In the early stage, there is compensated insulin resistance resulting from obesity or aging with normal or even impaired glucose tolerance as well as nearly normal insulin secretory capacity. As such, any factors that affect islet function in this stage may delay or accelerate the onset of diabetes. In this regard, it is noteworthy to study the regulation of such factors in islet function in order to prevent the development of T2DM. Thus, in the second part, we investigated how islet function was regulated by a widely used lipid-lowering drug, niacin (nicotinic acid), in obese mice and aged mice. Niacin has been known to impair euglycemic control during prolonged and high dose treatments but the underlying mechanism(s) whereby the islets are involved remains unclear. As such, we aimed at elucidating whether this hyperglycemic effect is due to the dysfunction of pancreatic islet and, if so, the underlying mechanism(s) involved. We investigated the direct effects of niacin on islet function and insulin resistance in HFD-induced obese (DIO) mice and aged mice. Our results showed that eight-week treatments with niacin impaired glycemic control and islet function in DIO and aged mice. Moreover, niacin treatments significantly induced PPARγ and GPR109a expression but decreased SIRT1 expression in pancreatic islets, while islet morphology remained unchanged. In vitro studies showed that niacin decreased glucose-stimulated insulin secretion (GSIS), cAMP, NAD/NADH ratio, and mitochondrial membrane potential (ΔΨm) but increased reactive oxygen species (ROS) transiently, while upregulated expression levels of UCP2, P, Collectively, our study has revealed that inhibition of DPP-4 or SGLT2 alone can improve islet function, and combined inhibition of DPP-4 and SGLT2 works additively to exhibit benefits to islet cell function/morphology, inflammation and insulin resistance, thus improving glycemic control. On the other hand, we have also elucidated that niacin impairs islet β cell function through GPR109a and downstream signaling pathways such as PPARγ and SIRT1. Taken together, the present study has shown the regulation of is let β cell function by different factors, which has an added advance to our knowledge about the intricate relationship between islet function and hyperglycemia and T2DM., Detailed summary in vernacular field only., Chen, Lihua., Thesis (Ph.D.)--Chinese University of Hong Kong, 2013., Includes bibliographical references (leaves 168-195)., s also in Chinese., p.i, 摘要 --- p.iv, Acknowledgement --- p.vii, List of Publications --- p.viii, List of Abbreviations, Chapter Chapter 1 --- General Introduction --- p.1, Chapter 1.1 --- Endocrine pancreas --- p.2, Chapter 1.1.1 --- Structure and composition of endocrine pancreas --- p.3, Chapter 1.1.2 --- Architecture and composition of the islet --- p.3, Chapter 1.1.3 --- Endocrine cells and their function --- p.5, Chapter 1.2 --- Disorders of the endocrine pancreas --- p.9, Chapter 1.3 --- Insulin --- p.10, Chapter 1.3.1 --- Insulin Structure --- p.10, Chapter 1.3.2 --- Insulin actions and insulin receptor --- p.11, Chapter 1.3.3 --- Insulin secretion --- p.12, Chapter 1.3.3.1 --- Glucose-induced insulin secretion --- p.13, Chapter 1.3.3.2 --- Phasic insulin secretion --- p.14, Chapter 1.3.4 --- The regulation of insulin secretion --- p.16, Chapter 1.3.5 --- Autocrine insulin feedback --- p.20, Chapter 1.4 --- Diabetes mellitus --- p.21, Chapter 1.4.1 --- Type 1 diabetes mellitus (T1DM) --- p.22, Chapter 1.4.2 --- Type 2 diabetes mellitus (T2DM) --- p.23, Chapter 1.4.3 --- Obesity and T2DM --- p.23, Chapter 1.4.4 --- Islet dysfunction and T2DM --- p.25, Chapter 1.5 --- Incretin hormones and DPP-4 inhibition --- p.27, Chapter 1.5.1 --- Incretin hormones --- p.27, Chapter 1.5.2 --- Functions of incretin hormones --- p.30, Chapter 1.5.3 --- Regulation of GLP-1 --- p.34, Chapter 1.5.4 --- Incretin-based therapy for T2DM --- p.35, Chapter 1.6 --- Sodium-dependent glucose cotransporter 2 (SGLT2) and its inhibitors --- p.38, Chapter 1.6.1 --- Sodium-dependent glucose cotransporter 2 (SGLT2) --- p.38, Chapter 1.6.2 --- Rationale for SGLT2 inhibition --- p.40, Chapter 1.6.3 --- Consequences of SGLT2 inhibition --- p.41, Chapter 1.6.4 --- Strategies of SGLT2 inhibition --- p.43, Chapter 1.6.4.1 --- SGLT2 inhibitors --- p.44, Chapter 1.6.4.1 --- SGLT2 inhibitors --- p.47, Chapter 1.7 --- Niacin (nicotinic acid) and its clinical usage --- p.49, Chapter 1.7.1 --- Niacin general introduction --- p.49, Chapter 1.7.2 --- General roles of niacin --- p.49, Chapter 1.7.3 --- Anti-lipolytic effect --- p.50, Chapter 1.7.4 --- Niacin receptor --- p.51, Chapter 1.7.5 --- Hyperglycemic effect of niacin --- p.52, Chapter 1.8 --- General hypothesis --- p.54, Chapter Chapter 2 --- General Materials and Methods --- p.56, Chapter 2.1 --- Experimental animal models --- p.57, Chapter 2.1.1 --- Animal model of type 2 diabetes --- p.57, Chapter 2.1.2 --- High-fat diet-induced obese mice --- p.58, Chapter 2.1.3 --- Aged mice --- p.59, Chapter 2.2 --- INS-1E cell culture and treatment --- p.59, Chapter 2.2.1 --- Mouse pancreatic islet isolation --- p.59, Chapter 2.2.2 --- Primary culture of isolated pancreatic islets --- p.60, Chapter 2.3 --- Pancreatic islet isolation and culture --- p.60, Chapter 2.4 --- Glucose-stimulated insulin secretion (GSIS) assay --- p.61, Chapter 2.5 --- Assessment of glucose homeostasis --- p.61, Chapter 2.6 --- Determination of mRNA expression --- p.62, Chapter 2.6.1 --- Design of specific primers --- p.63, Chapter 2.6.2 --- Total RNA extraction and cDNA synthesis --- p.63, Chapter 2.6.3 --- Real-time PCR analysis --- p.64, Chapter 2.7 --- Detection of protein expression --- p.64, Chapter 2.7.1 --- Western blotting analysis --- p.64, Chapter 2.7.2 --- Immunofluorescent staining --- p.65, Chapter 2.8 --- Biochemical analyses --- p.65, Chapter 2.8.1 --- Plasma insulin and blood HbA1c levels --- p.65, Chapter 2.8.2 --- Detection of cAMP --- p.66, Chapter 2.8.3 --- NAD and NADH determination --- p.66, Chapter 2.9 --- Detection of intracellular ROS --- p.67, Chapter 2.10 --- Detection of mitochondrial membrane potential --- p.67, Chapter 2.11 --- Statistical analysis --- p.67, Chapter Chapter 3 --- Effects of Combining Linagliptin Treatment with BI-38335, A Novel SGLT2 Inhibitor, on Pancreatic Islet Function and Inflammation in db/db Mice --- p.70, Chapter 3.1 --- Abstract --- p.71, Chapter 3.2 --- Introduction --- p.72, Chapter 3.3 --- Materials and Methods --- p.74, Chapter 3.3.1 --- Animal model and experimental design --- p.74, Chapter 3.3.2 --- In vivo glucose homeostasis --- p.75, Chapter 3.3.3 --- Pancreas and islet studies --- p.76, Chapter 3.3.4 --- Biochemical analyses --- p.77, Chapter 3.3.5 --- Real-time PCR analyses --- p.77, Chapter 3.3.6 --- Statistical analysis. --- p.78, Chapter 3.4 --- Results --- p.78, Chapter 3.4.1 --- Treatments with DPP-4 and SGLT2 inhibitors lower plasma glucose --- p.78, Chapter 3.4.2 --- Treatments with DPP-4 and SGLT2 inhibitors improve glycemic --- p.80, Chapter 3.4.3 --- Pancreatic islet function in db/db mice --- p.83, Chapter 3.4.4 --- Pancreatic islet and peripheral tissue inflammation --- p.86, Chapter 3.4.5 --- Islet morphology and preserved beta cells --- p.89, Chapter 3.5 --- Discussion --- p.93, Chapter Chapter 4 --- Niacin-Induced Hyperglycemia Is Mediated via Niacin Receptor GPR109a in Pancreatic Islets --- p.98, Chapter 4.1 --- Abstract --- p.99, Chapter 4.2 --- Introduction --- p.100, Chapter 4.3 --- Research design and methods --- p.102, Chapter 4.3.1 --- Animal model and experimental design --- p.102, Chapter 4.3.2 --- In vivo glucose homeostasis --- p.102, Chapter 4.3.3 --- Pancreas and islet studies --- p.103, Chapter 4.3.4 --- INS-1E cell culture and treatment --- p.103, Chapter 4.3.5 --- Construction of small interfering RNA for GPR109a --- p.103, Chapter 4.3.6 --- Real-time PCR analyses --- p.104, Chapter 4.3.7 --- Western blotting assay --- p.104, Chapter 4.3.8 --- Detection of intracellular and mitochondrial ROS --- p.105, Chapter 4.3.9 --- Detection of mitochondrial membrane potential (ΔΨm) --- p.105, Chapter 4.3.10 --- Measurement of cAMP levels --- p.105, Chapter 4.3.11 --- Determination of NAD and NADH levels --- p.106, Chapter 4.3.12 --- Measurement of cell viability --- p.106, Chapter 4.3.13 --- Statistical analysis --- p.106, Chapter 4.4 --- Results --- p.106, Chapter 4.4.1 --- Glycemic control in HFD-induced obese mice --- p.106, Chapter 4.4.2 --- Pancreatic islet function in HFD-induced obese mice --- p.110, Chapter 4.4.3 --- Pancreatic islet morphology and gene expression --- p.112, Chapter 4.4.4 --- INS-1E function and intracellular levels of cAMP, NAD, and NADH --- p.114, Chapter 4.4.5 --- Gene expression in INS-1E cells --- p.117, Chapter 4.4.6 --- Status of ROS and ΔΨm in INS-1E cells --- p.119, Chapter 4.4.7 --- GPR109a knockdown in INS-1E cells --- p.122, Chapter 4.5 --- Discussion --- p.129, Chapter Chapter 5 --- Niacin Impairs Pancreatic Islet Glucose-Stimulated Insulin Secretion in Aged Mice through The Suppression of SIRT1 Signaling --- p.134, Chapter 5.1 --- Abstract --- p.135, Chapter 5.2 --- Introduction --- p.136, Chapter 5.3 --- Research design and methods --- p.139, Chapter 5.3.1 --- Animal model and experimental design --- p.139, Chapter 5.3.2 --- In vivo glucose homeostasis --- p.139, Chapter 5.3.3 --- Pancreas and islet studies --- p.140, Chapter 5.3.4 --- Real-time PCR analyses --- p.140, Chapter 5.3.5 --- Western blotting assay --- p.140, Chapter 5.3.6 --- NAD and NADH determination --- p.141, Chapter 5.3.7 --- NEFA determination --- p.141, Chapter 5.3.8 --- Statistical analysis --- p.141, Chapter 5.4 --- Results --- p.142, Chapter 5.4.1 --- Glycemic control in middle aged mice --- p.142, Chapter 5.4.2 --- Pancreatic islet function in HFD-induced obese mice --- p.147, Chapter 5.4.3 --- NAD, NADH levels in pancreatic islet --- p.149, Chapter 5.4.4 --- Genes expression in pancreatic islet --- p.151, Chapter 5.5 --- Discussion --- p.150, Chapter Chapter 6 --- General discussion --- p.156, Chapter 6.1 --- Combined inhibition of DPP-4 with SGLT2 on islet function, inflammation and insulin resistance in T2DM --- p.158, Chapter 6.2 --- Niacin impairs islet function in high-fat diet-induced obese mice and aged mice --- p.161, Chapter 6.3 --- General conclusion --- p.164, Chapter 6.4 --- Future directions --- p.166, Chapter Chapter 7 --- Bibliography --- p.167, http://library.cuhk.edu.hk/record=b5549766, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

In the early decades of the eighteenth century, the Hakka-speaking groups in south Taiwan were initially addressed "ke" (guest) in the writings by the Hoklo-speaking groups in a discriminatory manner. Nevertheless, they established their social status via the assistance to official troops in times of disturbances and via the expression of a collective consciousness through their advocacy of the Pavilion of Loyalty and Righteousness. Their identities were expressed in connection with their native places in the household registrations that were meant for baojia organization, taxation and in particular for imperial examinations. Clearly, the concept of Hakka as an ethnic group was not existent until some officials in the Japanese colonial government, who were influenced by the western idea of race, regarded Hakka-speaking groups as the Hakka race. Even so, more frequently the colonial officials categorized the Hakka-speaking groups "the Guangdong race," which directly applied the native places as their ethnic label. On one hand, this race category was fixed through official household registration, and on the other hand, colonial intellectuals endeavored to accentuate many cultural traits of the Hakka-speaking groups. This process gained legitimacy of the Hakka-speaking groups to be eventually ethnical within the colonial empire. It also perplexed the definitions of the Hakka in the process of the Liudui society's integration into the political and economic structure of the Japanese empire., In today's Taiwan society, the promotion and construction of the Hakka as a recognized ethnic group is in the ascendant. The Liudui area in the south, together with Taoyuan, Xinzhu and Miaoli counties in the north, are generally acknowledged as the two main congregation areas of the Hakka in Taiwan. "Liudui," derived from the name of a local trans-village military organization in the Qing dynasty, was established by Hakka -dialect speakers in this region. Their religious center was the Pavilion of Loyalty and Righteousness (zhongyi ting) founded to worship the martyrs sacrificed for fighting the rebels. The concept of Liudui has transited from an alliance of Hakka-speaking villages to the symbol representing Taiwan Hakka to the present day. This thesis explores how the complex interaction between the local society and the three different states (the Qing empire, the Japanese colonial government and the Republic of China) in the past four centuries eventually led to the construction of the Hakka identity in the Liudui society., The construction of the Taiwan Hakka ethnicity was influenced by different classifications in different periods of time. The transition in the wartime colonial period, in particular, was crucial for us to reconsider the relationship between the ethnicity and state as well as the historical process of ethnic construction., The Japanese colonial government performed assimilation policy and evolved to violent "Kominka" movement in the last decade of her rule in Taiwan. Nevertheless, it was exactly during this wartime period that the construction of the Hakka as a nationality which exported from southern China and Southeast Asia became highly feasible. In particular, the launch of the "Greater East Asia Co-Prosperity Sphere" brought opportunities for the integration of different nationalities within the Japanese ruling areas to come into reality. The vision of an enormous empire eventually collapsed because of the defeat of Japan, yet, this process paved the way for the postwar nation-state building in the same line. After the war, some people from the Chinese Mainland and some of them even originated from the Liudui area bore the Hakka identity and settled in Taiwan. They held important military and political positions in the republican government while in China, and they continued to play a crucial role in integrating the Hakka into the post-war nation-building process. It was under such political setting that the integration of Taiwan into the Chinese nation-state and the process of Taiwan's decolonization purported to utilize the historical sources of the Liudui society to be converged toward the ongoing construction of Hakka nationality in the Chinese Mainland., 陳麗華., Adviser: David Zame., Source: Dissertation Abstracts International, Volume: 72-01, Section: A, page: ., Thesis (doctoral)--Chinese University of Hong Kong, 2010., Includes bibliographical references (p. 164-191)., Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web., Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web., s in Chinese and English., Chen Lihua., isbn: 9781124360423, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

In this thesis, we deal with the worst-case portfolio optimization problem occuring in discrete-time markets. First, we consider the discrete-time market model in the presence of crash threats. We construct the discrete worst-case optimal portfolio strategy by the indifference principle in the case of the logarithmic utility. After that we extend this problem to general utility functions and derive the discrete worst-case optimal portfolio processes, which are characterized by a dynamic programming equation. Furthermore, the convergence of the discrete worst-case optimal portfolio processes are investigated when we deal with the explicit utility functions. In order to further study the relation of the worst-case optimal value function in discrete-time models to continuous-time models we establish the finite-difference approach. By deriving the discrete HJB equation we verify the worst-case optimal value function in discrete-time models, which satisfies a system of dynamic programming inequalities. With increasing degree of fineness of the time discretization, the convergence of the worst-case value function in discrete-time models to that in continuous-time models are proved by using a viscosity solution method.

In this thesis, we deal with the worst-case portfolio optimization problem occuring in discrete-time markets. First, we consider the discrete-time market model in the presence of crash threats. We construct the discrete worst-case optimal portfolio strategy by the indifference principle in the case of the logarithmic utility. After that we extend this problem to general utility functions and derive the discrete worst-case optimal portfolio processes, which are characterized by a dynamic programming equation. Furthermore, the convergence of the discrete worst-case optimal portfolio processes are investigated when we deal with the explicit utility functions. In order to further study the relation of the worst-case optimal value function in discrete-time models to continuous-time models we establish the finite-difference approach. By deriving the discrete HJB equation we verify the worst-case optimal value function in discrete-time models, which satisfies a system of dynamic programming inequalities. With increasing degree of fineness of the time discretization, the convergence of the worst-case value function in discrete-time models to that in continuous-time models are proved by using a viscosity solution method.

In this thesis, we deal with the worst-case portfolio optimization problem occuring in discrete-time markets. First, we consider the discrete-time market model in the presence of crash threats. We construct the discrete worst-case optimal portfolio strategy by the indifference principle in the case of the logarithmic utility. After that we extend this problem to general utility functions and derive the discrete worst-case optimal portfolio processes, which are characterized by a dynamic programming equation. Furthermore, the convergence of the discrete worst-case optimal portfolio processes are investigated when we deal with the explicit utility functions. In order to further study the relation of the worst-case optimal value function in discrete-time models to continuous-time models we establish the finite-difference approach. By deriving the discrete HJB equation we verify the worst-case optimal value function in discrete-time models, which satisfies a system of dynamic programming inequalities. With increasing degree of fineness of the time discretization, the convergence of the worst-case value function in discrete-time models to that in continuous-time models are proved by using a viscosity solution method.