IL-6/JAK1 DRIVES PD-L1 PHOSPHORYLATION AND GLYCOSYLATION TO PROMOTE CANCER IMMUNE EVASION

Glycosylation of immune receptors and ligands, such as T-cell receptor (TCR), major histocompatibility complex (MHC), and co-inhibitory molecules, regulates immune signaling activation, antigen presentation, and immune surveillance. Recent studies revealed that the glycan structures of co-inhibitory molecules are required for receptor-ligand interaction, a critical feature for activating cancer immune evasion. However, it is unclear how oncogenic signaling initiates glycosylation of co-inhibitory molecules to induce immunosuppression. Here we show interleukin (IL)-6-activated Janus kinase 1 (JAK1) phosphorylates programmed death-ligand 1 (PD-L1)-Tyr112, leading to the recruitment of endoplasmic reticulum (ER)-associated N-glycosyltransferase, STT3A, which catalyzes the glycosylation of PD-L1, contributing to its stability. A positive correlation between IL-6 and PD-L1 expression levels was observed in tumor samples from patients with hepatocellular carcinoma (HCC). Furthermore, IL-6 blockade led to downregulation of PD-L1 and increased sensitivity to anti-T-cell immunoglobulin mucin-3 (Tim-3) immune checkpoint therapies in animal models. These results identify a mechanism regulating initiation of PD-L1 glycosylation and suggest that the combination of anti-IL-6 and anti-Tim-3 is an effective, biomarker-driven, therapeutic strategy in HCC

Going Global: Cases for Relationship Marketing in Chinese Higher Education

The integration of the global economy is a phenomena that is increasingly evident in our everyday lives. Ranging from rapid economic growth in developing nations to the flow of capital across continents, globalization is affecting almost all corners of modern society. This includes the higher education sector, in which recent years have seen unprecedented growth in Asia as the economy increasingly becomes “knowledge-based”. The integration of a “knowledge-based” economy is also accelerating global competition amongst higher education institutions. This thesis takes three distinctive Chinese universities into account as case studies, interviewing respective administrators on policies and strategies concerning international student recruitment, management, and relationship management. Furthermore, interviews and surveys with Swedish students from Lund University should reveal another perspective regarding the attracting elements and factors for studying abroad, and specifically China. Models involving relationship marketing (RM) and customer relationship marketing (CRM) theories will be explored in the context of higher education sector and international student relationship management (ISRM)

Modeling Typhoon Event-Induced Landslides Using GIS-Based Logistic Regression: A Case Study of Alishan Forestry Railway, Taiwan

This study develops a model for evaluating the hazard level of landslides at Alishan Forestry Railway, Taiwan, by using logistic regression with the assistance of a geographical information system (GIS). A typhoon event-induced landslide inventory, independent variables, and a triggering factor were used to build the model. The environmental factors such as bedrock lithology from the geology database; topographic aspect, terrain roughness, profile curvature, and distance to river, from the topographic database; and the vegetation index value from SPOT 4 satellite images were used as variables that influence landslide occurrence. The area under curve (AUC) of a receiver operator characteristic (ROC) curve was used to validate the model. Effects of parameters on landslide occurrence were assessed from the corresponding coefficient that appears in the logistic regression function. Thereafter, the model was applied to predict the probability of landslides for rainfall data of different return periods. Using a predicted map of probability, the study area was classified into four ranks of landslide susceptibility: low, medium, high, and very high. As a result, most high susceptibility areas are located on the western portion of the study area. Several train stations and railways are located on sites with a high susceptibility ranking

A systematic review of the genus Bolbelasmus Boucomont (Coleoptera, Geotrupidae, Bolboceratinae) from Indochina and surrounding areas

Indochinese species of the genus Bolbelasmus (Coleoptera, Geotrupidae, Bolboceratinae) are reviewed. Three new species, Bolbelasmus chifengi Wang & Li, sp. nov., Bolbelasmus concavisuturalis Li & Wang, sp. nov. and Bolbelasmus yutangi Li & Wang, sp. nov., are described and illustrated. An annotated checklist and modified key to species of the genus are provided. Information for each species in the checklist includes literature review, synonymy, distribution and type locality

Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.

Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate

Taming Encoder for Zero Fine-tuning Image Customization with Text-to-Image Diffusion Models

This paper proposes a method for generating images of customized objects specified by users. The method is based on a general framework that bypasses the lengthy optimization required by previous approaches, which often employ a per-object optimization paradigm. Our framework adopts an encoder to capture high-level identifiable semantics of objects, producing an object-specific embedding with only a single feed-forward pass. The acquired object embedding is then passed to a text-to-image synthesis model for subsequent generation. To effectively blend a object-aware embedding space into a well developed text-to-image model under the same generation context, we investigate different network designs and training strategies, and propose a simple yet effective regularized joint training scheme with an object identity preservation loss. Additionally, we propose a caption generation scheme that become a critical piece in fostering object specific embedding faithfully reflected into the generation process, while keeping control and editing abilities. Once trained, the network is able to produce diverse content and styles, conditioned on both texts and objects. We demonstrate through experiments that our proposed method is able to synthesize images with compelling output quality, appearance diversity, and object fidelity, without the need of test-time optimization. Systematic studies are also conducted to analyze our models, providing insights for future work

Subchronic and Genetic Safety Assessment of a New Medicinal Dendrobium

Dendrobium Taiseed Tosnobile is a new species of herba dendrobii (Shi-Hu) that was developed by crossbreeding D. tosaense and D. nobile. Its pharmacological activity and active component have been reported, but its subchronic toxicity and genetic safety have not yet been investigated. This study assessed the 90-day oral toxicity and genetic safety of the aqueous extracts of D. Taiseed Tosnobile (DTTE) in male and female Sprague-Dawley (SD) rats. Eighty rats were divided into four groups, each consisting of ten male and ten female rats. DTTE was given orally to rats at 800, 1600, or 2400 mg/kg for 90 consecutive days, and distilled water was used for the control group. Genotoxicity studies were performed using a bacterial reverse mutation assay and in vivo mammalian cell micronucleus test in ICR mice and analyzed using flow cytometry. Throughout the study period, no abnormal changes were observed in clinical signs and body weight or on ophthalmological examinations. Additionally, no significant differences were found in urinalysis, hematology, and serum biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated no treatment-related changes. Based on results, the no-observed-adverse-effect level of DTTE is greater than 2400 mg/kg in SD rats

Suppressor of K+ transport growth defect 1 (SKD1) interactswith RING-type ubiquitin ligase and sucrose non-fermenting1-related protein kinase (SnRK1) in the halophyte ice plant

SKD1 (suppressor of K+ transport growth defect 1) is an AAA-type ATPase that functions as a molecular motor. It was previously shown that SKD1 accumulates in epidermal bladder cells of the halophyte Mesembryanthemum crystallinum. SKD1 knock-down Arabidopsis mutants showed an imbalanced Na+/K+ ratio under salt stress. Two enzymes involved in protein post-translational modifications that physically interacted with McSKD1 were identified. McCPN1 (copine 1), a RING-type ubiquitin ligase, has an N-terminal myristoylation site that links to the plasma membrane, a central copine domain that interacts with McSKD1, and a C-terminal RING domain that catalyses protein ubiquitination. In vitro ubiquitination assay demonstrated that McCPN1 was capable of mediating ubiquitination of McSKD1. McSnRK1 (sucrose non-fermenting 1-related protein kinase) is a Ser/Thr protein kinase that contains an N-terminal STKc catalytic domain to phosphorylate McSKD1, and C-terminal UBA and KA1 domains to interact with McSKD1. The transcript and protein levels of McSnRK1 increased as NaCl concentrations increased. The formation of an SKD1–SnRK1–CPN1 ternary complex was demonstrated by yeast three-hybrid and bimolecular fluorescence complementation. It was found that McSKD1 preferentially interacts with McSnRK1 in the cytosol, and salt induced the re-distribution of McSKD1 and McSnRK1 towards the plasma membrane via the microtubule cytoskeleton and subsequently interacted with RING-type E3 McCPN1. The potential effects of ubiquitination and phosphorylation on McSKD1, such as changes in the ATPase activity and cellular localization, and how they relate to the functions of SKD1 in the maintenance of Na+/K+ homeostasis under salt stress, are discussed

Seroprevalence of enterovirus 71 and no evidence of crossprotection of enterovirus 71 antibody against the other enteroviruses in kindergarten children in Taipei city

Background/PurposeEnterovirus 71 (EV71) infection may cause severe neurological and cardiopulmonary complications, especially in preschool children. This study is to investigate the seroprevalence and seroconversion of EV71, and the crossprotection of EV71 antibody against other enteroviruses among kindergarteners.MethodsOverall 228 children in a public kindergarten were enrolled during two academic years, 2006 and 2007, in Taipei, Taiwan and we measured their EV71 neutralizing antibody. When the participants had herpangina; hand, foot and mouth disease (HFMD); febrile illness or respiratory symptoms, throat swabs were sampled and processed for viral culture and enterovirus real-time reverse transcriptase polymerase chain reaction (RT-PCR). Questionnaires, completed by the participants’ guardians, surveyed the history of allergy and annual incidence of symptoms related to enterovirus infection.ResultsSeropositive rates of EV71 were 20% (32/163) in 2006 and 6% (4/65) in 2007. The rate of EV71 seropositivity increased with age (p < 0.01) in 2006 but it did not differ between genders (p = 0.14). No seroconversion was observed from 2006 to 2007. Herpangina occurred in 64% of children with EV71 seropositivity and 48% of those without EV71 antibodies (p = 0.12). Non-71 enterovirus infection, confirmed by viral study, occurred in 53% (19/36) of the EV71-seropositive children and in 53% (102/192) of EV71-seronegative children (p = 0.89). No participants had EV71 infection during the study period.ConclusionEV71 did not frequently circulate in Taipei City from September 2006 to June 2008. Presence of EV71 neutralizing antibody was not associated with lower incidence of enterovirus infection caused by non-71 serotypes