RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.

Targeted nanoprobe for magnetic resonance imaging-guided enhanced antitumor via synergetic photothermal/immunotherapy.

Synergistic photothermal/immunotherapy has garnered significant attention for its potential to enhance tumor therapeutic outcomes. However, the fabrication of an intelligent system with a simple composition that simultaneously exerts photothermal/immunotherapy effect and imaging guidance function still remains a challenge. Herein, a glutathione (GSH)-responsive theranostic nanoprobe, named HA-MnO2/ICG, was elaborately constructed by loading photothermal agent (PTA) indocyanine green (ICG) onto the surface of hyaluronic acid (HA)-modified manganese dioxide nanosheets (HA-MnO2) for magnetic resonance (MR) imaging-guided synergetic photothermal/immuno-enhanced therapy. In this strategy, HA-MnO2 nanosheets were triggered by the endogenous GSH in tumor microenvironment to generate Mn2+ for MR imaging, where the longitudinal relaxation rate of HA-MnO2/ICG was up to 14.97 mM-1s-1 (∼24 times than that found in a natural environment), demonstrating excellent intratumoral MR imaging. Moreover, the HA-MnO2/ICG nanoprobe demonstrates remarkable photothermal therapy (PTT) efficacy, generating sufficient heat to induce immunogenic cell death (ICD) within tumor cells. Meanwhile the released Mn2+ ions from the nanosheets function as potent immune adjuvants, amplifying the immune response against cancer. In vivo experiments validated that HA-MnO2/ICG-mediated PTT was highly effective in eradicating primary tumors, while simultaneously enhancing immunogenicity to prevent the growth of distal metastasis. This hybrid HA-MnO2/ICG nanoprobe opened new avenues in the design of MR imaging-monitored PTT/immuno-enhanced synergistic therapy for advanced cancer.

pH/glutathione-responsive theranostic nanoprobes for chemoimmunotherapy and magnetic resonance imaging of ovarian cancer cells.

The integration of immunotherapy and standard chemotherapy holds great promise for enhanced anticancer effects. In this study, we prepared a pH- and glutathione (GSH)-sensitive manganese-doped mesoporous silicon (MMSNs) based drug delivery system by integrating paclitaxel (PTX) and anti-programmed cell death-ligand 1 antibody (aPD-L1), and encapsulating with polydopamine (PDA) for chemoimmunosynergic treatment of ovarian cancer cells. The nanosystem was degraded in response to the tumor weakly acidic and reductive microenvironment. The Mn2+ produced by degradation can be used as a contrast agent for magnetic resonance (MR) imaging to provide visual exposure to tumor tissue. The released PTX can not only kill tumor cells directly, but also induce immunogenic death (ICD) of tumor cells, which can play a synergistic therapeutic effect with aPD-L1. Therefore, our study is expected to provide a promising strategy for improving the efficacy of cancer immunotherapy and the detection rate of cancer.

Microbiome in gynecologic malignancies: a bibliometric analysis from 2012 to 2022.

Microbiome and microbial dysbiosis have been proven to be involved in the carcinogenesis and treatment of gynecologic malignancies. However, there is a noticeable gap in the literature, as no comprehensive papers have covered general information, research status, and research frontiers in this field. This study addressed this gap by exploring the relationship between the gut and female reproductive tract (FRT) microbiome and gynecological cancers from a bibliometric perspective. Using VOSviewer 1.6.18, CiteSpace 6.1.R6, and HistCite Pro 2.1 software, we analyzed data retrieved from the Web of Science (WOS) Core Collection (WoSCC) database. Our dataset, consisting of 204 articles published from 2012 to 2022, revealed a consistent and upward publication trend. The United States and the United Kingdom were the primary driving forces, attributed to their prolificacy, high-quality output, and extensive cooperation. The University of Arizona Cancer Center, which is affiliated with the United States, ranked first among the top ten most prolific institutions. Frontiers in Cellular and Infection Microbiology emerged as the leading publisher. Herbst-Kralovetz MM led as the most productive author. Mitra A was the most influential author. Cervical cancer is notably associated with the microbiome, while endometrial and ovarian cancers are receiving increased attention in the last year. Intersections between the gut microbiome and estrogen are of growing importance. Current research focuses on identifying specific microbial species for etiological diagnosis, while frontiers mainly focus on the anticancer potential of microorganisms, such as regulating the effects of immune checkpoint inhibitors. In conclusion, this study sheds light on a novel and burgeoning direction of research, providing a one-stop overview of the microbiome in gynecologic malignancies. Its findings aim to help young researchers to identify research directions and future trends for ongoing investigations.

Effects of supplementing coated methionine in a high plant-protein diet on growth, antioxidant capacity, digestive enzymes activity and expression of TOR signaling pathway associated genes in gibel carp, Carassius auratus gibelio.

This study explored the impacts of supplementation of different levels of coated methionine (Met) in a high-plant protein diet on growth, blood biochemistry, antioxidant capacity, digestive enzymes activity and expression of genes related to TOR signaling pathway in gibel carp (Carassius auratus gibeilo). A high-plant protein diet was formulated and used as a basal diet and supplemented with five different levels of coated Met at 0.15, 0.30, 0.45, 0.60 and 0.75%, corresponding to final analyzed Met levels of 0.34, 0.49, 0.64, 0.76, 0.92 and 1.06%. Three replicate groups of fish (initial mean weight, 11.37 ± 0.02 g) (20 fish per replicate) were fed the test diets over a 10-week feeding period. The results indicated that with the increase of coated Met level, the final weight, weight gain (WG) and specific growth rate initially boosted and then suppressed, peaking at 0.76% Met level (P< 0.05). Increasing dietary Met level led to significantly increased muscle crude protein content (P< 0.05) and reduced serum alanine aminotransferase activity (P< 0.05). Using appropriate dietary Met level led to reduced malondialdehyde concentration in hepatopancreas (P< 0.05), improved superoxide dismutase activity (P< 0.05), and enhanced intestinal amylase and protease activities (P< 0.05). The expression levels of genes associated with muscle protein synthesis such as insulin-like growth factor-1, protein kinase B, target of rapamycin and eukaryotic initiation factor 4E binding protein-1 mRNA were significantly regulated, peaking at Met level of 0.76% (P< 0.05). In conclusion, supplementing optimal level of coated Met improved on fish growth, antioxidant capacity, and the expression of TOR pathway related genes in muscle. The optimal dietary Met level was determined to be 0.71% of the diet based on quadratic regression analysis of WG.

Attrition in Conversational Agent-Delivered Mental Health Interventions: Systematic Review and Meta-Analysis.

BACKGROUND: Conversational agents (CAs) or chatbots are computer programs that mimic human conversation. They have the potential to improve access to mental health interventions through automated, scalable, and personalized delivery of psychotherapeutic content. However, digital health interventions, including those delivered by CAs, often have high attrition rates. Identifying the factors associated with attrition is critical to improving future clinical trials. OBJECTIVE: This review aims to estimate the overall and differential rates of attrition in CA-delivered mental health interventions (CA interventions), evaluate the impact of study design and intervention-related aspects on attrition, and describe study design features aimed at reducing or mitigating study attrition. METHODS: We searched PubMed, Embase (Ovid), PsycINFO (Ovid), Cochrane Central Register of Controlled Trials, and Web of Science, and conducted a gray literature search on Google Scholar in June 2022. We included randomized controlled trials that compared CA interventions against control groups and excluded studies that lasted for 1 session only and used Wizard of Oz interventions. We also assessed the risk of bias in the included studies using the Cochrane Risk of Bias Tool 2.0. Random-effects proportional meta-analysis was applied to calculate the pooled dropout rates in the intervention groups. Random-effects meta-analysis was used to compare the attrition rate in the intervention groups with that in the control groups. We used a narrative review to summarize the findings. RESULTS: The systematic search retrieved 4566 records from peer-reviewed databases and citation searches, of which 41 (0.90%) randomized controlled trials met the inclusion criteria. The meta-analytic overall attrition rate in the intervention group was 21.84% (95% CI 16.74%-27.36%; I2=94%). Short-term studies that lasted ≤8 weeks showed a lower attrition rate (18.05%, 95% CI 9.91%- 27.76%; I2=94.6%) than long-term studies that lasted >8 weeks (26.59%, 95% CI 20.09%-33.63%; I2=93.89%). Intervention group participants were more likely to attrit than control group participants for short-term (log odds ratio 1.22, 95% CI 0.99-1.50; I2=21.89%) and long-term studies (log odds ratio 1.33, 95% CI 1.08-1.65; I2=49.43%). Intervention-related characteristics associated with higher attrition include stand-alone CA interventions without human support, not having a symptom tracker feature, no visual representation of the CA, and comparing CA interventions with waitlist controls. No participant-level factor reliably predicted attrition. CONCLUSIONS: Our results indicated that approximately one-fifth of the participants will drop out from CA interventions in short-term studies. High heterogeneities made it difficult to generalize the findings. Our results suggested that future CA interventions should adopt a blended design with human support, use symptom tracking, compare CA intervention groups against active controls rather than waitlist controls, and include a visual representation of the CA to reduce the attrition rate. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022341415; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022341415.

Fraxetin inhibits proliferation and induces apoptosis of bladder cancer through the Akt pathway in vitro and in vivo.

Fraxetin, a natural compound extracted from the Chinese herb Cortex Fraxini, is reported to boast extensive antitumor properties in various cancers. However, whether fraxetin exhibited an anticancer effect on bladder cancer remains unknown. In this study, cell counting kit-8 was utilized to detect cell viability. Flow cytometry analysis was performed for cell apoptosis analysis. Western blot analysis and real-time PCR were used to ascertain gene expression analysis. A mouse bladder cancer xenograft model was established and subjected to fraxetin treatment. Fraxetin reduced the viability of bladder cancer cells, induced apoptosis in vitro, and inhibited the growth of bladder cancer in vivo. Fraxetin inhibited the Akt pathway in J82 cells. In conclusion, the growth inhibitory properties of fraxetin against bladder cancer may be mediated via an Akt inhibitory effect and cell apoptosis promotion.

Instability in a carbon pool driven by multiple dissolved organic matter sources in a eutrophic lake basin: Potential factors for increased greenhouse gas emissions.

Lakes serve as vital reservoirs of dissolved organic matter (DOM) and play pivotal roles in biogeochemical carbon cycles. However, the sources and compositions of DOM in freshwater lakes and their potential effects on lake sediment carbon pools remain unclear. In this study, seven inflowing rivers in the Lake Taihu basin were selected to explore the potential effects of multi-source DOM inputs on the stability of the lake sediment carbon pool. The results showed the high concentrations of dissolved organic carbon in the Lake Taihu basin, accompanied by a high complexity level. Lignins constituted the majority of DOM compounds, surpassing 40% of the total, while the organic carbon content was predominantly composed of humic acids (1.02-3.01 g kg-1). The high amounts of lignin oxidative cleavage led to CHO being the main molecular structure in the DOM of the seven rivers. The carbon constituents within the sediment carbon reservoir exhibited a positive correlation with dissolved CH4 and CO2, with a notable emphasis on humic acid and dissolved CH4 (R2 = 0.86). The elevated concentration of DOM, coupled with its intricate composition, contributed to the increases in dissolved greenhouse gases (GHGs). Experiments showed that the mixing of multi-source DOM can accelerate the organic carbon mineralization processes. The unit carbon emission efficiency was highest in the mixed group, reaching reached 160.9 µmol∙Cg-1, which also exhibited a significantly different carbon pool. The mixed decomposition of DOM from different sources influenced the roles of the lake carbon pool as source and sink, indicating that the multi-source DOM of this lake basin was a potential driving factor for increased carbon emissions. These findings have improved our understanding of the sources and compositions of DOM in lake basins and revealed their impacts on carbon emissions, thereby providing a theoretical basis for improving assessments of lake carbon emissions.

O2-Generating Fluorescent Carbon Dot-Decorated MnO2 Nanosheets for "Off/On" MR/Fluorescence Imaging and Enhanced Photodynamic Therapy.

Imaging-guided photodynamic therapy (PDT) has emerged as a promising protocol for cancer theragnostic. However, facile preparation of such a theranostic system for simultaneously achieving tumor location, real-time monitoring, and high-performance reactive oxygen species generation is highly desirable but remains challenging. Herein, we developed a reasonable tumor-targeting strategy based on carbon dots (CDs)-decorated MnO2 nanosheets (HA-MnO2-CDs) with an active magnetic resonance (MR)/fluorescence imaging and enhanced PDT effect. Under light irradiation, the addition of HA-MnO2-CDs increased the production of 1O2 by 2.5 times compared with CDs, providing favorable conditions for the PDT treatment effect on breast cancer. Moreover, HA-MnO2-CDs exhibited excellent performance in producing O2 in the presence of endogenous H2O2, which alleviated hypoxia in tumors and improved the therapeutic effect of PDT. In the presence of glutathione (GSH), the degraded MnO2 nanosheets released CDs and Mn2+ from HA-MnO2-CDs, restoring their fluorescence imaging function and increasing T1 relaxivity (r1) by 23 times. In vivo fluorescence and MR imaging suggested the excellent tumor-targeting property of HA-MnO2-CDs. By combining the complementary properties of nanoprobes and tumor microenvironments, the in vivo PDT therapeutic effect was significantly improved under the action of HA-MnO2-CDs. Overall, our reasonably designed HA-MnO2-CDs may inspire the future development of the next generation of high-performance tumor-responsive diagnostic and therapeutic agents to further enhance the targeted therapy effect of tumors.

Conversational Agents in Health Care: Expert Interviews to Inform the Definition, Classification, and Conceptual Framework.

BACKGROUND: Conversational agents (CAs), or chatbots, are computer programs that simulate conversations with humans. The use of CAs in health care settings is recent and rapidly increasing, which often translates to poor reporting of the CA development and evaluation processes and unreliable research findings. We developed and published a conceptual framework, designing, developing, evaluating, and implementing a smartphone-delivered, rule-based conversational agent (DISCOVER), consisting of 3 iterative stages of CA design, development, and evaluation and implementation, complemented by 2 cross-cutting themes (user-centered design and data privacy and security). OBJECTIVE: This study aims to perform in-depth, semistructured interviews with multidisciplinary experts in health care CAs to share their views on the definition and classification of health care CAs and evaluate and validate the DISCOVER conceptual framework. METHODS: We conducted one-on-one semistructured interviews via Zoom (Zoom Video Communications) with 12 multidisciplinary CA experts using an interview guide based on our framework. The interviews were audio recorded, transcribed by the research team, and analyzed using thematic analysis. RESULTS: Following participants' input, we defined CAs as digital interfaces that use natural language to engage in a synchronous dialogue using ≥1 communication modality, such as text, voice, images, or video. CAs were classified by 13 categories: response generation method, input and output modalities, CA purpose, deployment platform, CA development modality, appearance, length of interaction, type of CA-user interaction, dialogue initiation, communication style, CA personality, human support, and type of health care intervention. Experts considered that the conceptual framework could be adapted for artificial intelligence-based CAs. However, despite recent advances in artificial intelligence, including large language models, the technology is not able to ensure safety and reliability in health care settings. Finally, aligned with participants' feedback, we present an updated iteration of the conceptual framework for health care conversational agents (CHAT) with key considerations for CA design, development, and evaluation and implementation, complemented by 3 cross-cutting themes: ethics, user involvement, and data privacy and security. CONCLUSIONS: We present an expanded, validated CHAT and aim at guiding researchers from a variety of backgrounds and with different levels of expertise in the design, development, and evaluation and implementation of rule-based CAs in health care settings.

Nomogram based on pretreatment hepatic and renal function indicators for survival prediction of locally advanced esophageal squamous cell carcinoma with treatment of neoadjuvant chemoradiotherapy plus surgery.

The parameters for survival prediction of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiotherapy (NCRT) combined with surgery are unclear. Here, we aimed to construct a nomogram for survival prediction of ESCC patients treated with NCRT combined with surgery based on pretreatment serological hepatic and renal function tests. A total of 174 patients diagnosed as ESCC were enrolled as a training cohort from July 2007 to June 2019, and approximately 50% of the cases (n = 88) were randomly selected as an internal validation cohort. Univariate and multivariate Cox survival analyses were performed to identify independent prognostic factors to establish a nomogram. Predictive accuracy of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration curve. ALT, ALP, TBA, TP, AST, TBIL and CREA were identified as independent prognostic factors and incorporated into the construction of the hepatic and renal function test nomogram (HRFTNomogram). The C-index of the HRFTNomogram for overall survival (OS) was 0.764 (95% CI 0.701-0.827) in the training cohort, which was higher than that of the TNM staging system (0.507 (95% CI 0.429-0.585), P < 0.001). The 5-year OS calibration curve of the training cohort demonstrated that the predictive accuracy of the HRFTNomogram was satisfactory. Moreover, patients in the high-risk group stratified by the HRFTNomogram had poorer 5-year OS than those in the low-risk group in the training cohort (27.4% vs. 80.3%, P < 0.001). Similar results were observed in the internal validation cohort. A novel HRFTNomogram might help predict the survival of locally advanced ESCC patients treated with NCRT followed by esophagectomy.

ΔNp63α facilitates proliferation and migration, and modulates the chromatin landscape in intrahepatic cholangiocarcinoma cells.

p63 plays a crucial role in epithelia-originating tumours; however, its role in intrahepatic cholangiocarcinoma (iCCA) has not been completely explored. Our study revealed the oncogenic properties of p63 in iCCA and identified the major expressed isoform as ΔNp63α. We collected iCCA clinical data from The Cancer Genome Atlas database and analyzed p63 expression in iCCA tissue samples. We further established genetically modified iCCA cell lines in which p63 was overexpressed or knocked down to study the protein function/function of p63 in iCCA. We found that cells overexpressing p63, but not p63 knockdown counterparts, displayed increased proliferation, migration, and invasion. Transcriptome analysis showed that p63 altered the iCCA transcriptome, particularly by affecting cell adhesion-related genes. Moreover, chromatin accessibility decreased at p63 target sites when p63 binding was lost and increased when p63 binding was gained. The majority of the p63 bound sites were located in the distal intergenic regions and showed strong enhancer marks; however, active histone modifications around the Transcription Start Site changed as p63 expression changed. We also detected an interaction between p63 and the chromatin structural protein YY1. Taken together, our results suggest an oncogenic role for p63 in iCCA.

Tea polyphenols inhibit blooms caused by eukaryotic and prokaryotic algae.

With changes in global climate, blooms are becoming more frequent and difficult to control. Therefore, the selection of algal suppressor agents with effective inhibition and environmental safety is of paramount importance. One of the main treatment strategies is to inhibit the release of harmful algal toxins. Tea polyphenols (TP) are natural products that have been widely used in medicine, the environment, and other fields due to their antibacterial and antioxidant properties. To investigate their potential application in the treatment of algal blooms, TP were applied to three different microalgae. TP exhibited strong inhibitory effects towards all three microalgae. They stimulate the accumulation of ROS in algal cells, leading to lipid peroxidation and subsequent damage to the cell membrane, resulting in the rupture and necrosis of Cyclotella sp. and Chlorella vulgaris cells. Remarkably, it was observed that lower concentrations of TP exhibited the ability to induce apoptosis in M. aeruginosa cells without causing any structural damage. This outcome is particularly significant as it reduces the potential risk of microcystin release resulting from cell rupture. Overall, blooms dominated by different algae can be treated by adjusting the concentration of TP, a new algal suppressor, indicating strong potential treatment applications.

Scope, Characteristics, Behavior Change Techniques, and Quality of Conversational Agents for Mental Health and Well-Being: Systematic Assessment of Apps.

BACKGROUND: Mental disorders cause substantial health-related burden worldwide. Mobile health interventions are increasingly being used to promote mental health and well-being, as they could improve access to treatment and reduce associated costs. Behavior change is an important feature of interventions aimed at improving mental health and well-being. There is a need to discern the active components that can promote behavior change in such interventions and ultimately improve users' mental health. OBJECTIVE: This study systematically identified mental health conversational agents (CAs) currently available in app stores and assessed the behavior change techniques (BCTs) used. We further described their main features, technical aspects, and quality in terms of engagement, functionality, esthetics, and information using the Mobile Application Rating Scale. METHODS: The search, selection, and assessment of apps were adapted from a systematic review methodology and included a search, 2 rounds of selection, and an evaluation following predefined criteria. We conducted a systematic app search of Apple's App Store and Google Play using 42matters. Apps with CAs in English that uploaded or updated from January 2020 and provided interventions aimed at improving mental health and well-being and the assessment or management of mental disorders were tested by at least 2 reviewers. The BCT taxonomy v1, a comprehensive list of 93 BCTs, was used to identify the specific behavior change components in CAs. RESULTS: We found 18 app-based mental health CAs. Most CAs had <1000 user ratings on both app stores (12/18, 67%) and targeted several conditions such as stress, anxiety, and depression (13/18, 72%). All CAs addressed >1 mental disorder. Most CAs (14/18, 78%) used cognitive behavioral therapy (CBT). Half (9/18, 50%) of the CAs identified were rule based (ie, only offered predetermined answers) and the other half (9/18, 50%) were artificial intelligence enhanced (ie, included open-ended questions). CAs used 48 different BCTs and included on average 15 (SD 8.77; range 4-30) BCTs. The most common BCTs were 3.3 "Social support (emotional)," 4.1 "Instructions for how to perform a behavior," 11.2 "Reduce negative emotions," and 6.1 "Demonstration of the behavior." One-third (5/14, 36%) of the CAs claiming to be CBT based did not include core CBT concepts. CONCLUSIONS: Mental health CAs mostly targeted various mental health issues such as stress, anxiety, and depression, reflecting a broad intervention focus. The most common BCTs identified serve to promote the self-management of mental disorders with few therapeutic elements. CA developers should consider the quality of information, user confidentiality, access, and emergency management when designing mental health CAs. Future research should assess the role of artificial intelligence in promoting behavior change within CAs and determine the choice of BCTs in evidence-based psychotherapies to enable systematic, consistent, and transparent development and evaluation of effective digital mental health interventions.

Direct Identification and Quantitation of Protein Peptide Powders Based on Multi-Molecular Infrared Spectroscopy and Multivariate Data Fusion.

Given that protein peptide powders (PPPs) from different biological sources were inherited with diverse healthcare functions, which aroused adulteration of PPPs. A high-throughput and rapid methodology, united multi-molecular infrared (MM-IR) spectroscopy with data fusion, could determine the types and component content of PPPs from seven sources as examples. The chemical fingerprints of PPPs were thoroughly interpreted by tri-step infrared (IR) spectroscopy, and the defined spectral fingerprint region of protein peptide, total sugar, and fat was 3600-950 cm-1, which constituted MIR finger-print region. Moreover, the mid-level data fusion model was of great applicability in qualitative analysis, in which the F1-score reached 1 and the total accuracy was 100%, and a robust quantitative model was established with excellent predictive capacity (Rp: 0.9935, RMSEP: 1.288, and RPD: 7.97). MM-IR coordinated data fusion strategies to achieve high-throughput, multi-dimensional analysis of PPPs with better accuracy and robustness which meant a significant potential for the comprehensive analysis of other powders in food as well.

VIRMA facilitates intrahepatic cholangiocarcinoma progression through epigenetic augmentation of TMED2 and PARD3B mRNA stabilization.

BACKGROUND: N6-methyladenine modification of RNA, a critical component of the regulatory role at the post-transcriptional level, has a crucial effect on tumor development and progression. vir-Like m6A methyltransferase associated (VIRMA) has been recently discovered as an N6-methyladenine methyltransferase; however, its specific role in intrahepatic cholangiocarcinoma (ICC) remains to be investigated in-depth. METHODS: VIRMA expression and its association with clinicopathological characteristics were evaluated using The Cancer Genome Atlas (TCGA) dataset and tissue microarrays. In vivo and in vitro assays were performed to determine the role of VIRMA in ICC proliferation and metastasis. The underlying mechanism by which VIRMA influences ICC was clarified by RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), SLAM sequencing (SLAM-seq), RNA immunoprecipitation, a luciferase reporter assay, and chromatin immunoprecipitation assay. RESULTS: VIRMA showed high expression in ICC tissues, and this finding predicted a dismal prognostic outcome. The high expression of VIRMA in ICC was due to the demethylation of H3K27me3 modification in the promoter region. Functionally, VIRMA is required for the endothelial-mesenchymal transition (EMT) process in ICC cells, as shown by multiple ICC models in in vitro and in vivo experiments. Mechanistically, multi-omics analysis using ICC cells demonstrated that TMED2 and PARD3B were the direct downstream target of VIRMA. The methylated TMED2 and PARD3B transcripts were directly recognized by HuR, which exerted stabilizing effects on its bound RNA. VIRMA-induced expression of TMED2 and PARD3B activated the Akt/GSK/ß-catenin and MEK/ERK/Slug signaling pathways, thereby promoting ICC proliferation and metastasis. CONCLUSIONS: The present study showed that VIRMA plays a critical role in ICC development by stabilizing TMED2 and PARD3B expression through the m6A-HuR-mediated mechanism. Thus, demonstrating VIRMA and its pathway as candidate therapeutic targets for ICC treatment.

Dietary α-ketoglutarate alleviates glycinin and ß-conglycinin induced damage in the intestine of mirror carp (Cyprinus carpio).

This study investigated the glycinin and ß-conglycinin induced intestinal damage and α-ketoglutarate alleviating the damage of glycinin and ß-conglycinin in intestine. Carp were randomly divided into six dietary groups: containing fish meal (FM) as the protein source, soybean meal (SM), glycinin (FMG), ß-conglycinin (FMc), glycinin+1.0% α-ketoglutarate (AKG) (FMGA), ß-conglycinin+1.0% AKG (FMcA). The intestines were collected on 7th, and the hepatopancreas and intestines were collected on 56th. Fish treated with SM and FMc displayed reduced weight gain, specific growth rate, and protein efficiency. On 56th day, Fish fed on SM, FMG and FMc presented lower superoxide dismutase (SOD) activities. FMGA and FMcA had higher SOD activity than those fed on the FMG and FMc, respectively. In intestine, fish fed on the SM diets collected on 7th presented upregulated the expression of transforming growth factor beta (TGFß1), AMP-activated protein kinase beta (AMPKß), AMPKγ, and acetyl-CoA carboxylase (ACC). Fish fed FMG presented upregulated expression of tumor necrosis factor alpha (TNF-α), caspase9, and AMPKγ, while downregulated the expression of claudin7 and AMPKα. FMc group presented upregulated expression of TGFß1, caspase3, caspase8, and ACC. Fish fed FMGA showed upregulated expression of TGFß1, claudin3c, claudin7, while downregulating the expression of TNF-α and AMPKγ when compared to fish fed FMG diet. FMcA upregulated the expression of TGFß1, claudin3c than fed on the FMc. In intestine, the villus height and mucosal thickness of the proximal intestine (PI) and the distal intestine (DI) were decreased and crypt depth of the PI and mid intestine (MI) were increased in SM, FMG and FMc. In addition, fish fed on SM, FMG and FMc presented lower citrate synthase (CS), isocitrate dehydrogenase (ICD), α-ketoglutarate dehydrogenase complex (α-KGDHC) Na+/K+-ATPase activity in DI. FMGA had higher CS, ICD, α-KGDHC, and Na+/K+-ATPase activity in PI and MI than those fed on the FMG. FMcA had higher Na+/K+-ATPase activity in MI. In conclusion, dietary soybean meal destroys the intestine's health, the adverse effects are related to the presence of ß-conglycinin and glycinin, especially glycinin. AKG may regulate intestinal energy via tricarboxylic acid cycle, thereby alleviating the damage intestinal morphology caused by the dietary soybean antigen proteins.

Development of "LvL UP 1.0": a smartphone-based, conversational agent-delivered holistic lifestyle intervention for the prevention of non-communicable diseases and common mental disorders.

Background: Non-communicable diseases (NCDs) and common mental disorders (CMDs) are the leading causes of death and disability worldwide. Lifestyle interventions via mobile apps and conversational agents present themselves as low-cost, scalable solutions to prevent these conditions. This paper describes the rationale for, and development of, "LvL UP 1.0″, a smartphone-based lifestyle intervention aimed at preventing NCDs and CMDs. Materials and Methods: A multidisciplinary team led the intervention design process of LvL UP 1.0, involving four phases: (i) preliminary research (stakeholder consultations, systematic market reviews), (ii) selecting intervention components and developing the conceptual model, (iii) whiteboarding and prototype design, and (iv) testing and refinement. The Multiphase Optimization Strategy and the UK Medical Research Council framework for developing and evaluating complex interventions were used to guide the intervention development. Results: Preliminary research highlighted the importance of targeting holistic wellbeing (i.e., both physical and mental health). Accordingly, the first version of LvL UP features a scalable, smartphone-based, and conversational agent-delivered holistic lifestyle intervention built around three pillars: Move More (physical activity), Eat Well (nutrition and healthy eating), and Stress Less (emotional regulation and wellbeing). Intervention components include health literacy and psychoeducational coaching sessions, daily "Life Hacks" (healthy activity suggestions), breathing exercises, and journaling. In addition to the intervention components, formative research also stressed the need to introduce engagement-specific components to maximise uptake and long-term use. LvL UP includes a motivational interviewing and storytelling approach to deliver the coaching sessions, as well as progress feedback and gamification. Offline materials are also offered to allow users access to essential intervention content without needing a mobile device. Conclusions: The development process of LvL UP 1.0 led to an evidence-based and user-informed smartphone-based intervention aimed at preventing NCDs and CMDs. LvL UP is designed to be a scalable, engaging, prevention-oriented, holistic intervention for adults at risk of NCDs and CMDs. A feasibility study, and subsequent optimisation and randomised-controlled trials are planned to further refine the intervention and establish effectiveness. The development process described here may prove helpful to other intervention developers.

Evaluating Conversational Agents for Mental Health: Scoping Review of Outcomes and Outcome Measurement Instruments.

BACKGROUND: Rapid proliferation of mental health interventions delivered through conversational agents (CAs) calls for high-quality evidence to support their implementation and adoption. Selecting appropriate outcomes, instruments for measuring outcomes, and assessment methods are crucial for ensuring that interventions are evaluated effectively and with a high level of quality. OBJECTIVE: We aimed to identify the types of outcomes, outcome measurement instruments, and assessment methods used to assess the clinical, user experience, and technical outcomes in studies that evaluated the effectiveness of CA interventions for mental health. METHODS: We undertook a scoping review of the relevant literature to review the types of outcomes, outcome measurement instruments, and assessment methods in studies that evaluated the effectiveness of CA interventions for mental health. We performed a comprehensive search of electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, Embase (Ovid), PsychINFO, and Web of Science, as well as Google Scholar and Google. We included experimental studies evaluating CA mental health interventions. The screening and data extraction were performed independently by 2 review authors in parallel. Descriptive and thematic analyses of the findings were performed. RESULTS: We included 32 studies that targeted the promotion of mental well-being (17/32, 53%) and the treatment and monitoring of mental health symptoms (21/32, 66%). The studies reported 203 outcome measurement instruments used to measure clinical outcomes (123/203, 60.6%), user experience outcomes (75/203, 36.9%), technical outcomes (2/203, 1.0%), and other outcomes (3/203, 1.5%). Most of the outcome measurement instruments were used in only 1 study (150/203, 73.9%) and were self-reported questionnaires (170/203, 83.7%), and most were delivered electronically via survey platforms (61/203, 30.0%). No validity evidence was cited for more than half of the outcome measurement instruments (107/203, 52.7%), which were largely created or adapted for the study in which they were used (95/107, 88.8%). CONCLUSIONS: The diversity of outcomes and the choice of outcome measurement instruments employed in studies on CAs for mental health point to the need for an established minimum core outcome set and greater use of validated instruments. Future studies should also capitalize on the affordances made available by CAs and smartphones to streamline the evaluation and reduce participants' input burden inherent to self-reporting.