Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Unravelling CD4+ T cell diversity and tissue adaptation of Tregs in abdominal aortic aneurysms through single-cell sequencing.

Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4+ T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4+ T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4+ T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA.

ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.

Memory CD8+ T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8+ T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8+ T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8+ T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8+ T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8+ T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.

ARID5A stabilizes Indoleamine 2,3-dioxygenase expression and enhances CAR T cell exhaustion in colorectal cancer.

Resistance to chimeric antigen receptor (CAR) T-cell therapy remains a significant challenge in the treatment of solid tumors. This resistance is attributed to various factors, including antigen loss, immunosuppressive tumor microenvironment, and upregulated checkpoint molecules. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that promotes immune escape in tumors. In this study, we investigated the role of ARID5A (AT-rich interactive domain 5A) in resistance to CAR-T cell therapy. Our findings revealed that ARID5A upregulation in tumor cells induces T cell exhaustion and immune evasion. Mechanistically, ARID5A plays a crucial role in resistance to CAR-T cell therapy by stabilizing IDO1 mRNA, leading to upregulation of IDO1 expression. Elevated IDO1 expression facilitates the conversion of tryptophan to kynurenine, which contributes to CAR-T cell exhaustion. Moreover, kynurenine accumulation within CAR-T cells activates the aryl hydrocarbon receptor (AhR), further exacerbating the exhaustion phenotype. Importantly, we demonstrated that targeting the ARID5A-IDO1-AhR axis using AhR or IDO1 inhibitors effectively alleviated T cell exhaustion induced by ARID5A. These findings suggest that modulating the ARID5A-IDO1-AhR axis may represent a promising therapeutic strategy to overcome CAR T-cell therapy resistance in solid tumors and enhance treatment efficacy.

Network pharmacology analysis and experimental verification of the antitumor effect and molecular mechanism of isocryptomerin on HepG2 cells.

Isocryptomerin (ISO) is a flavonoid isolated from the natural medicine Selaginellae Herba, which has various pharmacological activities. This study investigated the antitumor effect and underlying molecular mechanism of ISO on hepatocellular carcinoma (HCC) HepG2 cells. The cell viability assay revealed that ISO has a considerable killing effect on HCC cell lines. The apoptosis assay showed that ISO induced mitochondria-dependent apoptosis through the Bad/cyto-c/cleaved (cle)-caspase-3/cleaved (cle)-PARP pathway. The network pharmacological analysis found 13 key target genes, and epidermal growth factor receptor (EGFR), AKT, mitogen-activated protein kinase (MAPK), and reactive oxygen species (ROS) signaling pathways were strongly associated with ISO against HCC. Further verification of the results showed that ISO induced apoptosis by increasing p-p38 and p-JNK expression and decreasing p-EGFR, p-SRC, p-ERK, and p-STAT3 expression. Furthermore, ISO induced G0/G1 phase arrest by downregulating p-AKT, Cyclin D, and CDK 4 expression and upregulating p21 and p27 expression in HepG2 cells. Moreover, ISO inhibited HepG2 cell migration by decreasing p-GSK-3ß, ß-catenin, and N-cadherin expression and increasing E-cadherin expression. Additionally, ISO promoted ROS accumulation in HepG2 cells, and ISO-induced apoptosis, arrest cell cycle, and inhibition of migration were reversed by an ROS scavenger, N-acetyl- l-cysteine. Overall, ISO induced cell apoptosis and cell cycle arrest and inhibited cell migration by ROS-mediated EGFR, AKT, and MAPK signaling pathways in HepG2 cells.

Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways.

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3ß, N-cadherin, and ß-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.

Monkeypox: An outbreak of a rare viral disease.

Monkeypox is a viral zoonotic disease rarely found outside Africa. Monkeypox can be spread from person to person through close contact with an infected person, and the rate of transmission is not very high. In addition, monkeypox and variola virus are both pox viruses, and the spread of monkeypox virus was also controlled to some extent by the smallpox campaign, so monkeypox was not widely paid attention to. However, as smallpox vaccination is phased out in various countries or regions, people's resistance to orthopoxviruses is decreasing, especially among people who have not been vaccinated against smallpox. This has led to a significant increase in the frequency and geographical distribution of human monkeypox cases in recent years, and the monkeypox virus has become the orthopoxvirus that poses the greatest threat to public health. Since the last large-scale monkeypox infection was detected in 2022, the number of countries or territories affected has exceeded 100. Many confirmed and suspected cases of monkeypox have been found in individuals who have not travelled to affected areas, and the route of infection is not obvious, making this outbreak of monkeypox a cause for concern globally. The purpose of this systematic review is to further understand the pathophysiological and epidemiological characteristics of monkeypox, as well as existing prevention and treatment methods, with a view to providing evidence for the control of monkeypox.

Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes.

Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD's role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis.

Analysis of cancer-associated fibroblasts in cervical cancer by single-cell RNA sequencing.

OBJECTIVE: Since scRNA-seq is an effective tool to study tumor heterogeneity, this paper intends to reveal the differences of cervical cancer in patients at the individual cell level by scRNA-seq, and focus on the biological functions of cancer-associated fibroblasts (CAFs) in cervical cancer, facilitating the provision of a new interpretation of the heterogeneity of the microenvironment of cervical cancer, and an in-depth exploration of the pathogenesis of cervical cancer as well as pursuit of effective means of treatment intake. METHODS: 3 cervical cancer specimens were collected by clinical surgery for single-cell RNA sequencing. Cell suspensions of fresh cervical cancer tissues were prepared, and cDNA libraries were created and sequenced on the machine. Furthermore, the sequencing data were analyzed using bioinformatics, including descending clustering of cells, identification of cell populations, mimetic time series analysis, inferCNV, cell communication analysis, and identification of transcription factors. RESULTS: A total of 9 cell types were identified, encompassing T cells, epithelial cells, smooth muscle cells, CAFs, endothelial cells, macrophages, B cells, lymphocytes, and plasma cells. CAFs were further divided into three cell subtypes, named type1 cells, type2 cells, and type3 cells. With key transcription factors for the three cells, TCF21, ZC3H11A, and MYEF2 obtained, this research revealed the communication relationship between CAFs and several other cells, and found an important role of CAFs in the MK signaling pathway. CONCLUSIONS: scRNA-seq technology contributed to exploring the tumor heterogeneity of cervical cancer more deeply, and also further gaining insight into the biological functions of CAFs in cervical cancer.

Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor.

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A2A adenosine receptor (A2AAR), and chalcone 2 displayed the best binding affinity to A2AAR, with the IC50 value of 33.5 nM, good A2AAR selectivity against A1AR, A2BAR, and A3AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA2AAR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A2AAR antagonists used in cancer immunotherapy.

Effective protection: the embryonic development and clinical outcomes of emergency vitrification of 1246 oocytes and Day 0-Day 5 embryos in a natural disaster.

STUDY QUESTION: Can emergency vitrification protect embryos and oocytes during natural disasters or other events that prevent normal practice to achieve satisfactory embryonic development and clinical outcomes at a later time? SUMMARY ANSWER: Emergency vitrification of oocytes and Day 0-Day 5 (D0-D5) embryos during disasters is a safe and effective protective measure. WHAT IS KNOWN ALREADY: When some destructive events such as floods, earthquakes, tsunamis, and other accidents occur, emergency vitrification in embryo laboratories to protect human embryos, oocytes, and sperm is one of the important measures of an IVF emergency plan. However, there are few detailed reports on emergency vitrification in a state of disaster, especially about oocytes and D0 zygotes. Therefore, the effectiveness and safety of emergency vitrification of oocytes and D0-D5 embryos in disaster states are still unclear. STUDY DESIGN, SIZE, DURATION: A retrospective study was made in the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University from January 2018 to November 2022. The record rainstorms in Zhengzhou, China, caused severe flooding, traffic disruptions, and power outages. From 17:30, 20 July 2021 to 17:30, 21 July 2021, 1246 oocytes and D0-D5 embryos of 155 patients were vitrified whilst the laboratory had only an emergency power supply. PARTICIPANTS/MATERIALS, SETTING, METHODS: As of 21 December 2021, 1149 emergency vitrified oocytes and D0-D5 embryos of 124 patients underwent frozen-thawed embryo transfer (FET). They were divided into the following four groups according to the days of embryo culture in vitro: oocyte group, Day 0-Day 1 (D0-D1) group, Day 2-Day 3 (D2-D3) group, and Day 4-Day 5 (D4-D5) group. Control groups for each were selected from fresh cycle patients who underwent IVF/ICSI from January 2018 to October 2021. Control and emergency vitrification patients were matched on criteria that included age, fertilization method, days of embryonic development, and number and grade of transferred embryos. A total of 493 control patients were randomly selected from the eligible patients and matched with the emergency vitrification groups in a ratio of 4:1. The results of assisted reproduction and follow-up of pregnancy were analyzed. The embryonic development, clinical outcomes, and birth outcomes in each group were statistically analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: A significant difference was observed in fertilization rate (81% versus 72%, P = 0.022) between the oocyte group and the control group. Significant differences were also observed in the monozygotic twin pregnancy rate (10% versus 0%, P = 0.038) and ectopic pregnancy rate (5% versus 0%, P = 0.039) between the D0-D1 group and the control group. No significant differences (P > 0.05) were observed between vitrified oocytes/D0-D1 embryos/D2-D3 embryos and the control group on the number of high-quality embryos (3.17 ± 3.00 versus 3.84 ± 3.01, P = 0.346; 5.04 ± 3.66 versus 4.56 ± 2.87, P = 0.346; 4.85 ± 5.36 versus 5.04 ± 4.64, P = 0.839), the number of usable blastocysts (1.22 ± 1.78 versus 1.21 ± 2.03, P = 0.981; 2.16 ± 2.26 versus 1.55 ± 2.08, P = 0.090; 2.82 ± 3.23 versus 2.58 ± 3.32, P = 0.706), clinical pregnancy rate (56% versus 57%, P = 0.915; 55% versus 55%, P = 1.000; 40% versus 50%, P = 0.488), miscarriage rate (30% versus 15%, P = 0.496; 5% versus 11%, P = 0.678; 17% versus 20%, P = 1.000), and live birth rate (39% versus 49%, P = 0.460; 53% versus 50%, P = 0.772; 33% versus 40%, P = 0.635). No significant differences (P > 0.05) were observed between the D4-D5 group and the control group on clinical pregnancy rate (40% versus 55%, P = 0.645), miscarriage rate (0% versus 18%, P = 1.000), and live birth rate (40% versus 45%, P = 1.000). LIMITATIONS, REASONS FOR CAUTION: The retrospective study design is a limitation. The timing and extent of natural disasters are unpredictable, so the sample size of vitrified oocytes, zygotes, and embryos is beyond experimental control. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first study analyzing embryonic development, clinical outcomes, and birth outcomes of large samples of oocytes, D0 zygotes, and D1-D5 embryos after emergency vitrification under the disaster conditions. The results show that emergency vitrification is a safe and effective protective measure applicable to oocytes and D0-D5 embryos. The embryology laboratories need to be equipped with an emergency uninterrupted power supply capable of delivering for 6-8 h at full load. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (grant 81871206). The authors declare that they have no conflicts of interest. All authors have completed the ICMJE Disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Dirac semimetal-assisted near-field radiative thermal rectifier and thermostat based on phase transition of vanadium dioxide.

The near-field thermal radiation has broad application prospects in micro-nano-scale thermal management technology. In this paper, we report the Dirac semimetal-assisted (AlCuFe quasicrystal) near-field radiative thermal rectifier (DSTR) and thermostat (DST), respectively. The DSTR is made of a Dirac semimetal-covered vanadium dioxide (VO2) plate and silicon dioxide (SiO2) plate separated by a vacuum gap. The left and right sides of DST are consisted of the SiO2 covered with Dirac semimetal, and the intermediate plate is the VO2. The strong coupling of the surface electromagnetic modes between the Dirac semimetal, SiO2, and insulating VO2 leads to enhance near-field radiative transfer. In the DSTR, the net radiative heat flux of VO2 in the insulating state is much larger than that in metallic state. When the vacuum gap distance d=100 nm, Fermi level EF=0.20 eV, and film thickness t=12 nm, the global rectification factor of DSTR is 3.5, which is 50% higher than that of structure without Dirac semimetal. In the DST, the equilibrium temperature of the VO2 can be controlled accurately to achieve the switching between the metallic and insulating state of VO2. When the vacuum gap distance d=60 nm, intermediate plate thickness δ=30 nm, and film thickness t=2 nm, with the modulation of Fermi level between 0.05-0.15 eV, the equilibrium temperature of VO2 can be controlled between 325-371 K. In brief, when the crystalline state of VO2 changes between the insulating and metallic state with temperature, the active regulation of near-field thermal radiation can be realized in both two-body and three-body parallel plate structure. This work will pave a way to further improve performance of near-field radiative thermal management and modulation.

Cognitive appraisal and depression in cancer patients undergoing chemotherapy: mediation by perceived stress and self-efficacy.

PURPOSE: Cancer patients undergoing chemotherapy are prone to suffering a higher incidence rate of depression, leading to poor quality of life. However, how cancer affects depression is unclear. This study aimed to examine whether the relationship between cognitive appraisal and depression is mediated by perceived stress and self-efficacy in cancer patients undergoing chemotherapy. METHODS: A total of 421 cancer patients undergoing chemotherapy participated in this cross-sectional survey. Cognitive appraisal of cancer, perceived stress, self-efficacy, and depression were measured with the Perceived Life Threat Scale, Perceived Stress Scale, General Self-efficacy Scale and Hospital Anxiety, and Depression Scale-Depression Scale, respectively. Path analysis was performed to analyze the mediating effects of perceived stress and self-efficacy on the relationship between cognitive appraisal of cancer and depression. RESULTS: Cognitive appraisal of cancer exerted direct (b = 0.066, SE = 0.020, p < 0.001, bias-corrected 95% CI = [0.027, 0.106]) and indirect (mediated by depression and insomnia) (b = 0.136, SE = 0.015, p < 0.001, bias-corrected 95% CI = [0.107, 0.167]) effects on depression. Perceived stress and self-efficacy were significant in mediating the relationship between cognitive appraisal of cancer and depression (b = 0.101, SE = 0.014, p < 0.001, bias-corrected 95% CI = [0.074, 0.132]; b = 0.021, SE = 0.006, p < 0.001, bias-corrected 95% CI = [0.006, 0.028], respectively). Additionally, a sequential mediating effect of perceived stress via self-efficacy was found, and the mediating effect size was 0.014 (p < 0.01, bias-corrected 95% CI = [0.010,0.034]). CONCLUSIONS: This study suggests that medical staff could prevent or relieve depression through improving self-efficacy or reducing perceived stress in cancer patients undergoing chemotherapy.

PCSK9 inhibition ameliorates experimental autoimmune myocarditis by reducing Th17 cell differentiation through LDLR/STAT-3/ROR-γt pathway.

Proprotein convertase subtilisin kexin type 9 (PCSK9) was characterized as a protein regulating circulating cholesterol metabolism; however, recent studies demonstrated a role for PCSK9 in inflammatory and autoimmune diseases unrelated to cholesterol alterations. The implication of PCSK9 in myocarditis is unclear and we aim at investigating the roles and mechanisms of PCSK9 in myocarditis. Male BALB/c mice received subcutaneous immunization with MyHC-α peptide on days 0 and 7 to establish the experimental autoimmune myocarditis (EAM) model. PCSK9 inhibitor, evolocumab, was administered subcutaneously once a week starting on day 0 and all mice were euthanized on day 21. Our results showed that PCSK9 inhibition ameliorated the cardiac inflammation of EAM mice. PCSK9 inhibition reduced both the levels of cardiac and peripheral blood PCSK9. We found that CD4+ T cells, CD8+ T cells, macrophages, and cardiomyocytes in the heart of EAM mice could express PCSK9. PCSK9 inhibition decreased the differentiation of cardiac Th17 cells by lowering ROR-γt levels but had no effects on Th1, Th2, and Treg cell differentiation. In vitro experiments of CD4+ T cells, we found that PCSK9 directly promoted Th17 cell differentiation through LDLR/STAT3/ROR-γt pathway. Collectively, we demonstrated that PCSK9 inhibition ameliorated the severity of EAM mice by reducing Th17 cell differentiation. PCSK9 is a promising target for treating myocarditis.

A 2-dimensional model framework for blood glucose prediction based on iterative learning control architecture.

The accurate, timely, and personalized prediction for future blood glucose (BG) levels is undoubtedly needed for further advancement of diabetes management technologies. Human inherent circadian rhythm and regular lifestyle resulting in similarity of daily glycemic dynamics play a positive role in the prediction of blood glucose. Inspired by the iterative learning control (ILC) method in the field of automatic control, a 2-dimensional (2-D) model framework is constructed to predict the future blood glucose levels by taking both the short-range information within a day (intra-day) and long-range information between days (inter-day) into account. In this framework, the radial basis function neural network was applied to capture nonlinear relationships in glycemic metabolism, that is, short-range temporal dependence and long-range contemporaneous dependence on previous days. We build models for each patient, and the models were tested on the in silico datasets at various prediction horizons (PHs). The learning model developed in the 2-D framework successfully increases the accuracy and reduces the delay of predictions. This modeling framework provides a new point of view for BG level prediction and contributes to the development of personalized glucose management, such as hypoglycemia warning and glycemic control.

ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein.

The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes-associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi-functional protein, is enriched along the crypt-villus axis. Intestinal cell-specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem "-like" cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid-based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis.

Detection of Hydroxychloroquine Retinopathy via Hyperspectral and Deep Learning through Ophthalmoscope Images.

Hydroxychloroquine, also known as quinine, is primarily utilized to manage various autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome. However, this drug has side effects, including diarrhea, blurred vision, headache, skin itching, poor appetite, and gastrointestinal discomfort. Blurred vision is caused by irreversible retinal damages and can only be mitigated by reducing hydroxychloroquine dosage or discontinuing the drug under a physician's supervision. In this study, color fundus images were utilized to identify differences in lesions caused by hydroxychloroquine. A total of 176 color fundus images were captured from a cohort of 91 participants, comprising 25 patients diagnosed with hydroxychloroquine retinopathy and 66 individuals without any retinopathy. The mean age of the participants was 75.67 ± 7.76. Following the selection of a specific region of interest within each image, hyperspectral conversion technology was employed to obtain the spectrum of the sampled image. Spectral analysis was then conducted to discern differences between normal and hydroxychloroquine-induced lesions that are imperceptible to the human eye on the color fundus images. We implemented a deep learning model to detect lesions, leveraging four artificial neural networks (ResNet50, Inception_v3, GoogLeNet, and EfficientNet). The overall accuracy of ResNet50 reached 93% for the original images (ORIs) and 96% for the hyperspectral images (HSIs). The overall accuracy of Inception_v3 was 87% for ORIs and 91% for HSI, and that of GoogLeNet was 88% for ORIs and 91% for HSIs. Finally, EfficientNet achieved an overall accuracy of 94% for ORIs and 97% for HSIs.

Optical Identification of Diabetic Retinopathy Using Hyperspectral Imaging.

The severity of diabetic retinopathy (DR) is directly correlated to changes in both the oxygen utilization rate of retinal tissue as well as the blood oxygen saturation of both arteries and veins. Therefore, the current stage of DR in a patient can be identified by analyzing the oxygen content in blood vessels through fundus images. This enables medical professionals to make accurate and prompt judgments regarding the patient's condition. However, in order to use this method to implement supplementary medical treatment, blood vessels under fundus images need to be determined first, and arteries and veins then need to be differentiated from one another. Therefore, the entire study was split into three sections. After first removing the background from the fundus images using image processing, the blood vessels in the images were then separated from the background. Second, the method of hyperspectral imaging (HSI) was utilized in order to construct the spectral data. The HSI algorithm was utilized in order to perform analysis and simulations on the overall reflection spectrum of the retinal image. Thirdly, principal component analysis (PCA) was performed in order to both simplify the data and acquire the major principal components score plot for retinopathy in arteries and veins at all stages. In the final step, arteries and veins in the original fundus images were separated using the principal components score plots for each stage. As retinopathy progresses, the difference in reflectance between the arteries and veins gradually decreases. This results in a more difficult differentiation of PCA results in later stages, along with decreased precision and sensitivity. As a consequence of this, the precision and sensitivity of the HSI method in DR patients who are in the normal stage and those who are in the proliferative DR (PDR) stage are the highest and lowest, respectively. On the other hand, the indicator values are comparable between the background DR (BDR) and pre-proliferative DR (PPDR) stages due to the fact that both stages exhibit comparable clinical-pathological severity characteristics. The results indicate that the sensitivity values of arteries are 82.4%, 77.5%, 78.1%, and 72.9% in the normal, BDR, PPDR, and PDR, while for veins, these values are 88.5%, 85.4%, 81.4%, and 75.1% in the normal, BDR, PPDR, and PDR, respectively.

Evaluation of a community-based integrated care model (CIE) for frail older people in rural Foshan, China: study protocol for a stepped-wedge cluster randomized controlled trial {1}.

BACKGROUND: While community-based eldercare has proven to be effective in qualitative studies, there is limited evidence on the effectiveness of this geriatric care model in rural communities where caring for older people is traditionally the responsibility of family members, but a formal long-term care was recently introduced in China. CIE is a rural community-embedded intervention using multidisciplinary team, to provide evidenced-based integrated care services for frail older people including social care services and allied primary healthcare and community-based rehabilitation services. METHODS: CIE is a prospective stepped-wedge cluster randomized trial conducted at 5 community eldercare centers in rural China. The multifaceted CIE intervention, guided by chronic care model and integrated care model, consists of five components: comprehensive geriatric assessment, individualized care planning, community-based rehabilitation, interdisciplinary case management, and care coordination. The intervention is rolled out in a staggered manner in these clusters of centers at an interval of 1 month. The primary outcomes include functional status, quality of life, and social support. Process evaluation will also be conducted. Generalized linear mixed model is employed for binary outcomes. DISCUSSION: This study is expected to provide important new evidence on clinical effectiveness and implementation process of an integrated care model for frail older people. The CIE model is also unique as the first registered trial implementing a community-based eldercare model using multidisciplinary team to promote individualized social care services integrated with primary healthcare and community-based rehabilitation services for frail older people in rural China, where formal long-term care was recently introduced. TRIAL REGISTRATION {2A}: China Clinical Trials Register ( http://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR2200060326 ). May 28th, 2022.

Photoisomerization-controlled wavelength-tunable plasmonic lasers.

We demonstrate photoisomerization-controlled wavelength-tunable plasmonic lasers by integrating spiropyran derivative-doped PMMA films with two-dimensional Ag nanoparticle arrays. The controllable transformation between spiropyran derivatives and its isomers with different refractive indices by photoexcitation allows for a dynamical and continuous change of the refractive index in the host PMMA film, which is able to tune the lattice plasmon resonance, and hence the lasing wavelength. This result opens up a new avenue for engineering wavelength tunable plasmonic lasers toward practical photonic integration.