Hepatocyte estrogen sulfotransferase inhibition protects female mice from concanavalin A-induced T cell-mediated hepatitis independent of estrogens.

Autoimmune hepatitis (AIH) is a typical T cell-mediated chronic liver disease with a higher incidence in females. However, the molecular mechanism for the female predisposition is poorly understood. Estrogen sulfotransferase (Est) is a conjugating enzyme best known for its function in sulfonating and deactivating estrogens. The goal of this study is to investigate whether and how Est plays a role in the higher incidence of AIH in females. Concanavalin A (ConA) was used to induce T cell-mediated hepatitis in female mice. We first showed that Est was highly induced in the liver of ConA-treated mice. Systemic or hepatocyte-specific ablation of Est, or pharmacological inhibition of Est, protected female mice from ConA-induced hepatitis regardless of ovariectomy, suggesting the effect of Est inhibition was estrogen independent. In contrast, we found that hepatocyte-specific transgenic reconstitution of Est in the whole-body Est knockout (EstKO) mice abolished the protective phenotype. Upon the ConA challenge, EstKO mice exhibited a more robust inflammatory response with elevated production of proinflammatory cytokines and changed liver infiltration of immune cells. Mechanistically, we determined that ablation of Est led to the hepatic induction of lipocalin 2 (Lcn2), whereas ablation of Lcn2 abolished the protective phenotype of EstKO females. Our findings demonstrate that hepatocyte Est is required for the sensitivity of female mice to ConA-induced and T cell-mediated hepatitis in an estrogen-independent manner. Est ablation may have protected female mice from ConA-induced hepatitis by upregulating Lcn2. Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH.

Phosphine-Capped Effects Enable Full-Color Clusteroluminescence in Nonconjugated Polyesters.

Full-color luminophores have advanced applications in materials and engineering, but constructing color-tunable clusteroluminescence (CL) from nonconjugated polymers based on through-space interactions remains a huge challenge. Herein, we develop phosphine-capped nonconjugated polyesters exhibiting blue-to-red CL (400-700 nm) based on phosphine-initiated copolymerization of epoxides and cyclic anhydrides, especially P1-0.5TPP, which exhibits red CL (610 nm) with a high quantum yield of 32%. Experiments and theoretical calculations disclose that the phosphine-capped effect in polyesters brings about conformational changes and induces phosphine-ester clusters by through-space (n,π*) interactions. Moreover, CL colors and efficiencies can be easily tailored by types of phosphines, compositions and structures of polyesters, and concentration. Significantly, the role of polymer motions (group, segmental, and chain motions) on CL originating from microregions inside polyesters is revealed. Further, phosphine-capped nonconjugated polyesters are demonstrated to be nonconjugated dyes and fluorescent fibers and are also used for multicolor light-emitting diodes including white light. This work not only provides an engineering strategy based on the end-group effect to prepare full-color clusteroluminogens but also broadens the prospects for material applications.

Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology.

In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.

Crystal-Plane-Engineered TiO2-Anchored Vanadium Single Atoms and Clusters for Boosting Ultradeep Aerobic Oxidative Desulfurization of Diesel.

The crystal plane effect has gained extensive attention in heterogeneous catalysis reactions; however, it is far from being systematically probed in titanium dioxide (TiO2)-supported vanadium catalysts. Herein, a series of vanadium (V) single atoms and clusters anchored on TiO2 with different crystal planes was fabricated by an improved "top-down" protocol. The dispersion state, electronic structure, and redox properties of the V single-atom and VOx cluster-supported catalysts were systematically analyzed by a series of characterization methods, including X-ray absorption near edge structure (XANES) and density functional theory (DFT) calculations, and their catalytic performances were examined for aerobic oxidative desulfurization (AODS) of 4,6-dimethyl-dibenzothiophen (4,6-DMDBT) with O2 as the oxidant. The results unveiled that the synergistic effect between the V single atom and the VOx cluster perceptibly promoted the catalytic performances of VOx/TiO2 samples. Therein, VOx/TiO2-(001) shows the lowest apparent activation energy (Ea) value of 46.3 kJ/mol and the optimal AODS performance with complete 4,6-DMDBT conversion to 4,6-dimethyldibenzothiophene sulfone (4,6-DMDBTO2) within 60 min at 120 °C as compared with VOx/TiO2-(101) (81.9 kJ/mol and 180 min) and VOx/TiO2-(100) (68.0 kJ/mol and 240 min), which should be attributed to its higher V5+/V4+ ratio, the optimal redox behavior of the V species, the moderate adsorption energy between 4,6-DMDBT and VOx active centers, and the synthetic effect of V single atoms and VOx clusters. Moreover, VOx/TiO2-(001) exhibits robust durability in seven cycles of reuse, showcasing the potential for practical applications in the future.

Significance of High-Frequency Sonography for the Subclinical Progression of Rheumatoid Arthritis.

OBJECTIVES: This study aims to investigate the use of high-frequency sonography as a tool for detecting inflammatory and destructive changes in the hand and foot joints of patients with early and long-term RA. METHODS: This study employs a prospective cohort design involving 162 patients diagnosed with Rheumatoid arthritis (RA) who meet the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. Patients were divided into two groups based on disease duration: Group 1 (n = 74) included patients with a disease duration of up to 2 years, or early РА (ERA;), Group 2 (n = 88) consisted of patients with a disease duration exceeding 2 years, or long-term persistent РА (LtRA). All patients underwent a clinical assessment of their joints, as well as radiography and arthrosonography, at the beginning of the study and again at 6 and 12 months later. RESULTS: In the general group of patients, ultrasound examination revealed signs of synovitis in the joints of the hands more frequently (66%) compared with clinical examination (56% by a number of swollen joints [NSJ] and 55% by a number of painful joints [NPJ], P < .01). After 6 months of treatment, 12% of the patients achieved full US remission and 24% achieved partial US remission. CONCLUSIONS: Within the scope of comprehensive RA diagnostics, arthrosonography of the joints of the hands and feet, utilizing a combination of greyscale and power Doppler, may surpass radiography in detecting early RA. This method allows for a more accurate assessment of disease activity and progression rates.

Near-Infrared Emission Beyond 900†nm from Stable Radicals in Nonconjugated Poly(diphenylmethane).

Organic radicals with narrow energy gaps are highly sought-after for the production of near-infrared (NIR) fluorophores. However, the current repertoire of developed organic radicals is notably limited, facing challenges related to stability and low fluorescence efficiency. This study addresses these limitations by achieving stable radicals in nonconjugated poly(diphenylmethane) (PDPM). Notably, PDPM exhibits a well-balanced structural flexibility and rigidity, resulting in a robust intra-/inter-chain through-space conjugation (TSC). The stable radicals within PDPM, coupled with strong TSC, yield a remarkable full-spectrum emission spanning from blue to NIR beyond 900 nm. This extensive tunability is achieved through careful adjustments of concentration and excitation wavelength. The findings highlight the efficacy of polymerization in stabilizing radicals and introduce a novel approach for developing nonconjugated NIR emitters based on triphenylmethane subunits.

Reconstructed glycosylase base editors GBE2.0 with enhanced C-to-G base editing efficiency and purity.

Base editing techniques were developed for precise base conversion on cellular genomic DNA, which has great potential for the treatment of human genetic diseases. The glycosylase base editor (GBE) recently developed in our lab was used to perform C-to-G transversions in mammalian cells. To improve the application prospects of GBE, it is necessary to further increase its performance. With this aim, we replaced the human Ung in GBE with Ung1 from Saccharomyces cerevisiae. The resulting editor APOBEC-nCas9-Ung1 was tested at 17 chromosomal loci and was found to have an increased C-to-G editing efficiency ranging from 2.63% to 52.3%, with an average of 23.48%, which was a significant improvement over GBE, with an average efficiency of 15.54%, but with a decreased purity. For further improvement, we constructed APOBEC(R33A)-nCas9-Rad51-Ung1 with two beneficial modifications adapted from previous reports. This base editor was able to achieve even higher editing efficiency ranging from 8.70% to 72.1%, averaging 30.88%, while also exhibiting high C-to-G purity ranging from 35.57% to 92.92%, and was designated GBE2.0. GBE2.0 provides high C-to-G editing efficiency and purity in mammalian cells, making it a powerful genetic tool for scientific research or potential genetic therapies for disease-causing G/C mutations.

Volatile-Based Diagnosis for Pathogenic Wood-Rot Fungus Fulvifomes siamensis by Electronic Nose (E-Nose) and Solid-Phase Microextraction/Gas Chromatography/Mass Spectrometry.

Wood rot fungus Fulvifomes siamensis infects multiple urban tree species commonly planted in Singapore. A commercial e-nose (Cyranose 320) was used to differentiate some plant and fungi volatiles. The e-nose distinctly clustered the volatiles at 0.25 ppm, and this sensitivity was further increased to 0.05 ppm with the use of nitrogen gas to purge the system and set up the baseline. Nitrogen gas baseline resulted in a higher magnitude of sensor responses and a higher number of responsive sensors. The specificity of the e-nose for F. siamensis was demonstrated by distinctive clustering of its pure culture, fruiting bodies collected from different tree species, and in diseased tissues infected by F. siamensis with a 15-min incubation time. This good specificity was supported by the unique volatile profiles revealed by SPME GC-MS analysis, which also identified the signature volatile for F. siamensis-1,2,4,5-tetrachloro-3,6-dimethoxybenzene. In field conditions, the e-nose successfully identified F. siamensis fruiting bodies on different tree species. The findings of concentration-based clustering and host-tree-specific volatile profiles for fruiting bodies provide further insights into the complexity of volatile-based diagnosis that should be taken into consideration for future studies.

NIR Clusteroluminescence of Non-conjugated Phenolic Resins Enabled by Through-Space Interactions.

Clusteroluminescence (CL) and through-space interactions (TSIs) of non-conjugated molecules have drawn more attention due to their unique photophysical behaviors that are different from largely conjugated luminogens. However, achieving red and even near-infrared (NIR) emission from such systems is still challenging due to the intrinsic drawbacks of non-conjugated molecules and the lack of theories for structure-property relationships. In this work, six phenolic resins are designed and synthesized based on two molecule-engineering strategies: increasing the number of TSIs units and introducing electron-donating/-withdrawing groups. All phenolic resins are verified as luminogens with CL property (CLgens), and the first example of CLgens with NIR emission (maximum emission wavelength ≥680 nm) and high absolute quantum yield (47 %) is reported. Experiments and theoretical analysis reveal that two TSIs types, through-space locally excited state and through-space charge transfer state, play essential roles in achieving CL from these non-conjugated polymers, which could be manipulated via changing structural conformation and electron density or altering electron transition behaviors. This work not only provides an approach to manipulate TSIs and CL of non-conjugated polymers but also endows commercially available phenolic resins with high practical value as luminescence materials.

NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1ß-mediated neuroinflammation.

BACKGROUND: Patients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke. METHODS: In this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1ß neutralizing antibody was injected to test potential therapeutic effect on heat stroke. RESULTS: Prior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1ß in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1ß production with prior infection condition. Furthermore, IL-1ß neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke. CONCLUSIONS: Based on the above results, NLRP3/IL-1ß induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1ß may serve as a biomarker for heat stroke severity and potential therapeutic method.

Development of a nomogram model to predict survival outcomes in patients with primary hepatic neuroendocrine tumors based on SEER database.

BACKGROUND: Primary hepatic neuroendocrine tumors (PH-NETs) are extremely rare and unknown. Because of its rarity, its prognosis features and influencing factors are not well established. METHODS: Data of 140 patients with PH-NETs diagnosed in the SEER database from 1975 to 2016 were collected. The demographics and clinic-pathological features were described. By using propensity-score matching (PSM) analysis, three associated cohorts were selected to describe the malignancy of PH-NETs and univariate analysis was conducted. Then, multivariate Cox analyses were performed and a predicting nomograph was constructed. C-index, receiver operating characteristic (ROC) curve and calibration curves were used to evaluate the predictive value of nomogram. RESULTS: The overall survival outcomes of PH-NETs were superior to hepatocellular carcinoma (HCC) with a mean survival time 30.64 vs 25.11 months (p = 0.052), but inferior to gastrointestinal tract neuroendocrine tumors in situ (GI-NETs in situ) with a mean survival time 30.64 vs 41.62 months (p = 0.017). With reference to gastrointestinal neuroendocrine tumors with liver metastasis (GI-NETs-LM), GI-NETs-LM had better outcomes in short time (1-year survival rate: 64.75% vs 56.43%) but was worse in long time (5-year survival rate: 8. 63% vs 18.57%). Multivariate Cox analyses showed that tumor grade and surgery were two independent factors for prognosis of the patients (p < 0.00). Tumor grade and surgery were used to construct the predicting nomogram. The C-index was 0.79 (95%CI = 0.75-0.83). The area under curve (AUC) values in ROC were 0.868 in 1-year and 0.917 in 3-year survival and the calibration curves showed good consistency. CONCLUSIONS: The overall prognosis PH-NETs is generally favorable, better than HCC and GI-NETs-LM in long term. Preoperative biopsy and complete pathological diagnosis were recommended. Radical surgical intervention including transplantation was the first choice in PH-NETs therapy.

Establishment of an anti-inflammation-based bioassay for the quality control of the 13-component TCM formula (Lianhua Qingwen).

CONTEXT: Owing to the complexity of chemical ingredients in traditional Chinese medicine (TCM), it is difficult to maintain quality and efficacy by relying only on chemical markers. OBJECTIVE: Lianhua Qingwen capsule (LHQW) was selected as an example to discuss the feasibility of a bioassay for quality control. MATERIALS AND METHODS: Network pharmacology was used to screen potential targets in LHQW with respect to its anti-inflammatory effects. An in vitro cell model was used to validate the prediction. An anti-inflammatory bioassay was established for the quality evaluation of LHQW in 40 batches of marketed products and three batches of destructed samples. RESULTS: The tumor necrosis factor/interleukin-6 (TNF/IL-6) pathway via macrophage was selected as the potential target of LHQW. The IC50 value of LHQW on RAW 264.7 was 799.8 µg/mL. LHQW had significant inhibitory effects on the expression of IL-6 in a dose-dependent manner (p < 0.05). The anti-inflammatory biopotency of LHQW was calculated based on the inhibitory bioactivity on IL-6. The biopotency of 40 marketed samples ranged from 404 U/µg to 2171 U/µg, with a coefficient of variation (CV) of 37.91%. By contrast, the contents of forsythin indicated lower CV (28.05%) than the value of biopotency. Moreover, the biopotencies of destructed samples declined approximate 50%, while the contents of forsythin did not change. This newly established bioassay revealed a better ability to discriminate the quality variations of LHQW as compared to the routine chemical determination. CONCLUSIONS: A well-established bioassay may have promising ability to reveal the variance in quality of TCM.

LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma.

BACKGROUND: Growing evidence suggests that suppressor of tumorigenicity 7 antisense RNA 1 (ST7-AS1) is an oncogenic long noncoding RNA (lncRNA). However, little is known on its clinical significance, biological functions, or molecular mechanisms in lung adenocarcinoma (LUAD). METHODS: The expression of ST7-AS1 and miR-181b-5p were examined by qRT-PCR. The correlations between ST7-AS1 level and different clinicopathological features were analysed. In vitro, LUAD cells were examined for cell viability, migration and invasion by MTT, wound healing and Transwell assay, respectively. Epithelial-mesenchymal transition (EMT) biomarkers were detected by Western blot. The regulations between ST7-AS1, miR-181b-5p, and KPNA4 were examined by luciferase assay, RNA immunoprecipitation, RNA pulldown. Both gain- and loss-of-function strategies were used to assess the importance of different signalling molecules in malignant phenotypes of LUAD cells. The in vivo effect was analysed using the xenograft and the experimental metastasis mouse models. RESULTS: ST7-AS1 was upregulated in LUAD tissues or cell lines, correlated with tumours of positive lymph node metastasis or higher TNM stages, and associated with shorter overall survival of LUAD patients. ST7-AS1 essentially maintained the viability, migration, invasion, and EMT of LUAD cells. The oncogenic activities of ST7-AS1 were accomplished by sponging miR-181b-5p and releasing the suppression of the latter on KPNA4. In LUAD tissues, ST7-AS1 level positively correlated with that of KPNA4 and negatively with miR-181b-5p level. In vivo, targeting ST7-AS1 significantly inhibited xenograft growth and metastasis. CONCLUSIONS: ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of LUAD cells. Targeting ST7-AS1 and KPNA4 or up-regulating miR-181b-5p, therefore, may benefit the treatment of LUAD.

[Rapid establishment of traditional Chinese medicine prevention and treatment of 2019-nCoV based on clinical experience and molecular docking].

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using "back-to-back" manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription "Keguan Yihao", immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.

RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide; however, clinical and pathological parameters have limited ability in discriminating between clinically significant and indolent ESCC. Since RasGRP3 transcript levels have prognostic value in discriminating ESCC with different clinical aggressiveness, we decided to investigate its putative oncogenic role in ESCC. We found that RasGRP3 was highly expressed in ESCC cells. Suppression of endogenous RasGRP3 expression in esophageal cell lines reduced Ras-GTP formation as well as AKT phosphorylation. RasGRP3 suppression also inhibited cell invasion and migration and reduced proliferation, demonstrating the importance of RasGRP3 for the transformed phenotype of melanoma cells. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth and migration, confirming the functional role of RasGRP3 in the altered behaviour of these cells. This suggests that RasGRP3 may function as a Ras activator in the phosphoinositide signalling pathway and may potentially serve as a new therapeutic target.

Observation of clinical efficacy of application of enhanced recovery after surgery in perioperative period on esophageal carcinoma patients.

PURPOSE: To observe the clinical efficacy of the application of enhanced recovery after surgery (ERAS) in the perioperative period of esophageal carcinoma patients. METHODS: A total of 114 patients who were admitted to Affiliated Hospital of Jining Medical University for surgical treatment of esophageal carcinoma between June 2012 and June 2016 were enrolled and randomly divided into the intervention group and the regular group according to the difference of management procedures during the perioperative period. ERAS was carried out in 57 patients in the intervention group, while conventional management procedures were applied in 57 patients in the regular group. Thereafter, compared were the fluctuations in nutritional indicators and immunological indicators, postoperative complications, time to recovery of gastrointestinal function, length of stay (LOS) in hospital and cost of patients between the two groups. RESULTS: Seven days post-operation in the intervention group, the evaluation indexes of nutrition status, including total protein (TP), albumin (ALB), prealbumin (PA) and transferrin (TF), and of immunological functions, including immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM) and total blood lymphocyte count (TLC), were significantly higher than those in the regular group. As for postoperative complications, the incidence rate of the intervention group was remarkably lower than that of the regular group; the recovery time of gastrointestinal function in the intervention group was shorter than that in the regular group; the LOS in the intervention group was also shorter than that in the regular group; the in-hospital cost in the intervention group was also lower than that in the regular group. All differences above were statistically significant (p<0.05). CONCLUSION: During the perioperative period of esophageal carcinoma patients, ERAS should be fully applied to sustain the good status, and promote the recovery of immunological functions and gastrointestinal functions; at the same time, ERAS also reduces the incidence rate of postoperative complications, LOS and in-hospital cost, and we maintain that ERAS should be performed in clinical practice.

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.

BACKGROUND: The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1ß and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue. METHODS: We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated. RESULTS: Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1ß and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1ß production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1ß levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1ß levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered. CONCLUSIONS: These findings suggest that LPS-induced fatigue is an IL-1ß-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

Integrated Bioinformatics Analysis Revealed Immune Checkpoint Genes Relevant to Type 2 Diabetes.

Objective: Chronic low-grade inflammation of the pancreatic islets is the characteristic of type 2 diabetes (T2D), and some of the immune checkpoints may play important roles in the pancreatic islet inflammation. Thus, we aim to explore the immune checkpoint genes (ICGs) associated with T2D, thereby revealing the role of ICGs in the pathogenesis of T2D based on bioinformatic analyses. Methods: Differentially expressed genes (DEGs) and immune checkpoint genes (ICGs) of islets between T2D and control group were screened from datasets of the Gene Expression Omnibus (GEO). A risk model was built based on the coefficients of ICGs calculated by ridge regression. Functional enrichment analysis and immune cell infiltration estimation were conducted. Correlations between ICGs and hub genes, T2D-related disease genes, insulin secretion genes, and beta cell function-related genes were analyzed. Finally, we conducted RT-PCR to verify the expression of these ICGs. Results: In total, pancreatic islets from 19 cases of T2D and 84 healthy subjects were included. We identified 458 DEGs. Six significantly upregulated ICGs (CD44, CD47, HAVCR2, SIRPA, TNFSF9, and VTCN1) in T2D were screened out. These ICGs were significantly correlated with several hub genes and T2D-related genes; furthermore, they were correlated with insulin secretion and ß cell function-related genes. The analysis of immune infiltration showed that the concentrations of eosinophils, T cells CD4 naive, and T cells regulatory (Tregs) were significantly higher, but CD4 memory resting T cells and monocytes were lower in islets of T2D patients. The infiltrated immune cells in T2D pancreatic islet were associated with these six ICGs. Finally, the expression levels of four ICGs were confirmed by RT-PCR, and three ICGs were validated in another independent dataset. Conclusion: In conclusion, the identified ICGs may play an important role in T2D. Identification of these differential genes may provide new clues for the diagnosis and treatment of T2D.

A novel breast cancer image classification model based on multiscale texture feature analysis and dynamic learning.

Assistive medical image classifiers can greatly reduce the workload of medical personnel. However, traditional machine learning methods require large amounts of well-labeled data and long learning times to solve medical image classification problems, which can lead to high training costs and poor applicability. To address this problem, a novel unsupervised breast cancer image classification model based on multiscale texture analysis and a dynamic learning strategy for mammograms is proposed in this paper. First, a gray-level cooccurrence matrix and Tamura coarseness are used to transfer images to multiscale texture feature vectors. Then, an unsupervised dynamic learning mechanism is used to classify these vectors. In the simulation experiments with a resolution of 40 pixels, the accuracy, precision, F1-score and AUC of the proposed method reach 91.500%, 92.780%, 91.370%, and 91.500%, respectively. The experimental results show that the proposed method can provide an effective reference for breast cancer diagnosis.

Self-Reported Outdoor Light Exposure Time and Incident Heart Failure.

BACKGROUND: A healthy lifestyle is an important factor for preventing heart failure. However, the association between outdoor light exposure time and heart failure is still unknown. The aim of this study was to examine the association between outdoor light exposure time and the incidence of heart failure. METHODS AND RESULTS: This cohort study included participants from the UK Biobank recruited from 2006 to 2010 who were 40 to 70 years of age and free of heart failure at baseline. The mean follow-up time was 12.61 years. The outdoor light exposure time was self-reported at baseline. A restricted cubic spline was performed to examine the potential nonlinear relationship between outdoor light exposure and the incidence of heart failure. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs. During a mean follow-up of 12.61 years, 13 789 participants were first diagnosed with heart failure. There was a nonlinear (J-shaped) trend between outdoor light time and heart failure risk. Cox proportional hazard regression models showed that, compared with participants who received an average of 1.0 to 2.5 hours of outdoor light per day, those with <1.0 hours or >2.5 hours had a higher risk of heart failure after the model was adjusted for age and sex (<1.0 hours: HR, 1.27 [95% CI, 1.18-1.36]; >2.5 hours: HR, 1.11 [95% CI, 1.07-1.15]). These associations were still significant in the fully adjusted models (<1.0 hours: HR, 1.10 [95% CI, 1.03-1.18]; >2.5 hours: HR, 1.07 [95% CI, 1.03-1.11]). CONCLUSIONS: We found a J-shaped association between outdoor light exposure time and the risk of incident heart failure, suggesting that moderate exposure to outdoor light may be a prevention strategy for heart failure.