Beneficial effects of Dendrobium officinale National Herbal Drink on metabolic immune crosstalk via regulate SCFAs-Th17/Treg.

BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.

Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Environmentally relevant concentrations of microplastics from agricultural mulch and cadmium negatively impact earthworms by triggering neurotoxicity and disrupting homeostasis.

Recent research has highlighted the ecological risk posed by microplastics (MPs) from mulching film and heavy metals to soil organisms. However, most studies overlooked real environmental levels of MPs and heavy metals. To address this gap, pristine and aged polyethylene (PE) mulching film-derived MPs (PMPs, 500 mg/kg; AMPs, 500 mg/kg) were combined with cadmium (Cd, 0.5 mg/kg) to assess the acute toxicity to earthworms and investigate associated molecular mechanisms (oxidative stress, osmoregulation pressure, gut microbiota, and metabolic responses) at environmentally relevant concentrations. Compared to Cd alone and Cd + PMPs treatments (11.15 ± 4.19 items/g), Cd + AMPs treatment resulted in higher MPs bioaccumulation (23.73 ± 13.14 items/g), more severe tissue lesions, and increased cell membrane osmotic pressure in earthworms' intestines. Cd + AMPs induced neurotoxicity through elevated levels of glutamate and acetylcholinesterase. Earthworm intestines (0.98 ± 0.49 to 3.33 ± 0.37 mg/kg) exhibited significantly higher Cd content than soils (0.19 ± 0.01 to 0.51 ± 0.06 mg/kg) and casts (0.15 ± 0.01 to 0.25 ± 0.05 mg/kg), indicating PE-MPs facilitated Cd transport in earthworms' bodies. Metabolomic analysis showed Cd + AMPs exposure depleted energy and nucleotide metabolites, disrupted cell homeostasis more profoundly than Cd and Cd + PMPs treatments. Overall, co-exposure to AMPs + Cd induced more severe neurotoxicity and disruption of homeostasis in earthworm than Cd and PMPs + Cd treatments. Our study, using Cd and MPs with environmental relevance, underscores MPs' role in amplifying Cd accumulation and toxicity in earthworms.

Hemifacial Spasm Associated With the Specific Offending Vein.

BACKGROUND AND OBJECTIVES: Hemifacial spasm (HFS) caused by venous compression is a rare occurrence. Currently, there is no relevant research on the venous characteristics and potential pathogenic mechanisms causing venous HFS. Exploring the venous characteristics in venous-type HFS may reduce the likelihood of repeated surgery. METHODS: The authors presented 4 cases of HFS caused by veins of middle cerebellar peduncle (V. of Mid.Cer.Ped) successfully treated with microvascular decompression. RESULTS: Based on intraoperative observations and abnormal muscle response (AMR) monitoring, it was determined that V. of Mid.Cer.Ped were offending vessels in these patients. Moreover, veins crossed between the facial and vestibulocochlear nerves, and then surrounded the ventral aspect of the facial nerve root. Microvascular decompression for the offending vessel was successfully performed, and AMR disappeared for each patient. These patients were discharged without any complications and involuntary contractions or twitching of facial muscles. CONCLUSION: The study demonstrated that veins can indeed induce HFS. The characteristic of the V. of Mid.Cer.Ped that leads to HFS is that these veins traverse between the facial nerve and the vestibulocochlear nerve, and then surround the ventral aspect of the facial nerve root. The dynamic influence of cerebrospinal fluid leads to pulsatile impingement of the facial nerve on the vein, resulting in facial nerve bending and deformation at the location of the vein. Significantly, in the context of surgery, if it is noticed that the V. of Mid.Cer.Ped surrounds the ventral aspect of the facial nerve root and the facial nerve is compressed and deformed, when AMR disappears after decompression of the artery, it may be necessary to perform vein decompression.

TREM1+ tumor-associated macrophages secrete CCL7 to promote hepatocellular carcinoma metastasis.

PURPOSE: Tumor-associated macrophages (TAMs) play a critical role in hepatocellular carcinoma (HCC) progression and metastasis. Systematic investigation of the cross-talk between TAMs and HCC may help in searching for the critical target to guard against HCC metastasis. METHODS AND RESULTS: Herein, we found that TREM1 highly expressed in HCC tissue by analyzing the data obtain from GEO database. Interestingly, the results indicated that TREM1 was primarily expressed by monocytes. Immune infiltration studies further validated that TREM1 expression was positively related with increased infiltration of macrophages in HCC tissues. In vitro, we observed that TREM1 knockdown significantly abrogated the effect of TAMs in promoting the metastasis and epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, cytokine array detection identified CCL7 as the main responsive cytokine following with TREM1 knockdown in TAMs. CONCLUSION: Taken together, our findings strongly suggested that high expression of TREM1 was positively associated with metastasis and poor prognosis of HCC. Furthermore, TAMs expressing TREM1 contribute to EMT-based metastasis through secreting CCL7. These results provide a novel insight into the potential development of targeting the TREM1/CCL7 pathway for preventing metastatic HCC.

Antigen specific VNAR screening in whitespotted bamboo shark (Chiloscyllium plagiosum) with next generation sequencing.

IgNAR exhibits significant promise in the fields of cancer and anti-virus biotherapies. Notably, the variable regions of IgNAR (VNAR) possess comparable antigen binding affinity with much smaller molecular weight (∼12 kDa) compared to IgNAR. Antigen specific VNAR screening is a changeling work, which limits its application in medicine and therapy fields. Though phage display is a powerful tool for VNAR screening, it has a lot of drawbacks, such as small library coverage, low expression levels, unstable target protein, complicating and time-consuming procedures. Here we report VANR screening with next generation sequencing (NGS) could effectively overcome the limitations of phage display, and we successfully identified approximately 3000 BAFF-specific VNARs in Chiloscyllium plagiosum vaccinated with the BAFF antigen. The results of modelling and molecular dynamics simulation and ELISA assay demonstrated that one out of the top five abundant specific VNARs exhibited higher binding affinity to the BAFF antigen than those obtained through phage display screening. Our data indicates NGS would be an alternative way for VNAR screening with plenty of advantages.

Diagnostic performance of PIVKA-II in identifying recurrent hepatocellular carcinoma following curative resection: a retrospective cohort study.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) plays a critical role in the diagnosis of hepatocellular carcinoma (HCC), however, studies on its efficacy in diagnosing recurrent HCC were rarely found. A multicenter, retrospective, and observational study was conducted. During the overall follow-up of 5 years, HCC patients who had curative resection were monitored every 3 months in the first year post-surgery and every 6 months thereafter if no recurrence occurred. Tumor markers were collected at the diagnosis of recurrence for those with recurrence and at the last follow-up for those without recurrence. The median serum levels of PIVKA-II and AFP in the recurrence group were significantly higher than those in the non-recurrence group (PIVKA-II: 84.62 vs. 18.76 mAU/ml, p < 0.001; AFP: 4.90 vs. 3.00 ng/ml, p < 0.001) and there is a significant correlation between PIVKA-II and AFP (R = 0.901, p < 0.001). PIVKA-II showed better accuracy than AFP in the diagnosis of overall recurrent HCC (AUC: 0.883 vs. 0.672; p < 0.0001), but also in patients with negative PIVKA-II before curative resection (AUC: 0.878 vs. 0.680, p = 0.001). Clinician should pay more attention to serum PIVKA-II values when following patients after curative HCC resection to detect early recurrence.Clinical trial registration: ChiCTR2300070874.

The effects of Atractylodes macrocephala extract BZEP self-microemulsion based on gut-liver axis HDL/LPS signaling pathway to ameliorate metabolic dysfunction-associated fatty liver disease in rats.

OBJECTIVES: To elucidate the therapeutic effects and mechanisms of Atractylodes macrocephala extract crystallize (BZEP) and BZEP self-microemulsion (BZEPWR) on metabolic dysfunction-associated fatty liver disease (MAFLD) induced by "high sugar, high fat, and excessive alcohol consumption" based on the gut-liver axis HDL/LPS signaling pathway. METHODS: In this study, BZEP and BZEPWR were obtained via isolation, purification, and microemulsification. Furthermore, an anthropomorphic MAFLD rat model of "high sugar, high fat, and excessive alcohol consumption" was established. The therapeutic effects of BZEPWR and BZEP on the model rats were evaluated in terms of liver function, lipid metabolism (especially HDL-C), serum antioxidant indexes, and liver and intestinal pathophysiology. To determine the lipoproteins in the serum sample, the amplitudes of a plurality of NMR spectra were derived via deconvolution of the composite methyl signal envelope to yield HDL-C subclass concentrations. The changes in intestinal flora were detected via 16 S rRNA gene sequencing. In addition, the gut-liver axis HDL/LPS signaling pathway was validated using immunohistochemistry, immunofluorescence, and western blot. RESULTS: The findings established that BZEPWR and BZEP improved animal signs, serum levels of liver enzymes (ALT and AST), lipid metabolism (TC, TG, HDL-C, and LDL-C), and antioxidant indexes (GSH, SOD, and ROS). In addition, pathological damage to the liver, colon, and ileum was ameliorated, and the intestinal barrier function of the model rats was restored. At the genus level, BZEPWR and BZEP exerted positive effects on beneficial bacteria, such as Lactobacillus and norank_f__Muribaculaceae, and inhibitory effects on harmful bacteria, such as unclassified_f__Lachnospiraceae and Blautia. Twenty HDL-C subspecies were detected, and their levels were differentially increased in both BZEPWR and BZEP groups, with BZEPWR exhibiting a stronger elevating effect on specific HDL-C subspecies. Also, the gut-liver axis HDL/LPS signaling pathway was studied, which indicated that BZEPWR and BZEP significantly increased the expressions of ABCA1, LXR, occludin, and claudin-1 proteins in the gut and serum levels of HDL-C. Concomitantly, the levels of LPS in the serum and TLR4, Myd88, and NF-κB proteins in the liver were decreased. CONCLUSION: BZEPWR and BZEP exert restorative and reversal effects on the pathophysiological damage to the gut-liver axis in MAFLD rats, and the therapeutic mechanism may be related to the regulation of the intestinal flora and the HDL/LPS signaling pathway.

Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor. AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Demethylases in tumors and the tumor microenvironment: Key modifiers of N6-methyladenosine methylation.

RNA methylation modifications are widespread in eukaryotes and prokaryotes, with N6-methyladenosine (m6A) the most common among them. Demethylases, including Fat mass and obesity associated gene (FTO) and AlkB homolog 5 (ALKBH5), are important in maintaining the balance between RNA methylation and demethylation. Recent studies have clearly shown that demethylases affect the biological functions of tumors by regulating their m6A levels. However, their effects are complicated, and even opposite results have appeared in different articles. Here, we summarize the complex regulatory networks of demethylases, including the most important and common pathways, to clarify the role of demethylases in tumors. In addition, we describe the relationships between demethylases and the tumor microenvironment, and introduce their regulatory mechanisms. Finally, we discuss evaluation of demethylases for tumor diagnosis and prognosis, as well as the clinical application of demethylase inhibitors, providing a strong basis for their large-scale clinical application in the future.

Bioinformatics and LC-QTOF-MS based discovery of pharmacodynamic and Q-markers of Pitongshu against functional dyspepsia.

ETHNOPHARMACOLOGICAL RELEVANCE: Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. OBJECTIVE: To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. METHOD: In this study, we used "irregular feeding + chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. RESULT: Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. CONCLUSION: PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.

Enhanced protective efficacy of an OprF/PcrV bivalent DNA vaccine against Pseudomonas aeruginosa using a hydrogel delivery system.

Pseudomonas aeruginosa (PA) is one of the leading pathogens responsible for hospital-acquired infections. With the increasing antibiotic resistance of PA, clinical treatment has become increasingly challenging. DNA vaccines represent a promising approach for combating PA infection. However, the immune response induced by a single antigen is limited, and combination vaccines hold greater therapeutic potential. The highly conserved OprF and PcrV genes are attractive candidate antigens for vaccine development, but the poor delivery of such vaccines has limited their clinical application. In this study, we constructed an OprF/PcrV bivalent DNA vaccine, and a polyaspartamide/polyethylene glycol di-aldehyde (PSIH/PEG DA) hydrogel was formulated to improve DNA delivery. The OprF/PcrV DNA vaccine formulated with the PSIH/PEG DA hydrogel was carefully characterized in vitro and in vivo and showed suitable compatibility. The PSIH/PEG DA hydrogel formulation induced a mixed Th1/Th2/Th17 immune response in mice, leading to a significant increase in antibody titers, lymphocyte proliferation rates, and cytokine levels compared to those in mice treated with single or combined vaccines. The PSIH/PEG DA hydrogel delivery system significantly enhanced the immune protection of the DNA vaccine in a murine pneumonia model, as revealed by the reduced bacterial burden and inflammation in the mouse lungs and increased survival rate. In conclusion, the PSIH/PEG DA hydrogel delivery system can further enhance the immune efficacy of the combination OprF/PcrV DNA vaccine. This research provides a novel optimized strategy for the prevention and treatment of PA infection using DNA vaccines.

A two-terminal fault location method for gas switch prefire in linear transformer driver.

Large-scale linear transformer drivers (LTDs) are composed of numerous high-power gas switches, and switch prefire is a frequent operational fault. To detect and locate the faulty switch accurately and efficiently, a two-terminal location method is proposed. A B-dot sensor is integrated on the gas switch's shell to collect the discharging signal. All the B-dot sensors are connected in parallel through cables of equal length. The fault position can be determined by the time delay of the signals at the two terminals. A diode is inserted between the B-dot sensor's coil and the cable core to ensure low-loss transmission of the signal. Two methods are applied in fault location, including time-of-arrival (TOA) and time reversal (TR). For the TOA method, an energy criterion and a phase criterion are applied and compared. The accuracy of the energy criterion is greatly influenced by the signal-to-noise ratio, while the phase criterion requires a reasonable estimate of the actual delay to account for the impact of phase periodicity. The TR method based on a precise simulation model is established, which demonstrates high precision in location. The TR method has been tested and validated on a single stage LTD module. Moreover, the location method for double switches prefire is discussed theoretically. The method proposed in this paper will be helpful to improve the efficiency of the commissioning, operation, and maintenance of the large-scale LTD devices.

Sex differences in cardiovascular health among children aged 6-8 years in Beijing City / 中国学校卫生

Objective@#To explore sex difference in the cardiovascular health (CVH) status of 6-8 year old children in Beijing, so as to inform the early intervention of CVH related lifestyles.@*Methods@#Based on the Beijing Children s Growth and Health Cohort (PROC), baseline physical examination, sequential questionnaire survey, and laboratory tests were conducted among 1 914 grade 1 students. Children s CVH and its subscales (health behaviors and health factors) scores were calculated according to the Life s Essential 8 (LE 8) index and categorized into high, moderate, and low CVH. CVH scores were reported as medians and interquartile ranges; sex differences were compared using the Chi square test and Wilcoxon test.@*Results@#Among the 1 914 participants, the percentages of high, moderate, and low CVH were 35.7%, 63.5%, and 0.8%, respectively, and the percentages of high, moderate, and low health behavior scores were 25.9%, 67.5%, and 6.6%, respectively, with no statistically significant differences between sex ( χ 2=2.30, 0.07, P >0.05). The rates of high, moderate, and low health factor scores for boys and girls were 61.1%, 36.0%, 2.9% and 71.1%, 28.4%, 0.5%, respectively, with a statistically significant sex difference ( χ 2=31.88, P < 0.01). The overall CVH score was 76.0(70.0, 83.0), 76.0(69.0, 82.0) for boys, and 77.0(71.0, 83.0) for girls. Among the health behavior metrics, sleep scores were the best and physical activity scores were the worst[100.0(90.0,100.0), 40.0(20.0, 80.0 )]; among the health factor metrics, blood glucose scores were the best and lipid scores were the worst[100.0(100.0,100.0), 60.0(40.0,100.0)]. In respect to health factors, there were significant gender differences in body mass index, blood lipids, blood sugar, and blood pressure scores ( Z =-6.92, 3.01, -6.60, -2.30, <0.05), but there were no significant gender differences in diet, physical activity, nicotine exposure, or sleep scores with regards to health behaviors ( Z =0.99, 0.88, -0.13, 0.36, P > 0.05 ). Compared to boys, girls in the low and moderate CVH groups had high health factor scores despite low health behavior scores.@*Conclusion@#Most 6 to 8-year-old children in Beijing were found to have relatively good CVH, and optimization of children s CVH status can be achieved by promoting healthier lifestyles and monitoring health factors, especially among boys.

End-to-end prognostication in colorectal cancer by deep learning: a retrospective, multicentre study.

BACKGROUND: Precise prognosis prediction in patients with colorectal cancer (ie, forecasting survival) is pivotal for individualised treatment and care. Histopathological tissue slides of colorectal cancer specimens contain rich prognostically relevant information. However, existing studies do not have multicentre external validation with real-world sample processing protocols, and algorithms are not yet widely used in clinical routine. METHODS: In this retrospective, multicentre study, we collected tissue samples from four groups of patients with resected colorectal cancer from Australia, Germany, and the USA. We developed and externally validated a deep learning-based prognostic-stratification system for automatic prediction of overall and cancer-specific survival in patients with resected colorectal cancer. We used the model-predicted risk scores to stratify patients into different risk groups and compared survival outcomes between these groups. Additionally, we evaluated the prognostic value of these risk groups after adjusting for established prognostic variables. FINDINGS: We trained and validated our model on a total of 4428 patients. We found that patients could be divided into high-risk and low-risk groups on the basis of the deep learning-based risk score. On the internal test set, the group with a high-risk score had a worse prognosis than the group with a low-risk score, as reflected by a hazard ratio (HR) of 4·50 (95% CI 3·33-6·09) for overall survival and 8·35 (5·06-13·78) for disease-specific survival (DSS). We found consistent performance across three large external test sets. In a test set of 1395 patients, the high-risk group had a lower DSS than the low-risk group, with an HR of 3·08 (2·44-3·89). In two additional test sets, the HRs for DSS were 2·23 (1·23-4·04) and 3·07 (1·78-5·3). We showed that the prognostic value of the deep learning-based risk score is independent of established clinical risk factors. INTERPRETATION: Our findings indicate that attention-based self-supervised deep learning can robustly offer a prognosis on clinical outcomes in patients with colorectal cancer, generalising across different populations and serving as a potentially new prognostic tool in clinical decision making for colorectal cancer management. We release all source codes and trained models under an open-source licence, allowing other researchers to reuse and build upon our work. FUNDING: The German Federal Ministry of Health, the Max-Eder-Programme of German Cancer Aid, the German Federal Ministry of Education and Research, the German Academic Exchange Service, and the EU.

Abnormal functional connectivity of the core olfactory network in patients with chronic rhinosinusitis accompanied by olfactory dysfunction.

Objective: To review and analyze the functional connectivity (FC) abnormalities in the brain olfactory network (ON) of patients with chronic rhinosinusitis with olfactory dysfunction (CRSwOD) and explore the relationship between these FC abnormalities and olfactory dysfunction, providing clues to the neurophysiological mechanisms underlying CRSwOD. Methods: FC analysis on the ON of patients with CRSwOD and patients with chronic rhinosinusitis without olfactory dysfunction (CRSsOD) identified the regions of the ON with abnormal FC in CRSwOD patients, and the correlation between abnormal FC and clinical scales for chronic rhinosinusitis was analyzed. Results: (1) Compared with the CRSsOD group, CRSwOD patients showed decreased FC between the bilateral orbitofrontal cortex (OFC) and the right middle frontal gyrus, (2) Receiver operating characteristic (ROC) curve analysis revealed that the FC value between the right middle frontal gyrus and the left OFC (area under the curve (AUC) = 0.852, sensitivity: 0.821, specificity: 0.800, p < 0.001) was more capable of distinguishing whether CRS patients may have olfactory dysfunction than the FC value between the right middle frontal gyrus and the right OFC (AUC = 0.827, sensitivity: 0.893, specificity: 0.667, p < 0.001), and (3) Lund-Kennedy scores were positively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = 0.443, p < 0.018). Lund-Mackay scores were also positively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = 0.468, p < 0.012). Questionnaire of Olfactory Disorders-Negative Statements scores were negatively correlated with the FC values between the right middle frontal gyrus and the left OFC (r = -0.481, p < 0.001). Conclusion: Persistent nasal inflammation affects the FC between the middle frontal gyrus and the OFC, which may serve as a potential imaging marker for identifying CRSwOD. The severity of nasal inflammation and olfactory damage is closely related to the FC between the middle frontal gyrus and OFC, and the abnormal changes in this FC can be used to explain the neurophysiological mechanisms behind the occurrence of olfactory dysfunction in patients.

Trigeminal neuralgia secondary to osteoma and vascular compression: illustrative case.

BACKGROUND: Trigeminal neuralgia (TN) is a common neurosurgical issue that has a detrimental impact on patients' quality of life. Osteoma at the petrous apex is a rare etiology of TN. Here, the authors present a case involving the co-occurrence of petrous osteoma and a vascular loop around the trigeminal nerve. Both exerted pressure or compression on the exit of the trigeminal nerve. OBSERVATIONS: A 46-year-old male presented with a 3-year history of persistent severe pain in the right side of his face. Magnetic resonance tomographic angiography of the trigeminal nerve revealed an abnormal signal in the right prepontine cistern, along with a vascular loop accompanying the right trigeminal nerve. A computed tomography scan of the skull indicated a nodular calcified density. The combined anterior transpetrosal approach for petrous osteoma and microvascular decompression (MVD) for the offending vessel were successfully performed. The patient was discharged without any complications or facial pain. LESSONS: Although extremely rare, TN simultaneously secondary to petrous osteoma and offending vessels should be considered in the diagnosis. In this case, the combined surgical removal of petrous osteoma and MVD for the offending vessels proved to be an effective treatment for TN secondary to osteoma and vascular compression.

Experimental investigation and theoretical analysis of the breakdown time delay and jitter of multi-gap gas switch gaps.

The gas gap of a multi-gap gas switch can be classified as trigger and self-breakdown gaps based on the breakdown condition. A two-gap gas switch consisting of a trigger gap and a self-breakdown gap is developed to independently study the breakdown characteristics of these two types of switch gaps. Trigger experiments for the switch are conducted under various trigger voltage rise rates and different working coefficients. The experimental results indicate that the trigger gap has significantly more jitter than the self-breakdown gap, and the overall performance of the gas switch is determined primarily by the trigger gap. A novel pre-ionization structure with disks is implemented into the two-gap gas switch, considerably decreasing the breakdown delay of the trigger gap and reducing the jitter to a quarter or even less compared to that without pre-ionization. A calculation model of the breakdown time delay for the trigger gap is provided based on the foundational development of the avalanche. The probability distribution of the time required for the initial electron generation is derived in the absence of pre-ionization. The calculated breakdown time delay agrees well with the experimental results in cases with and without pre-ionization under most trigger settings. The method and principle of calculating the breakdown time delay can analyze the collapse of a gas gap with different electrode configurations (quasi-uniform or uniform electrical fields) and various gas media under a nanosecond pulse voltage.

Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.