Predicting distant metastasis in nasopharyngeal carcinoma using gradient boosting tree model based on detailed magnetic resonance imaging reports.

BACKGROUND: Development of distant metastasis (DM) is a major concern during treatment of nasopharyngeal carcinoma (NPC). However, studies have demonstrated improved distant control and survival in patients with advanced NPC with the addition of chemotherapy to concomitant chemoradiotherapy. Therefore, precise prediction of metastasis in patients with NPC is crucial. AIM: To develop a predictive model for metastasis in NPC using detailed magnetic resonance imaging (MRI) reports. METHODS: This retrospective study included 792 patients with non-distant metastatic NPC. A total of 469 imaging variables were obtained from detailed MRI reports. Data were stratified and randomly split into training (50%) and testing sets. Gradient boosting tree (GBT) models were built and used to select variables for predicting DM. A full model comprising all variables and a reduced model with the top-five variables were built. Model performance was assessed by area under the curve (AUC). RESULTS: Among the 792 patients, 94 developed DM during follow-up. The number of metastatic cervical nodes (30.9%), tumor invasion in the posterior half of the nasal cavity (9.7%), two sides of the pharyngeal recess (6.2%), tubal torus (3.3%), and single side of the parapharyngeal space (2.7%) were the top-five contributors for predicting DM, based on their relative importance in GBT models. The testing AUC of the full model was 0.75 (95% confidence interval [CI]: 0.69-0.82). The testing AUC of the reduced model was 0.75 (95%CI: 0.68-0.82). For the whole dataset, the full (AUC = 0.76, 95%CI: 0.72-0.82) and reduced models (AUC = 0.76, 95%CI: 0.71-0.81) outperformed the tumor node-staging system (AUC = 0.67, 95%CI: 0.61-0.73). CONCLUSION: The GBT model outperformed the tumor node-staging system in predicting metastasis in NPC. The number of metastatic cervical nodes was identified as the principal contributing variable.

Association Between Gut and Nasal Microbiota and Allergic Rhinitis: A Systematic Review.

Allergic rhinitis is a chronic non-infectious inflammation of the nasal mucosa mediated by specific IgE. Recently, the human microbiome has drawn broad interest as a potential new target for treating this condition. This paper succinctly summarizes the main findings of 17 eligible studies published by February 2024, involving 1044 allergic rhinitis patients and 954 healthy controls from 5 countries. These studies examine differences in the human microbiome across important mucosal interfaces, including the nasal and intestinal areas, between patients and controls. Overall, findings suggest variations in the gut microbiota between allergic rhinitis patients and healthy individuals, although the specific bacterial taxa that significantly changed were not always consistent across studies. Due to the limited scope of existing research and patient coverage, the relationship between the nasal microbiome and allergic rhinitis remains inconclusive. The article discusses the potential immune-regulating role of the gut microbiome in allergic rhinitis. Further well-designed clinical trials with large-scale recruitment of allergic rhinitis patients are encouraged.

Learning from the Codon Table: Convergent Recoding Provides Novel Understanding on the Evolution of A-to-I RNA Editing.

Adenosine-to-inosine (A-to-I) RNA editing recodes the genetic information. Apart from diversifying the proteome, another tempting advantage of RNA recoding is to correct deleterious DNA mutation and restore ancestral allele. Solid evidences for beneficial restorative editing are very rare in animals. By searching for "convergent recoding" under a phylogenetic context, we proposed this term for judging the potential restorative functions of particular editing site. For the well-known mammalian Gln>Arg (Q>R) recoding site, its ancestral state in vertebrate genomes was the pre-editing Gln, and all 470 available mammalian genomes strictly avoid other three equivalent ways to achieve Arg in protein. The absence of convergent recoding from His>Arg, or synonymous mutations on Gln codons, could be attributed to the strong maintenance on editing motif and structure, but the absence of direct A-to-G mutation is extremely unexpected. With similar ideas, we found cases of convergent recoding in Drosophila genus, reducing the possibility of their restorative function. In summary, we defined an interesting scenario of convergent recoding, the occurrence of which could be used as preliminary judgements for whether a recoding site has a sole restorative role. Our work provides novel insights to the natural selection and evolution of RNA editing.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

RNA-seq analysis reveals transcriptome reprogramming and alternative splicing during early response to salt stress in tomato root.

Salt stress is one of the dominant abiotic stress conditions that cause severe damage to plant growth and, in turn, limiting crop productivity. It is therefore crucial to understand the molecular mechanism underlying plant root responses to high salinity as such knowledge will aid in efforts to develop salt-tolerant crops. Alternative splicing (AS) of precursor RNA is one of the important RNA processing steps that regulate gene expression and proteome diversity, and, consequently, many physiological and biochemical processes in plants, including responses to abiotic stresses like salt stress. In the current study, we utilized high-throughput RNA-sequencing to analyze the changes in the transcriptome and characterize AS landscape during the early response of tomato root to salt stress. Under salt stress conditions, 10,588 genes were found to be differentially expressed, including those involved in hormone signaling transduction, amino acid metabolism, and cell cycle regulation. More than 700 transcription factors (TFs), including members of the MYB, bHLH, and WRKY families, potentially regulated tomato root response to salt stress. AS events were found to be greatly enhanced under salt stress, where exon skipping was the most prevalent event. There were 3709 genes identified as differentially alternatively spliced (DAS), the most prominent of which were serine/threonine protein kinase, pentatricopeptide repeat (PPR)-containing protein, E3 ubiquitin-protein ligase. More than 100 DEGs were implicated in splicing and spliceosome assembly, which may regulate salt-responsive AS events in tomato roots. This study uncovers the stimulation of AS during tomato root response to salt stress and provides a valuable resource of salt-responsive genes for future studies to improve tomato salt tolerance.

Ovarian function in patients with systemic lupus erythematosus: Pathogenesis, drug application and prospective therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women. Currently, glucocorticoids and immunosuppressants are widely used to treat SLE patients. However, ovarian dysfunction occurs following the use of these drugs in women with SLE. Here, we summarize recent progress in terms of understanding ovarian injury, the effects of drug application and strategies to improve ovarian function in women with SLE. This review could be helpful to precisely cure SLE in women desiring to have offspring.

An Anti-Scaling Strategy for Electrochemical Wastewater Treatment: Leveraging Tip-Enhanced Electric Fields.

Electrode scaling poses a critical barrier to the adoption of electrochemical processes in wastewater treatment, primarily due to electrode inactivation and increased internal reactor resistance. We introduce an antiscaling strategy using tip-enhanced electric fields to redirect scale-forming compounds (e.g., Mg(OH)2 and CaCO3) from the electrode-electrolyte interface to the bulk solution. Our study utilized Cu nanowires (Cu NW) with high-curvature nanostructures as the cathode, in contrast to Cu nanoparticles (Cu NP), Cu foil (CF), and Cu mesh (CM), to evaluate the electrochemical nitrate reduction reaction (NO3RR) performance in hard water conditions. The Cu NW/CF cathode demonstrated superior NO3RR efficiency, with an apparent rate constant (Kapp) of 1.04 h-1, significantly outperforming control electrodes under identical conditions (Kapp < 0.051 h-1). Through experimental and theoretical analysis, including COMSOL simulations, we show that the high-curvature design of Cu NW induced localized electric field enhancements, propelling OH- ions away from the electrode surface into the bulk solution, thus mitigating scale formation on the cathode. Testing with real nitrate-contaminated wastewater confirms that the Cu NW/CF cathode maintained excellent denitrification efficiency over a 60-day period. This study offers a promising perspective on preventing electrode scaling in electrochemical wastewater treatment, paving the way for more efficient and sustainable practices.

[Three-dimensional finite element analysis of lumbar disc herniation under different body positions].

OBJECTIVE: To campare biomechanical effects of different postural compression techniques on three-dimensional model of lumbar disc herniation (LDH) by finite element analysis. METHODS: Lumbar CT image of a 48-year-old female patient with LDH (heighted 163 cm, weighted 53 kg) was collected. Mimics 20.0, Geomagic Studio, Solidwords and other software were used to establish three-dimensional finite element model of LDH on L4,5 segments. Compression techniques under horizontal position, 30° forward bending and 10° backward extension were simulated respectively. After applying the pressure, the effects of compression techniques under different positions on stress, strain and displacement of various tissues of intervertebral disc and nerve root were observed. RESULTS: L4, 5 segment finite element model was successfully established, and the model was validated. When compression manipulation was performed on the horizontal position, 30° flexion and 10° extension, the annular stress were 0.732, 5.929, 1.286 MPa, the nucleus pulposus stress were 0.190, 1.527, 0.295 MPa, and the annular strain were 0.097, 0.922 and 0.424, the strain sizes of nucleus pulposus were 0.153, 1.222 and 0.282, respectively. The overall displacement distance of intervertebral disc on Y direction were -3.707, -18.990, -4.171 mm, and displacement distance of nerve root on Y direction were +7.836, +5.341, +3.859 mm, respectively. The relative displacement distances of nerve root and intervertebral disc on Y direction were 11.543, 24.331 and 8.030 mm, respectively. CONCLUSION: Compression manipulation could make herniated intervertebral disc produce contraction and retraction trend, by increasing the distance between herniated intervertebral disc and nerve root, to reduce symptoms of nerve compression, to achieve purpose of treatment for patients with LDH, in which the compression manipulation is more effective when the forward flexion is 30°.

The association between circulating leukocytes and inflammatory bowel disease: a two-sample Mendelian randomization study.

Background: Inflammatory bowel disease (IBD) is a highly prevalent, recurrent, chronic intestinal inflammatory disease. Several observational studies have shown that circulating leukocytes are strongly associated with IBD. However, whether alterations in leukocytes are causally related to IBD remains uncertain. The present study explores this issue with the Mendelian randomization (MR) analysis method. Methods: The Genome wide association study (GWAS) statistical data related to circulating leukocytes and IBD were obtained from the Blood Cell Consortium and the IEU Qpen GWAS project, respectively. Inverse variance weighting (IVW) was used as the main MR analytical method, coupled with a series of sensitivity analyses to ensure the reliability of the results. Results: The results of IVW showed that increased monocyte count (especially CD14- CD16+ monocyte absolute counts) was negatively correlated with the risk of IBD and its main subtypes. Increased neutrophil count was positively associated with the risk of IBD and ulcerative colitis. Meanwhile, there was no causal relationship between basophil, eosinophil, lymphocyte counts and IBD risk. Conclusion: These results indicate that a causal relationship exists between circulating leukocytes and the risk of IBD and its subtypes, which confirms the important role that the leukocyte immune system plays in IBD. Our findings provide additional research directions for the clinical prevention and treatment of IBD.

Extracellular vesicles derived from stored red blood cell suspensions enhance invasion and migration of lung cancer cells by miR1246 and miR150-3p.

BACKGROUND AND OBJECTIVES: Aged red blood cell (RBC) transfusions in lung cancer patients are often related to cancer recurrence and shorter lifespans. Extracellular vesicles (EVs) accumulated in stored RBC suspensions may be one of the important influential factors. This study aims to investigate how EVs derived from RBC suspensions affect the progress of lung cancer through the most enriched microRNAs (miRNAs) previously reported in our research. STUDY DESIGN AND METHODS: EVs derived from stored RBC suspensions in Weeks 1, 3 and 5 were harvested via ultracentrifugation. Lung adenocarcinoma H1975 cells were co-cultured with EVs and transfected with miR1246 and miR150-3p mimics to evaluate alterations in their proliferation, invasion and migration abilities in vitro. Proteomics and bioinformatics were performed to predict the signalling pathway related to invasion and migration of H1975, which were verified by western blotting (WB) and flow cytometry. RESULTS: EVs derived from stored RBC suspensions in Weeks 3 and 5 could significantly enhance the invasion and migration ability of H1975 cells and also increase the expression of miR1246 and miR150-3p. After transfection with miR1246 and miR150-3p mimics, invasion, migration and proliferation of H1975 cells were obviously enhanced. Proteomics analysis demonstrated that EVs co-cultivation and miRNA transfection groups were both enriched in cell adhesion molecules. WB and cytometry indicated that integrin beta-1 (ITGB1) and Rap1b were increased. CONCLUSIONS: EVs derived from stored RBC suspensions can enhance invasion and migration ability of lung cancer cells via the most accumulated miR1246 and miR150-3p, which may increase the expression of ITGB1 through Rap1 signalling pathway.

Does coevolution in refugia drive mimicry in bumble bees? Insights from a South Asian mimicry group.

Müllerian mimicry was proposed to be an example of a coevolved mutualism promoted by population isolation in glacial refugia. This, however, has not been well supported in butterfly models. Here, we use genomic data to test this theory while examining the population genetics behind mimetic diversification in a pair of co-mimetic bumble bees, Bombus breviceps Smith and Bombus trifasciatus Smith. In both lineages, populations were structured by geography but not as much by color pattern, suggesting sharing of color alleles across regions of restricted gene flow and formation of mimicry complexes in the absence of genetic differentiation. Demographic analyses showed mismatches between historical effective population size changes and glacial cycles, and niche modeling revealed only mild habitat retraction during glaciation. Moreover, mimetic subpopulations of the same color form in the two lineages only in some cases exhibit similar population history and genetic divergence. Therefore, the current study supports a more complex history in this comimicry than a simple refugium-coevolution model.

Grape seed extract prevents oestrogen deficiency-induced bone loss by modulating the gut microbiota and metabolites.

Proanthocyanidin-rich grape seed extract (GSE) has been shown to have the potential to protect bones, although the underlying mechanism remains unknown. The current study aims to explore GSE's preventive and therapeutic impact on bone loss induced by oestrogen deficiency and the underlying mechanism through the gut microbiota (GM) and metabolomic responses. In oestrogen-deficient ovariectomized (OVX) mice, GSE ameliorated bone loss by inhibiting the expansion of bone marrow adipose tissue (BMAT), restoring BMAT lipolysis and promoting bone formation. GSE regulated OVX-induced GM dysbiosis by reducing the abundance of opportunistic pathogenic bacteria, such as Alistipes, Turicibacter and Romboutsia, while elevating the abundance of beneficial bacteria, such as Bifidobacterium. The modified GM primarily impacted lipid and amino acid metabolism. Furthermore, the serum metabolites of GSE exhibited a significant enrichment in lipid metabolism. In summary, GSE shows potential as a functional food for preventing oestrogen deficiency-induced bone loss by modulating GM and metabolite-mediated lipid metabolism.

Research on the pharmacognostic characteristics, physicochemical properties and in vitro antioxidant potency of Rosa laxa Retz. flos.

Rosa laxa Retz. is an unexplored Rosaceae plant in Xinjiang, China, and its flower is traditionally used in Kazak to treat the common cold, fever, and epileptic seizures and lessen the effects of aging. In the present study, the pharmacognostic profiles, physicochemical properties, phytochemical characteristics, and in vitro antioxidant potency of Rosa laxa Retz. flos (RLF) were presented. In the pharmacognostic evaluation of RLF, organoleptic characteristics, internal structures, and powder information were observed, and physicochemical parameters, including moisture content, ash, pH value, swelling degree, and extractives were examined. The quantitative analysis of the chemical composition of four different polar extracts of RLF showed that the aqueous part had the highest total triterpene acid, flavonoid, and polyphenol content (4.50 ± 0.04 mg/g, 50.56 ± 0.03 mg/g, and 60.20 ± 0.09 mg/g, respectively). A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. In the set concentration range, the linear relationship among the four components was good (r > 0.999), the average recoveries were 97.36%-100.54%. The contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF samples were (9.46 ± 2.31) mg/g, (10.60 ±0.75) mg/g, (1.13 ± 2.50) mg/g, and (1.11 ± 2.65) mg/g, respectively. The types of its secondary metabolites were determined by fluorescence, color reaction by chemical solvent method, and ultraviolet-visible (UV-Vis) spectroscopy. The functional groups of its secondary metabolites were determined by Fourier transform infrared (FTIR) spectroscopy. Results showed that RLF contains a variety of secondary metabolic products, including flavonoids, phenolic acid, glycoside, and organic acid. TLC identification showed it contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol-3-O-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of different polar parts of RLF was investigated by DPPH, ABTS, and reduction performance experiments. The aqueous extract had the strongest antioxidant capacity, consistent with the high content of triterpene acids, flavonoids, and polyphenolic compounds. These findings will provide critical information for the study of quality standards and medicinal value of RLF and its extracts, justify its usage in traditional medicinal systems, and encourage the use of this plant in disease prevention and treatment. Its phytochemical composition and pharmacological studies need to be explored in future. RESEARCH HIGHLIGHTS: Optical microscope and scanning electron microscope (SEM) were used to observe the morphology, and microstructure of Rosa laxa Retz. flos (RLF). The physicochemical properties, fluorescence and phytochemical composition of four different polar extracts of RLF were analyzed by UV-Vis and FTIR. Determination of total triterpenic acid, total flavonoids, and total polyphenols in four different polar extracts of RLF by UV spectrophotometry. A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. TLC confirmed that RLF contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol 3-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of RLF was studied by DPPH, ABTS, and reducing ability experiments.

Interfamily Grafted Hybrids Vitis vinifera/Schisandra chinensis Resulted in Transcriptomic, Phenotypic, and Metabolic Changes.

Long-distance transfer of genetic material and metabolites between rootstock and scions is well documented in homo-grafted hybrids but has rarely been reported in genetically-distant grafts where the rootstock and scion belong to different families. In this study, we grafted Vitis vinifera scions onto Schisandra chinensis stocks and obtained 20 vegetative hybrids, Vitis vinifera/Schisandra chinensis (Vs). After 25 years of growth, we found that the phenotypes of the leaves, internodes, and fruits of the Vs hybrids above the graft union resembled an intermediate phenotype between V. vinifera and S. chinensis, and the new traits were stable when propagated vegetatively. We further analyzed genetic differences between Vv plants and Vs hybrids using high-throughput sequencing, while metabolomes were analyzed by liquid chromatography-mass spectrometry (LC-MS). We found a total of 2113 differentially expressed genes (DEGs). GO annotation and KEGG pathway enrichment analysis showed that these DEGs enriched mainly in oxidation-reduction and metabolic processes. Seventy-nine differentially expressed miRNAs (DEMs) containing 27 known miRNAs and 52 novel miRNAs were identified. A degradation analysis detected 840 target genes corresponding to 252 miRNAs, of which 12 DEMs and their corresponding target gene expression levels were mostly negatively correlated. Furthermore, 1188 differential metabolic compounds were identified. In particular, in Vs hybrids, the abundance of the metabolites schizandrin and gomisin as the main medicinal ingredients in S. chinensis were down-regulated and up-regulated, respectively. Our data demonstrated the effects of interfamily grafts on the phenotype, transcript profile and metabolites of the scion, and also provided new insight into the genetic, phenotypic, and metabolic plasticity associated with genetically distant grafted hybrids.

Treatment and nursing care of a patient diagnosed with malignant hyperthermia after general anesthesia: a case report.

Malignant hyperthermia (MH), characterized by severe myoclonus, pyrexia, tachycardia, hypertension, elevated muscle enzymes, and hypercapnia, often occurs in patients with congenital deformities or genetic disorders. Although the reported incidence rate is as low as 1:5000 to 1:100,000, patients with MH exhibit rapid aggravation and an elevated mortality rate. Thus, MH is associated with substantial perioperative risk. Successful treatment of patients with MH largely depends on early diagnosis and timely effective treatment. This clinical report provides a detailed description of a patient with newly diagnosed MH who developed a rapid rise in body temperature, end-tidal carbon dioxide, and heart rate during maxillary osteotomy. After successful rescue, the patient recovered smoothly during the postoperative period, indicating the importance of intraoperative monitoring, early diagnosis, effective treatment, and postoperative monitoring. This case is expected to serve as a reference for future interventions and healthcare practices in managing other patients with MH.

[The Identification Idea of Antibodies Against Ku and Other High-Frequency Antigens].

OBJECTIVE: This study was aimed to provide ideas for identifying the antibodies to high-frequency antigens by analyzing a female case of high-frequency antigen antibody (anti-Ku) using serological and sequencing method. METHODS: The methods for identification of blood group, erythrocyte antigen, screening and identification of antibody were used to detect the blood type and antibody in the proband. The proband's serum and reagent screening cells treated with Sulfhydryl reagent were applied to judge the type and characteristics of this antibodies when reacted with the regaent screening cells or proband's serum respectively. Gene sequencing was used to determine the genotype of the proband's blood group. RESULTS: The proband's red blood cells were determined as O type RhD positive, whose serum showed strong positive reaction to antibody-screening cells and antibody identification cells with the same intensity in saline and IAT medium, however, the self-cells showed negative effect. The Direct Antihuman Globulin of proband's red blood cells also showed weak positive reaction, and the other blood types were CcEe, Jk(a+b-), P1-, Le(a-b -), Lu (a-b +), K-, k-, Kp(a-b-). Serum of the proband treated with 2-ME still react with three groups of screening cells in IAT medium. The reaction intensity of proband's serum was also unchanged with the cells modified with papain and bromelain, but showed negative effect when the cells were treated with sulfhydryl agents including DTT and 2-ME. Gene sequencing revealed that the KEL genotype of the patient was KEL*02N.24 . This patient had a rare K0 phenotype. CONCLUSION: The rare Kell-null blood group (also known as K0) were identified by serological and molecular tests in the proband who produced both IgG and IgM type of antibody to high-frequency antigen (anti-Ku). These two methods are of great significance in the identification of this rare blood group as well as the antibody to high frequency antigen.

Phelligridimer A enhances the expression of mitofusin 2 and protects against cerebral ischemia/reperfusion injury.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play pivotal roles in the pathology of cerebral ischemia. In this study, we investigated whether phelligridimer A (PA), an active compound isolated from the medicinal and edible fungus Phellinus igniarius, ameliorates ischemic cerebral injury by restoring mitochondrial function and restricting ER stress. An in vitro cellular model of ischemic stroke-induced neuronal damage was established by exposing HT-22 neuronal cells to oxygen-glucose deprivation/reoxygenation (OGD/R). An in vivo animal model was established in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The results showed that PA (1-10 µM) dose-dependently increased HT-22 cell viability, reduced OGD/R-induced lactate dehydrogenase release, and reversed OGD/R-induced apoptosis. PA reduced OGD/R-induced accumulation of reactive oxygen species, restored mitochondrial membrane potential, and increased ATP levels. Additionally, PA reduced the expression of the 78-kDa glucose-regulated protein (GRP78) and the phosphorylation of inositol-requiring enzyme-1α (p-IRE1α) and eukaryotic translation-initiation factor 2α (p-eIF2α). PA also inhibited the activation of the mitogen-activated protein kinase (MAPK) pathway in the OGD/R model. Moreover, treatment with PA restored the expression of mitofusin 2 (Mfn-2), a protein linking mitochondria and ER. The silencing of Mfn-2 abolished the protective effects of PA. The results from the animal study showed that PA (3-10 mg/kg) significantly reduced the volume of cerebral infarction and neurological deficits, which were accompanied by an increased level of Mfn-2, and decreased activation of the ER stress in the penumbra of the ipsilateral side after MCAO/R in rats. Taken together, these results indicate that PA counteracts cerebral ischemia-induced injury by restoring mitochondrial function and reducing ER stress. Therefore, PA might be a novel protective agent to prevent ischemia stroke-induced neuronal injury.

Hydrogen sulfide maintains mitochondrial homeostasis and regulates ganoderic acids biosynthesis by SQR under heat stress in Ganoderma lucidum.

Hydrogen sulfide (H2S) has recently been recognized as an important gaseous transmitter with multiple physiological effects in various species. Previous studies have shown that H2S alleviated heat-induced ganoderic acids (GAs) biosynthesis, an important quality index of Ganoderma lucidum. However, a comprehensive understanding of the physiological effects and molecular mechanisms of H2S in G. lucidum remains unexplored. In this study, we found that heat treatment reduced the mitochondrial membrane potential (MMP) and mitochondrial DNA copy number (mtDNAcn) in G. lucidum. Increasing the intracellular H2S concentration through pharmacological and genetic means increased the MMP level, mtDNAcn, oxygen consumption rate level and ATP content under heat treatment, suggesting a role for H2S in mitigating heat-caused mitochondrial damage in G. lucidum. Further results indicated that H2S activates sulfide-quinone oxidoreductase (SQR) and complex III (Com III), thereby maintaining mitochondrial homeostasis under heat stress in G. lucidum. Moreover, SQR also mediated the negative regulation of H2S to GAs biosynthesis under heat stress. Furthermore, SQR might be persulfidated under heat stress in G. lucidum. Thus, our study reveals a novel physiological function and molecular mechanism of H2S signalling under heat stress in G. lucidum with broad implications for research on the environmental response of microorganisms.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Daldiconoids A-G: 3,4-Secolanostane triterpenoids from the fruiting bodies of Daldinia concentrica and their anti-inflammatory activity.

Seven undescribed 3,4-secolanostane triterpenoids, daldiconoids A-G (1-7), were isolated from the fruiting bodies of Daldinia concentrica. Daldiconoid A (1) was a highly modified 4,6,28,29-tetranorlanostane triterpenoid alkaloid featuring an unusual δ-lactam fused with a flanking cyclopentenone architecture. Their structures were determined by spectroscopic data, NMR calculations coupled with the DP4+ analysis, X-ray single-crystal diffraction, and chemical transformation. The plausible biosynthetic pathway for 1 was proposed. Compounds 1, 2, and 4-6 inhibited the expressions of IL-1ß, IL-6, and TNF-α in lipopolysaccharide stimulated RAW264.7 cells at a concentration of 10 µM. Mechanistically, Compounds 1 and 2 blocked the JAK2/STAT3 signaling pathway induced by lipopolysaccharide.