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.

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.

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.

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.

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.

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.

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.

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.

[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°.

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.

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.

[Characterization of Metal Elements in Atmospheric Fine Particulate Matter and Their Sources in Winter in the Southern Sichuan Urban Agglomeration].

To investigate the concentration characteristics and sources of metal elements in PM2.5 during winter heavy pollution in the southern Sichuan urban agglomeration (Zigong, Luzhou, Neijiang, and Yibin), the metal elements in PM2.5 were measured using membrane sampling methods from December 30, 2018 to January 14, 2019, and the enrichment factor method (EF) and positive matrix factorization(PMF) were applied to investigate the sources of metal elements. The metal element observation data of Zigong in the same period of 2015 were also used to investigate the changes in metal element pollution and enrichment in Zigong in the middle and end of the implementation of China's Air Pollution Prevention and Control Action Plan. The main findings were as follows:① The concentrations and percentages of metal elements in particulate matter in different cities did not differ significantly. The elements with higher concentrations in the four cities showed similarities, with Al, Sb, and Fe at the top. From the comparison of different observation periods in Zigong, the concentrations of all elements except Tl changed. ② The results of the enrichment factor calculation showed that the enrichment of the elements Cr (Zigong and Yibin), Ni, Cu, As, Se, Ag, Cd, Sb, Tl, and Pb in the urban agglomeration was high. The comparison of the enrichment levels of elements in Zigong for different observation periods showed that the enrichment levels of all elements, except Cu, tended to decrease in the winter observation period of 2018. ③ The results of PMF source analysis showed that the metal elements in each city mainly originated from dust sources, coal-fired sources, industrial sources, and traffic sources, whereas there was a mixed contribution among the sources. The contribution of the main sources differed among cities, in which Zigong was dominated by traffic dust sources and mixed sources, Luzhou was dominated by industrial sources, Neijiang had a similar contribution from different sources, and Yibin was dominated by traffic sources.

Biomimetic Leaf-Vein Aerogel for Electromagnetic Wave Absorption and Thermal Superinsulation.

Electromagnetic protection in extreme environments requires materials with excellent thermal insulation capability and mechanical property to withstand severe temperature fluctuations and complex external stresses. Achieving strong electromagnetic wave absorption (EMA) while sustaining these exceptional properties remains a significant challenge. Herein, a facile approach is demonstrated to fabricate a biomimetic leaf-vein MXene/CNTs/PI (MCP) aerogel with parallel venations through bidirectional freeze-casting method. Due to its multi-arch lamellar structure and parallel venations within the aerogel layers, the ultralight MCP aerogel (16.9 mg·cm-3) achieves a minimum reflection loss (RLmin) of -75.8 dB and a maximum effective absorption bandwidth (EABmax) of 7.14 GHz with an absorber content of only 2.4 wt%, which also exhibits superelasticity and structural stability over a wide temperature range from -196 to 400 °C. Moreover, this unique structure facilitates rapid heat dissipation within the layers, while significantly impeding heat transfer between adjacent layers, achieving an ultralow thermal conductivity of 15.3 mW·m-1·K-1 for thermal superinsulation. The combination of excellent EMA performance, robust structural stability, and thermal superinsulation provides a potential design scheme under extreme conditions, especially in aerospace applications.

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.

Metagenomic approach revealed the mobility and co-occurrence of antibiotic resistomes between non-intensive aquaculture environment and human.

BACKGROUND: Aquaculture is an important food source worldwide. The extensive use of antibiotics in intensive large-scale farms has resulted in resistance development. Non-intensive aquaculture is another aquatic feeding model that is conducive to ecological protection and closely related to the natural environment. However, the transmission of resistomes in non-intensive aquaculture has not been well characterized. Moreover, the influence of aquaculture resistomes on human health needs to be further understood. Here, metagenomic approach was employed to identify the mobility of aquaculture resistomes and estimate the potential risks to human health. RESULTS: The results demonstrated that antibiotic resistance genes (ARGs) were widely present in non-intensive aquaculture systems and the multidrug type was most abundant accounting for 34%. ARGs of non-intensive aquaculture environments were mainly shaped by microbial communities accounting for 51%. Seventy-seven genera and 36 mobile genetic elements (MGEs) were significantly associated with 23 ARG types (p < 0.05) according to network analysis. Six ARGs were defined as core ARGs (top 3% most abundant with occurrence frequency > 80%) which occupied 40% of ARG abundance in fish gut samples. Seventy-one ARG-carrying contigs were identified and 75% of them carried MGEs simultaneously. The qacEdelta1 and sul1 formed a stable combination and were detected simultaneously in aquaculture environments and humans. Additionally, 475 high-quality metagenomic-assembled genomes (MAGs) were recovered and 81 MAGs carried ARGs. The multidrug and bacitracin resistance genes were the most abundant ARG types carried by MAGs. Strikingly, Fusobacterium_A (opportunistic human pathogen) carrying ARGs and MGEs were identified in both the aquaculture system and human guts, which indicated the potential risks of ARG transfer. CONCLUSIONS: The mobility and pathogenicity of aquaculture resistomes were explored by a metagenomic approach. Given the observed co-occurrence of resistomes between the aquaculture environment and human, more stringent regulation of resistomes in non-intensive aquaculture systems may be required. Video Abstract.

Immunotherapy combined with antiangiogenic therapy as third- or further-line therapy for stage IV non-small cell lung cancer patients with ECOG performance status 2: A retrospective study.

BACKGROUND: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2. METHODS: In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. RESULTS: Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths. CONCLUSIONS: Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.

SIRT5-Mediated Desuccinylation of RAB7A Protects Against Cadmium-Induced Alzheimer's Disease-Like Pathology by Restoring Autophagic Flux.

Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of autophagy on environmental Cd-induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd-impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aß deposition and memory deficits, and the desuccinylation of RAB7A in Cd-exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in other cell clusters in the brains of AD patients according to single-nucleus RNA sequencing data from the public dataset GSE188545. This study reveals that SIRT5-catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd-induced autophagic flux blockade and AD-like pathogenesis.

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.

Conserved A-to-I RNA editing with non-conserved recoding expands the candidates of functional editing sites.

Adenosine-to-inosine (A-to-I) RNA editing recodes the genome and confers flexibility for the organisms to adapt to the environment. It is believed that RNA recoding sites are well suited for facilitating adaptive evolution by increasing the proteomic diversity in a temporal-spatial manner. The function and essentiality of a few conserved recoding sites are recognized. However, the experimentally discovered functional sites only make up a small corner of the total sites, and there is still the need to expand the repertoire of such functional sites with bioinformatic approaches. In this study, we define a new category of RNA editing sites termed 'conserved editing with non-conserved recoding' and systematically identify such sites in Drosophila editomes, figuring out their selection pressure and signals of adaptation at inter-species and intra-species levels. Surprisingly, conserved editing sites with non-conserved recoding are not suppressed and are even slightly overrepresented in Drosophila. DNA mutations leading to such cases are also favoured during evolution, suggesting that the function of those recoding events in different species might be diverged, specialized, and maintained. Finally, structural prediction suggests that such recoding in potassium channel Shab might increase ion permeability and compensate the effect of low temperature. In conclusion, conserved editing with non-conserved recoding might be functional as well. Our study provides novel aspects in considering the adaptive evolution of RNA editing sites and meanwhile expands the candidates of functional recoding sites for future validation.

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.