Genome-wide analysis of the passion fruit invertase gene family reveals involvement of PeCWINV5 in hexose accumulation.

BACKGROUND: Invertases (INVs) are key enzymes in sugar metabolism, cleaving sucrose into glucose and fructose and playing an important role in plant development and the stress response, however, the INV gene family in passion fruit has not been systematically reported. RESULTS: In this study, a total of 16 PeINV genes were identified from the passion fruit genome and named according to their subcellular location and chromosome position. These include six cell wall invertase (CWINV) genes, two vacuolar invertase (VINV) genes, and eight neutral/alkaline invertase (N/AINV) genes. The gene structures, phylogenetic tree, and cis-acting elements of PeINV gene family were predicted using bioinformatics methods. Results showed that the upstream promoter region of the PeINV genes contained various response elements; particularly, PeVINV2, PeN/AINV3, PeN/AINV5, PeN/AINV6, PeN/AINV7, and PeN/AINV8 had more response elements. Additionally, the expression profiles of PeINV genes under different abiotic stresses (drought, salt, cold temperature, and high temperature) indicated that PeCWINV5, PeCWINV6, PeVINV1, PeVINV2, PeN/AINV2, PeN/AINV3, PeN/AINV6, and PeN/AINV7 responded significantly to these abiotic stresses, which was consistent with cis-acting element prediction results. Sucrose, glucose, and fructose are main soluble components in passion fruit pulp. The contents of total soluble sugar, hexoses, and sweetness index increased significantly at early stages during fruit ripening. Transcriptome data showed that with an increase in fruit development and maturity, the expression levels of PeCWINV2, PeCWINV5, and PeN/AINV3 exhibited an up-regulated trend, especially for PeCWINV5 which showed highest abundance, this correlated with the accumulation of soluble sugar and sweetness index. Transient overexpression results demonstrated that the contents of fructose, glucose and sucrose increased in the pulp of PeCWINV5 overexpressing fruit. It is speculated that this cell wall invertase gene, PeCWINV5, may play an important role in sucrose unloading and hexose accumulation. CONCLUSION: In this study, we systematically identified INV genes in passion fruit for the first time and further investigated their physicochemical properties, evolution, and expression patterns. Furthermore, we screened out a key candidate gene involved in hexose accumulation. This study lays a foundation for further study on INV genes and will be beneficial on the genetic improvement of passion fruit breeding.

OsWRKY70 Plays Opposite Roles in Blast Resistance and Cold Stress Tolerance in Rice.

The transcription factor WRKYs play pivotal roles in the adapting to adverse environments in plants. Prior research has demonstrated the involvement of OsWRKY70 in resistance against herbivores and its response to abiotic stress. Here, we reported the functional analysis of OsWRKY70 in immunity against fungal diseases and cold tolerance. The results revealed that OsWRKY70 was induced by various Magnaporthe oryzae strains. Knock out mutants of OsWRKY70, which were generated by the CRISPR/Cas9 system, exhibited enhanced resistance to M. oryzae. This was consistent with fortifying the reactive oxygen species (ROS) burst after inoculation in the mutants, elevated transcript levels of defense-responsive genes (OsPR1b, OsPBZ1, OsPOX8.1 and OsPOX22.3) and the observation of the sluggish growth of invasive hyphae under fluorescence microscope. RNA sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) validations demonstrated that differentially expressed genes were related to plant-pathogen interactions, hormone transduction and MAPK cascades. Notably, OsbHLH6, a key component of the JA signaling pathway, was down-regulated in the mutants compared to wild type plants. Further investigation confirmed that OsWRKY70 bound to the promoter of OsbHLH6 by semi-in vivo chromatin immunoprecipitation (ChIP). Additionally, the loss-function of OsWRKY70 impaired cold tolerance in rice. The enhanced susceptibility in the mutants characterized by excessive ROS production, elevated ion leakage rate and increased malondialdehyde content, as well as decreased activity of catalase (CAT) and peroxidase (POD) under low temperature stress was, which might be attributed to down-regulation of cold-responsive genes (OsLti6b and OsICE1). In conclusion, our findings indicate that OsWRKY70 negatively contributes to blast resistance but positively regulates cold tolerance in rice, providing a strategy for crop breeding with tolerance to stress.

Golden Flower Tibetan Tea Polysaccharides Alleviate Constipation in Mice by Regulating Aquaporins-Mediated Water Transport System and Gut Microbiota.

Constipation, a widespread gastrointestinal disorder, often leads to the exploration of natural remedies. This study examines the efficacy of Golden Flower Tibetan Tea Polysaccharides (GFTTPs) in alleviating constipation in mice. Chemical analyses reveal that GFTTPs possess O-H, carboxyl, carboxylic acid (-COOH), and C-O-C groups, alongside a porous crystal structure with thermal stability. In animal experiments, GFTTPs significantly upregulated aquaporin 3 (AQP3) and aquaporin 8 (AQP8) expressions in the colon, enhancing water absorption and reducing fecal water content. At a 400 mg/kg dosage, GFTTPs notably improved colonic tissue alterations and serum levels of excitatory neurotransmitters caused by loperamide hydrochloride. They also beneficially altered gut microbiota, increasing Coprococcus, Lactobacillus, and Pediococcus populations. These changes correlated with improved stool frequency, consistency, and weight in constipated mice. Importantly, GFTTPs at 200 and 400 mg/kg doses exhibited comparable effects to the normal control group in key parameters, such as gastrointestinal transit rate and fecal moisture. These findings suggest that GFTTPs may serve as a potent natural remedy for constipation, offering significant therapeutic potential within the context of gut health and with promising implications for human applications.

Overexpression of OsRbohH Enhances Heat and Drought Tolerance through ROS Homeostasis and ABA Mediated Pathways in Rice (Oryza sativa L.).

Respiratory burst oxidase homologs (Rbohs) are the primary producers of reactive oxygen species (ROS), which have been demonstrated to play critical roles in plant responses to abiotic stress. Here, we explored the function of OsRbohH in heat and drought stress tolerance by generating overexpression lines (OsRbohH-OE). OsRbohH was highly induced by various abiotic stress and hormone treatments. Compared to wild-type (WT) controls, OsRbohH-OE plants exhibited enhanced tolerance to heat and drought, as determined by survival rate analyses and total chlorophyll content. Histochemical staining revealed that OsRbohH-OE accumulated less ROS. This is consistent with the observed increase in catalase (CAT) and peroxidase (POD) activities, as well as a reduced electrolyte leakage rate and malondialdehyde (MDA) content. Moreover, OsRbohH-OE exhibited enhanced sensitivity to exogenous abscisic acid (ABA), accompanied by altered expression levels of ABA synthesis and catabolic genes. Further analysis indicated that transgenic lines had lower transcripts of ABA signaling-related genes (OsDREB2A, OsLEA3, OsbZIP66, and OsbZIP72) under heat but higher levels under drought than WT. In conclusion, these results suggest that OsRbohH is a positive regulator of heat and drought tolerance in rice, which is probably performed through OsRbohH-mediated ROS homeostasis and ABA signaling.

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM.

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenograms and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

Improving Perovskite Solar Cell Performance and Stability via Thermal Imprinting-Assisted Ion Exchange Passivation.

The latest development in perovskite solar cell (PSC) technology has been significantly influenced by advanced techniques aimed at passivating surface defects. This work presents a new approach called thermal imprinting-assisted ion exchange passivation (TIAIEP), which delivers a different approach to conventional solution-based methods. TIAIEP focuses on addressing surface imperfections in solid-state films by using a passivator that promotes ion exchange specifically at the defect sites within the perovskite layer. By adjusting the time and temperature of the TIAIEP process, we achieve substantial enhancement in the creation of a compositional gradient within the films. This optimization slows the cooling rate of hot carriers, leading to minimizing charge recombination and improving the device performance. Remarkably, devices treated with TIAIEP achieve a 22.29% power conversion efficiency and show outstanding stability, with unencapsulated PSCs maintaining 91% of their original efficiency after over 2000 h of storage and 90% efficiency after 1200 h of constant illumination. These results highlight TIAIEP's effectiveness in mitigating surface defects, improving both the photoelectric and stability performance of PSCs, and indicating significant potential for large-scale application in perovskite film passivation, promoting the widespread adoption of this technology.

Directly Characterizing the Capture Radius of Tethered Double-Stranded DNA by Single-Molecule Nanopipette Manipulation.

The tethered molecule exhibits characteristics of both free and fixed states, with the electrodynamics involved in its diffusion, electrophoresis, and stretching processes still not fully understood. We developed a Single-Molecule Manipulation, Identification, and Length Examination (SMILE) system by integrating piezoelectric devices with nanopipettes. This system enabled successful capture and stretching of tethered double-stranded DNA within the nanopore. Our research unveiled distinct capture (rcapture) and stretch radii (rstretch) surrounding the DNA's anchor point. Notably, consistent ratios of capture radius for DNA of varying lengths (2k, 4k, and 6k base pairs) were observed across different capturing voltages, approximately 1:1.4:1.83, showing a resemblance to their gyration radius ratios. However, the ratios of stretch radius are consistent to their contour length (L0), with the stretching ratio (rstretch/L0) increasing from 70 to 90% as the voltage rose from 100 to 1000 mV. Additionally, through numerical simulations, we identified the origin of capture and stretch radii, determined by the entropic elasticity-induced capture barrier and the electric field-dominant escape barrier. This research introduces an innovative methodology and outlines research perspectives for a comprehensive exploration of the conformational, electrical, and diffusion characteristics of tethered molecules.

Single cell RNA-sequencing delineates CD8+ tissue resident memory T cells maintaining rejection in liver transplantation.

Rationale: Understanding the immune mechanisms associated with liver transplantation (LT), particularly the involvement of tissue-resident memory T cells (TRMs), represents a significant challenge. Methods: This study employs a multi-omics approach to analyse liver transplant samples from both human (n = 17) and mouse (n = 16), utilizing single-cell RNA sequencing, bulk RNA sequencing, and immunological techniques. Results: Our findings reveal a comprehensive T cell-centric landscape in LT across human and mouse species, involving 235,116 cells. Notably, we found a substantial increase in CD8+ TRMs within rejected grafts compared to stable ones. The elevated presence of CD8+ TRMs is characterised by a distinct expression profile, featuring upregulation of tissue-residency markers (CD69, CXCR6, CD49A and CD103+/-,), immune checkpoints (PD1, CTLA4, and TIGIT), cytotoxic markers (GZMB and IFNG) and proliferative markers (PCNA and TOP2A) during rejection. Furthermore, there is a high expression of transcription factors such as EOMES and RUNX3. Functional assays and analyses of cellular communication underscore the active role of CD8+ TRMs in interacting with other tissue-resident cells, particularly Kupffer cells, especially during rejection episodes. Conclusions: These insights into the distinctive activation and interaction patterns of CD8+ TRMs suggest their potential utility as biomarkers for graft rejection, paving the way for novel therapeutic strategies aimed at enhancing graft tolerance and improving overall transplant outcomes.

CircRNA-Phf21a_0002 promotes pyroptosis to aggravate hepatic ischemia/ reperfusion injury by sponging let-7b-5p.

Hepatic ischemia‒reperfusion injury is a common injury in liver surgery and liver transplantation that can lead to liver function damage, including oxidative stress, apoptosis, autophagy and inflammatory reactions. Pyroptosis is a type of inflammatory programmed cell death that has been implicated in ischemia‒reperfusion injury-associated inflammatory reactions. Although circular RNAs can regulate cell death in hepatic ischemia‒reperfusion injury, their relationship with pyroptosis remains unclear. Therefore, this study aimed to investigate the effect of circular RNA on pyroptosis in hepatic ischemia‒reperfusion injury. We constructed a mouse hepatic ischemia‒reperfusion injury model for circular RNA sequencing and obtained 40 circular RNAs with significant differential expression, of which 39 were upregulated and 1 was downregulated. Subsequently, the endogenous competitive RNA network was constructed using TarBase, miRTarBase, TargetScan, RNAhybrid, and miRanda. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology functional analyses of downstream target genes revealed that circRNA-Phf21a_0002 might affect pyroptosis by regulating the mTOR signaling pathway and Bach1 by sponging let-7b-5p. The overexpression plasmid upregulated the expression of circRNA-Phf21a_0002 in a hypoxia/reoxygenation model, which aggravated pyroptosis in AML12 cells and apoptosis and necrosis of hepatocytes. Next, we investigated the underlying mechanism and found that circRNA-Phf21a_0002 enabled the expression of Bach1 through sponging of let-7b-5p. The aggravation of pyroptosis via overexpression of circRNA-Phf21a_0002 was reversed by let-7b-5p mimics in hypoxia/reoxygenation-subjected AML12 cells. Collectively, our study clarifies that circRNA-Phf21a_0002 aggravates the pyroptosis of hepatocytes related to ischemia-reperfusion by sponging let-7b-5p. These findings provide new molecular mechanisms and novel biomarkers for follow-up treatment.

Effects of aripiprazole on prolactin levels and differences in effectiveness in patients with schizophrenia: a post-hoc analysis of the real-world data of a multicenter study.

Objectives: To investigate the effect of aripiprazole on prolactin levels in patients with schizophrenia and analyze whether varying baseline prolactin levels affect the effectiveness and safety of aripiprazole, in a real-life diagnostic and therapeutic setting in a post-hoc analysis. Methods: In this post-hoc analysis, patients with schizophrenia in the acute phase were divided into an elevated-prolactin group and a normal-prolactin group. After 8 weeks of aripiprazole treatment, changes in the proportion of patients with an abnormal prolactin level were analyzed in both groups, and the efficacy and safety of aripiprazole were compared between the two groups. Results: The elevated-prolactin group had more women, a longer duration of disease, and lower Positive and Negative Syndrome Scale (PANSS) total and subscale scores at baseline compared with the normal-prolactin group (all P < 0.05), and there was no significant difference in the proportion of patients with prior use of antipsychotic medication between the two groups. Regardless of previous antipsychotic use, patients in both groups developed hyperprolactinemia (23/168 [13.7%] in those who had taken antipsychotics vs. 43/375 [11.4%] in those who had not). After 8 weeks of aripiprazole treatment, the proportion of patients with abnormal prolactin in the elevated-prolactin group significantly decreased with prolonged treatment (P < 0.001), and aripiprazole had no significant effect on the normal-prolactin group (P = 0.250). Normal-prolactin group showed better efficacy than the elevated-prolactin group, and the differences in efficacy between the two groups was observed from week 4 to the endpoint (all p<0.05). In total, 87.2% (68/78) patients experienced mild to moderate adverse events in the elevated-prolactin group, which was significantly more frequent compared with the normal-prolactin group 71.0% (365/514). Conclusions: In this real-world study, for patients with acute schizophrenia, aripiprazole was effective in lowering the proportion of patients with abnormal prolactin levels, while it had no significant effect on patients with normal baseline prolactin. After adjusting for factors such as sex, age, prior antipsychotic drugs use history and disease severity, effectiveness and safety of aripiprazole in patients with normal baseline prolactin was significantly better than that in patients with elevated baseline prolactin.

Neoadjuvant camrelizumab followed by concurrent camrelizumab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: a single-arm, phase II study.

Background: Neoadjuvant therapy combining camrelizumab with chemotherapy has emerged as a promising approach for treating locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal strategy for integrating immunotherapy with chemotherapy remains to be fully defined. This single-arm phase II study aimed to evaluate the efficacy and safety of neoadjuvant therapy with camrelizumab induction followed by camrelizumab plus chemotherapy in locally advanced ESCC. Methods: Patients with clinical stage cT2-4N0M0 or cTxN1-3M0 ESCC were enrolled in the study. Patients received one dose of camrelizumab (200 mg) followed by docetaxel (75 mg/m2) and nedaplatin (75 mg/m2) plus camrelizumab (200 mg) every 3 weeks for two cycles, and then underwent surgery within 3-4 weeks. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints included the pathological complete response (pCR) rate, R0 resection rate, downstaging rate, disease-free survival (DFS), overall survival (OS), and safety. Results: In total, 55 patients were enrolled in the study between 16 April 2020 and 30 October 2021. Of these 55 patients, 53 (96.4%) completed neoadjuvant therapy, and 48 (87.3%) underwent surgery. The MPR rate was 77.1% [37/48, 95% confidence interval (CI): 62.7-88.0%]. The pCR (ypT0N0) rate was 39.6% (19/48, 95% CI: 25.8-54.7%). All the patients had R0 resections. Primary tumor downstaging occurred in 44 (91.7%) patients, and nodal downstaging occurred in 19 (39.6%) patients. The 2-year DFS rate was 68.9% (95% CI: 53.0-80.4%), and the 2-year OS rate was 74.7% (95% CI: 60.2-84.6%). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 7 (12.7%) patients. Conclusions: In conclusion, neoadjuvant camrelizumab followed by camrelizumab plus chemotherapy showed promising efficacy in treating locally advanced ESCC and had a manageable safety profile.

Innovative integration of lung ultrasound and wearable monitoring for predicting pulmonary complications in colorectal surgery: A prospective study.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common in patients who undergo colorectal surgery. Studies have focused on how to accurately diagnose and reduce the incidence of PPCs. Lung ultrasound has been proven to be useful in preoperative monitoring and postoperative care after cardiopulmonary surgery. However, lung ultrasound has not been studied in abdominal surgeries and has not been used with wearable devices to evaluate the influence of postoperative ambulation on the incidence of PPCs. AIM: To investigate the relationship between lung ultrasound scores, PPCs, and postoperative physical activity levels in patients who underwent colorectal surgery. METHODS: In this prospective observational study conducted from November 1, 2019 to August 1, 2020, patients who underwent colorectal surgery underwent daily bedside ultrasonography from the day before surgery to postoperative day (POD) 5. Lung ultrasound scores and PPCs were recorded and analyzed to investigate their relationship. Pedometer bracelets measured the daily movement distance for 5 days post-surgery, and the correlation between postoperative activity levels and lung ultrasound scores was examined. RESULTS: Thirteen cases of PPCs was observed in the cohort of 101 patients. The mean (standard deviation) peak lung ultrasound score was 5.32 (2.52). Patients with a lung ultrasound score of ≥ 6 constituted the high-risk group. High-risk lung ultrasound scores were associated with an increased incidence of PPCs after colorectal surgery (logistic regression coefficient, 1.715; odds ratio, 5.556). Postoperative movement distance was negatively associated with the lung ultrasound scores [Spearman's rank correlation coefficient (r), -0.356, P < 0.05]. CONCLUSION: Lung ultrasound effectively evaluates pulmonary condition post-colorectal surgery. Early ambulation and respiratory exercises in the initial two PODs will reduce PPCs and optimize postoperative care in patients undergoing colorectal surgery.

ß-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.

Background: Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. ß-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear. Methods: Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay. Results: We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2. Conclusions: Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.

Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.

Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.

Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.

Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.

Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study.

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

Driving mechanism of groundwater quality and probabilistic health risk quantification in the central Yinchuan Plain.

The environmental changes from climatic, terrestrial and anthropogenic drivers can significantly influence the groundwater quality that may pose a threat to human health. However, the driving mechanism of groundwater quality and potential health risk still remains to be studied. In this paper, 165 groundwater samples were analyzed to evaluate the groundwater quality, driving mechanism, and probabilistic health risk in the central Yinchuan Plain by applying fuzzy comprehensive evaluation method (FCEM), redundance analysis (RDA) and Monte Carlo simulation. The results showed that hydrochemical evolution of groundwater were strongly influenced by water-rock interaction, evaporation and human activities. While 55.2% of groundwater samples reached the drinking water quality standard (Class I, II and III), 44.8% of samples exceeded the standard limits of Class III water quality (Class IV and V), indicating a high pollution level of groundwater. Mn, TDS, NH4+, NO3-, Fe, F-, NO2-, As were among major indicators that influence the groundwater quality due to the natural and anthropogenic processes. The RDA analysis revealed that climatic factors (PE: 10.9%, PRE: 1.1%), GE chemical properties (ORP: 20.7%, DO: 2.4%), hydrogeological factors (BD: 16.5%, K: 4.1%), and terrestrial factors (elevation: 1.2%; distanced: 5.6%, distancerl: 1.5%, NDVI: 1.2%) were identified as major driving factors influencing the groundwater quality in the study area. The HHRA suggested that TCR values of arsenic in infants, children and teens greatly exceeded the acceptable risk threshold of 1E-4, indicating a high cancer risk with a basic trend: infants > children > teens, while TCR values of adults were within the acceptable risk level. THI values of four age groups in the RME scenario were nearly ten times higher than those in the CTE scenario, displaying a great health effect on all age groups (HQ > 1). The present study provides novel insights into the driving mechanism of groundwater quality and potential health hazard in arid and semi-arid regions.

Numerical and experimental investigation on debonding detection in honeycomb sandwich using air-coupled local defect resonance and coda wave analysis.

Non-contact ultrasonic testing of debonding in honeycomb sandwich structure has been a major challenge in industry. In this study, the air-coupled local defect resonance (LDR) technique with coda wave analysis is proposed for nondestructive testing (NDT) of debonding in honeycomb sandwich structure. Numerical simulations have been conducted to visualize the LDR behavior of debonding in honeycomb sandwich structure by air-coupled excitations, and a decorrelation analysis method is proposed for determining the interval of coda wave from received signals. Results indicate that the start moment of coda wave should be determined as the time corresponding to decorrelation coefficient exceed to 0.2 and the duration is 2.5 ms. Air-coupled LDR scanning experiments were conducted on the honeycomb sandwich specimens with different deboning. Experimental results indicate that the proposed technique is effective for NDT of the debonding in honeycomb sandwich structures. The research provides an efficiency non-contact ultrasonic NDT method for honeycomb sandwich structure.

Clinical characteristics and detection of MYB-QKI fusions in patients with angiocentric glioma.

PURPOSE: Angiocentric glioma (AG), a benign tumor identified within the last two decades, was officially included in the 2007 WHO Classification of Tumors of the Central Nervous System, WHO grade I. The tumor is relatively rare, with only approximately 100 cases reported. We aim to complement the characteristics and long-term prognosis of AG, as well as to detect MYB-QKI fusions. METHODS: The characteristics of all cases collected between 1 March 2009 and 1 March 2023 at the Beijing Sanbo Brain Hospital, Capital Medical University, were summarized and analyzed. Additionally, all fourteen patients were tested for MYB-QKI fusions. RESULTS: AG more predominantly occurs in adolescents (median age 16.5-year-old), and commonly presents with drug-resistant epilepsy. AG is frequently localized in the supratentorial regions and only one patient is in the brainstem. Brain parenchyma atrophy, and stalk-like signs can observe in imaging. Pathologically, tumor cells are perivascular pseudorosettes, presenting immunoreactivity for GFAP, S-100, Vimentin, "dot-like" staining for EMA, and low proliferative activity. Focal cortex dysplasia was observed in four patients. Twelve of fourteen (85.7%) patients were found with MYB-QKI fusions. Completely surgical resection typically has a satisfactory prognosis with long-term follow-up. CONCLUSION: AG is a rare benign tumor with a favorable prognosis after complete resection, characterized by refractory epilepsy, frequently occurring in adolescents. MYB-QKI fusions were detected in most AG patients, as a good defining genetic alteration pathologically. The potential presence of focal cortical dysplasia (FCD) may affect the prognosis of epilepsy.