Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

Altered EEG Microstates Dynamics in Individuals with Subthreshold Depression When Generating Negative Future Events.

Negative bias in prospection may play a crucial role in driving and maintaining depression. Recent research suggests abnormal activation and functional connectivity in regions of the default mode network (DMN) during future event generation in depressed individuals. However, the neural dynamics during prospection in these individuals remain unknown. To capture network dynamics at high temporal resolution, we employed electroencephalogram (EEG) microstate analysis. We examined microstate properties during both positive and negative prospection in 35 individuals with subthreshold depression (SD) and 35 controls. We identified similar sets of four canonical microstates (A-D) across groups and conditions. Source analysis indicated that each microstate map partially overlapped with a subsystem of the DMN (A: verbal; B: visual-spatial; C: self-referential; and D: modulation). Notably, alterations in EEG microstates were primarily observed in negative prospection of individuals with SD. Specifically, when generating negative future events, the coverage, occurrence, and duration of microstate A increased, while the coverage and duration of microstates B and D decreased in the SD group compared to controls. Furthermore, we observed altered transitions, particularly involving microstate C, during negative prospection in the SD group. These altered dynamics suggest dysconnectivity between subsystems of the DMN during negative prospection in individuals with SD. In conclusion, we provide novel insights into the neural mechanisms of negative bias in depression. These alterations could serve as specific markers for depression and potential targets for future interventions.

The associations of psychopathology and metabolic parameters with serum bilirubin levels in patients with acute-episode and drug-free schizophrenia: a 5-year retrospective study using an electronic medical record system.

BACKGROUND: The oxidative system plays an important role in the pathogenesis of schizophrenia. Inconsistent associations were found between hyperbilirubinemia and psychopathology as well as glycolipid metabolism in patients with schizophrenia at different episodes. This current study aimed to examine these associations in patients with acute-episode and drug-free (AEDF) schizophrenia. METHODS: This is a retrospective study using 5 years of data from May 2017 to May 2022 extracted from the electronic medical record system of Chaohu Hospital of Anhui Medical University. Healthy controls (HCs) from the local medical screening center during the same period were also included. Participants' data of the bilirubin levels [total bilirubin (TB), conjugated bilirubin (CB), unconjugated bilirubin (UCB)], glycolipid metabolic parameters and the score of the Brief Psychiatric Rating Scale (BPRS) were collected. RESULTS: A total of 1468 case records were identified through the initial search. After screening, 89 AEDF patients and 100 HCs were included. Compared with HCs, patients had a higher CB level, and lower levels of glycolipid metabolic parameters excluding high density lipoprotein-cholesterol (HDL-C) (all P < 0.001). Binary logistic regression analyses revealed that high bilirubin levels in the patients were independently associated with higher total and resistance subscale scores of BPRS, a higher HDL-C level, and lower total cholesterol and triglyceride levels (all P < 0.05). CONCLUSION: Bilirubin levels are elevated in patients with AEDF schizophrenia. Patients with high bilirubin levels have more severe psychopathology and relatively optimized glycolipid metabolism. In clinical practice, regular monitoring of bilirubin levels in this patient population should be carried out.

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures.

AIMS: This study aimed to illuminate the neuropathological landscape of attention deficit hyperactivity disorder (ADHD) by a multiscale macro-micro-molecular perspective from in vivo neuroimaging data. METHODS: The "ADHD-200 initiative" repository provided multi-site high-quality resting-state functional connectivity (rsfc-) neuroimaging for ADHD children and matched typically developing (TD) cohort. Diffusion mapping embedding model to derive the functional connectome gradient detecting biologically plausible neural pattern was built, and the multivariate partial least square method to uncover the enrichment of neurotransmitomic, cellular and chromosomal gradient-transcriptional signatures of AHBA enrichment and meta-analytic decoding. RESULTS: Compared to TD, ADHD children presented connectopic cortical gradient perturbations in almost all the cognition-involved brain macroscale networks (all pBH <0.001), but not in the brain global topology. As an intermediate phenotypic variant, such gradient perturbation was spatially enriched into distributions of GABAA/BZ and 5-HT2A receptors (all pBH <0.01) and co-varied with genetic transcriptional expressions (e.g. DYDC2, ATOH7, all pBH <0.01), associated with phenotypic variants in episodic memory and emotional regulations. Enrichment models demonstrated such gradient-transcriptional variants indicated the risk of both cell-specific and chromosome- dysfunctions, especially in enriched expression of oligodendrocyte precursors and endothelial cells (all pperm <0.05) as well enrichment into chromosome 18, 19 and X (pperm <0.05). CONCLUSIONS: Our findings bridged brain macroscale neuropathological patterns to microscale/cellular biological architectures for ADHD children, demonstrating the neurobiologically pathological mechanism of ADHD into the genetic and molecular variants in GABA and 5-HT systems as well brain-derived enrichment of specific cellular/chromosomal expressions.

Effects of butylphthalide on cerebral vascular circulation, coagulation function, and neurological function in patients with acute severe ischemic stroke following intravenous thrombolysis: a preliminary study.

OBJECTIVE: To analyze the effects of Butylphthalide on cerebral vascular circulation, coagulation function, and neurological function in patients with acute severe ischemic stroke following intravenous thrombolysis. METHODS: Clinical efficacy, cerebral vascular circulation indicators [anterior cerebral artery (ACA), middle cerebral artery (MCA), vertebral artery (VA) blood flow velocity], coagulation function indicators [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB)], neurological function indicators [Activities of Daily Living (ADL) score. RESULTS: The total effective rate of treatment in the control group was 76.47%, while in the observation group, it was 96.08%, with the observation group showing a significantly higher total effective rate than the control group (p < 0.05). Before treatment, there was no significant difference in ACA, MCA, and VA blood flow velocity between the two groups (p > 0.05). However, after treatment, the ACA, MCA, and VA blood flow velocity in the observation group were significantly higher than those in the control group (p < 0.05). Before treatment, there was no significant difference in PT, APTT, TT, and FIB levels between the two groups (p > 0.05). CONCLUSION: In patients with acute severe ischemic stroke undergoing intravenous thrombolysis, the addition of Butylphthalide to the treatment regimen yields favorable clinical outcomes. Compared to Alteplase alone, the addition of Butylphthalide further improves cerebral vascular circulation and coagulation function, promoting the recovery and reconstruction of neurological function in patients. Importantly, the addition of Butylphthalide does not increase the risk of adverse reactions, making it a safe and ideal option for clinical application.

H-151 attenuates lipopolysaccharide-induced acute kidney injury by inhibiting the STING-TBK1 pathway.

Sepsis is a severe systemic infectious disease that often leads to multi-organ dysfunction. One of the common and serious complications of sepsis is renal injury. In this study, we aimed to investigate the potential mechanistic role of a novel compound called H-151 in septic kidney injury. We also examined its impact on renal function and mouse survival rates. Initially, we confirmed abnormal activation of the STING-TBK1 signaling pathway in the kidneys of septic mice. Subsequently, we treated the mice with H-151 and observed significant improvement in sepsis-induced renal dysfunction. This was evidenced by reductions in blood creatinine and urea nitrogen levels, as well as a marked decrease in inflammatory cytokine levels. Furthermore, H-151 substantially improved the seven-day survival rate of septic mice, indicating its therapeutic potential. Importantly, H-151 also exhibited an inhibitory effect on renal apoptosis levels, further highlighting its mechanism of protecting against septic kidney injury. These study findings not only offer new insights into the treatment of septic renal injury but also provide crucial clues for further investigations into the regulatory mechanisms of the STING-TBK1 signaling pathway and potential drug targets.

Income gap between male and female psychiatric nurses in China: A national survey.

AIM: To investigate gender differences in the actual and expected income among psychiatric nurses in China. BACKGROUND: Although studies have shown that male nurses earn more than female nurses in other countries, there are no published data regarding gender income differences among psychiatric nurses in China. METHODS: We conducted a cross-sectional study involving 41 representative psychiatric hospitals in China. Demographic, income, and job-related data were analyzed using the inverse probability of treatment weighting (IPTW) based on the propensity score. FINDINGS: The sample included 9256 psychiatric nurses, and nearly four-fifths (79.3%) were female. Males earned slightly higher average monthly incomes than female nurses, while initial analysis showed no significant overall gender income difference (p > 0.05). Notably, most participants (92.5%) desired an income increase of at least 10%, with over half (56.2%) expressing significant dissatisfaction with their current income. After adjustment using propensity score combined with IPTW, females in the junior and mid-level groups had significantly lower income than their male counterparts (all p < 0.01), despite having different night shift patterns. However, there were no significant gender differences in actual or expected income among senior-level psychiatric nurses (p > 0.05). CONCLUSION: A majority of psychiatric nurses in China express dissatisfaction with their current incomes and expect higher incomes. Male nurses earned significantly more than female nurses in the junior and mid-level professional groups, potentially due to their differences in night shifts. IMPLICATIONS FOR NURSING POLICY AND HEALTH POLICY: Policymakers and hospital administrators should optimize the income structures of nurses and develop targeted policies to address the gender income gap. Improving nurse income has the potential to enhance motivation and satisfaction within the profession.

HS-SPME-GC-MS Untargeted Analysis of Normal Rat Organs Ex Vivo: Differential VOC Discrimination and Fingerprint VOC Identification.

The investigation of volatile organic compounds (VOCs) in human metabolites has been a topic of interest as it holds the potential for the development of non-invasive technologies to screen for organ lesions in vivo. However, it remains unclear whether VOCs differ among healthy organs. Consequently, a study was conducted to analyze VOCs in ex vivo organ tissues obtained from 16 Wistar rats, comprising 12 different organs. The VOCs released from each organ tissue were detected by the headspace-solid phase microextraction-gas chromatography-mass spectrometry technique. In the untargeted analysis of 147 chromatographic peaks, the differential volatiles of rat organs were explored based on the Mann-Whitney U test and fold change (FC > 2.0) compared with other organs. It was found that there were differential VOCs in seven organs. A discussion on the possible metabolic pathways and related biomarkers of organ differential VOCs was conducted. Based on the orthogonal partial least squares discriminant analysis and receiver operating characteristic curve, we found that differential VOCs in the liver, cecum, spleen, and kidney can be used as the unique identification of the corresponding organ. In this study, differential VOCs of organs in rats were systematically reported for the first time. Profiles of VOCs produced by healthy organs can serve as a reference or baseline that may indicate the presence of disease or abnormalities in the organ's function. Differential VOCs can be used as the fingerprint of organs, and future integration with metabolic research may contribute to the development of healthcare.

Uncovering the Carboxylated Metabolome in Gut Microbiota-Host Co-metabolism: A Chemical Derivatization-Molecular Networking Approach.

Gut microbiota-host co-metabolites serve as essential mediators of communication between the host and gut microbiota. They provide nutrient sources for host cells and regulate gut microenvironment, which are associated with a variety of diseases. Analysis of gut microbiota-host co-metabolites is of great significance to explore the host-gut microbiota interaction. In this study, we integrated chemical derivatization, liquid chromatography-mass spectrometry, and molecular networking (MN) to establish a novel CD-MN strategy for the analysis of carboxylated metabolites in gut microbial-host co-metabolism. Using this strategy, 261 carboxylated metabolites from mouse feces were detected, which grouped to various classes including fatty acids, bile acids, N-acyl amino acids, benzoheterocyclic acids, aromatic acids, and other unknown small-scale molecular clusters in MN. Based on the interpretation of the bile acid cluster, a novel type of phenylacetylated conjugates of host bile acids was identified, which were mediated by gut microbiota and exhibited a strong binding ability to Farnesoid X receptor and Takeda G protein-coupled receptor 5. Our proposed strategy offers a promising platform for uncovering carboxylated metabolites in gut microbial-host co-metabolism.

Advanced Covalent Organic Framework-Based Membranes for Recovery of Ionic Resources.

Membrane technology has shown a viable potential in conversion of liquid-waste or high-salt streams to fresh waters and resources. However, the non-adjustability pore size of traditional membranes limits the application of ion capture due to their low selectivity for target ions. Recently, covalent organic frameworks (COFs) have become a promising candidate for construction of advanced ion separation membranes for ion resource recovery due to their low density, large surface area, tunable channel structure, and tailored functionality. This tutorial review aims to analyze and summarize the progress in understanding ion capture mechanisms, preparation processes, and applications of COF-based membranes. First, the design principles for target ion selectivity are illustrated in terms of theoretical simulation of ions transport in COFs, and key properties for ion selectivity of COFs and COF-based membranes. Next, the fabrication methods of diverse COF-based membranes are classified into pure COF membranes, COF continuous membranes, and COF mixed matrix membranes. Finally, current applications of COF-based membranes are highlighted: desalination, extraction, removal of toxic metal ions, radionuclides and lithium, and acid recovery. This review presents promising approaches for design, preparation, and application of COF-based membranes in ion selectivity for recovery of ionic resources.

Yeast ß-glucan modulates macrophages and improves antitumor NK-cell responses in cancer.

As the largest proportion of myeloid immune cells in tumors, macrophages play an important role in tumor growth and regression according to their different phenotypes, thus reprogramming macrophages has become a new research direction for cancer immunotherapy. Yeast-derived whole ß-glucan particles (WGPs) can induce M0 macrophages to differentiate into M1 macrophages and convert M2 macrophages and tumor-associated macrophages (TAMs) into M1 macrophages. In vitro, studies have confirmed that WGP-treated macrophages increase the activating receptors in natural killer cells (NK cells) and enhance the cytotoxicity of NK cells. The extracellular regulated protein kinases (ERK) signaling pathway is involved in WGP-mediated regulation of the macrophage phenotype. Further in vivo studies show that oral WGP can significantly delay tumor growth, which is related to the increased proportion of macrophages and NK cells, the macrophage phenotype reversal, and the enhancement of NK cell immune function. NK-cell depletion reduces the therapeutic efficacy of WGP in tumor-bearing mice. These findings revealed that in addition to T cells, NK cells also participate in the antitumor process of WGP. It was confirmed that WGP regulates the macrophage phenotype to regulate NK-cell function.

RC48-ADC treatment for patients with HER2-expressing locally advanced or metastatic solid tumors: a real-world study.

BACKGROUND: RC48-antibody-drug conjugates (ADC) link humanized anti-HER2 immunoglobulin with monomethyl auristatin E (MMAE). Clinical trials suggest promising antitumor activity in HER2-expressing solid tumors. This study probes RC48-ADC's efficacy and safety in patients with HER2-expressing advanced or metastatic solid tumors. METHOD: Data was collected from 23 advanced cancer patients treated with RC48-ADC at our oncology center between July 2021 and December 2022. These patients exhibited at least 1 + expression of HER2 immunohistochemistry, had previously experienced at least one failed systemic chemotherapy, and were treated with RC48-ADC until the occurrence of intolerable adverse reactions or disease progression. The primary endpoint was the disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: 23 of 25 screened patients received RC48 treatment. The ORR was 43.5% (95% CI, 23.2-63.7%) with a median PFS of 6.0 months (95% CI, 4.8-7.4). In the low-to-medium HER2 expression subgroup, ORR was 37.5%, median PFS 5.75 months. In the high HER2 expression subgroup, ORR was 57.1%, median PFS 7 months. For the cohort combining RC48 with PD-1 inhibitors, ORR was 53.8%, median PFS 8 months. In the concurrent local radiation therapy subgroup, ORR was 40.0%, median PFS 6.0 months. Treatment-related adverse events (TRAEs) were anemia (60.8%), leukopenia (56.2%), raised transaminases (52.17%), and neutropenia (43.5%). Five patients (21.7%) experienced Grade 3 symptoms, including anemia (21.7%) and neutropenia (14.0%). No Grade 4 adverse reactions or deaths were reported. CONCLUSION: RC48-ADC shows promising efficacy and manageable safety in HER2-expressing advanced or metastatic solid tumor patients.

Effects of Liquid Viscosity on the Formation and Attenuation of Capillary Waves Induced by AC Electrowetting-on-Dielectric.

The capillary waves induced by electrowetting-on-dielectric have great potential in terms of capillary propulsion and other applications. At present, these applications are limited by a lack of research on the effects of liquid viscosity, which is an important parameter in controlling this phenomenon. This paper examines the formation, propagation, and attenuation of electrowetting-on-dielectric-induced capillary waves (EWCWs) on a liquid-free surface with different levels of liquid viscosity. The formation and propagation of the capillary waves are visualized using a high-speed camera and a free-surface synthetic Schlieren method. A theoretical model is established to describe the wave amplitude and wave propagation of EWCWs. The results show that the liquid viscosity, as well as the surface tension, significantly affects the formation and propagation of EWCWs. Using the results presented in this paper, a new type of Stokes viscometer based on EWCWs is proposed, enabling accurate measurements of liquid viscosity over a wide range of viscosity and temperature conditions.

RNA m6A methylation regulators in sepsis.

N6-methyladenosine (m6A) modification is a class of epitope modifications that has received significant attention in recent years, particularly in relation to its role in various diseases, including sepsis. Epigenetic research has increasingly focused on m6A modifications, which is influenced by the dynamic regulation of three protein types: ?Writers" (such as METTL3/METTL14/WTAP)-responsible for m6A modification; ?Erasers" (FTO and ALKBH5)-involved in m6A de-modification; and ?Readers" (YTHDC1/2, YTHDF1/2/3)-responsible for m6A recognition. Sepsis, a severe and fatal infectious disease, has garnered attention regarding the crucial effect of m6A modifications on its development. In this review, we attempted to summarize the recent studies on the involvement of m6A and its regulators in sepsis, as well as the significance of m6A modifications and their regulators in the development of novel drugs and clinical treatment. The potential value of m6A modifications and modulators in the diagnosis, treatment, and prognosis of sepsis has also been discussed.

Type IV collagen-derived angiogenesis inhibitor: canstatin low expressing in brain-invasive meningiomas using liquid chromatography-mass spectrometry (LC-MS/MS).

PURPOSE: Brain invasion in meningiomas is considered an indicator of more aggressive behavior and worse prognosis. But the precise definition and the prognostic role of brain invasion remains unsolved duo to lacking a standardized workflow of surgical sampling and the histopathological detection. Searching for molecular biomarker expression correlating with brain invasion, could contribute to establish a molecular pathological diagnosis without problems of subjective interobserver variation and deeply understand the mechanism of brain invasion and develop innovative therapeutic strategies. METHODS: We utilized liquid chromatography tandem mass spectrometry to quantify protein abundances between non-invasive meningiomas (n = 21) and brain-invasive meningiomas (n = 21) spanning World Health Organization grades I and III. After proteomic discrepancies were analyzed, the 14 most up-regulated or down-regulated proteins were recorded. Immunohistochemical staining for glial fibrillary acidic protein and most likely brain invasion-related proteins was performed in both groups. RESULTS: A total of 6498 unique proteins were identified in non-invasive and brain-invasive meningiomas. Canstatin expression in the non-invasive group was 2.1-fold that of the brain-invasive group. The immunohistochemical staining showed canstatin expressed in both groups, and the non-invasive group showed stronger staining for canstatin in the tumor mass (p = 0.0132) than the brain-invasive group, which showed moderate intensity. CONCLUSION: This study demonstrated the low expression of canstatin in meningiomas with brain invasion, a finding that provide a basis for understanding the mechanism of brain invasion of meningiomas and may contribute to establish molecular pathological diagnosis and identify novel therapeutic targets for personalized care.

Depression severity mediates stigma and quality of life in clinically stable people with schizophrenia in rural China.

BACKGROUND: Depressive symptoms associated with schizophrenia are closely related to stigma and quality of life(QOL). There is, however, no thorough research on the connection between the three. This study sought to investigate the possible factors influencing depressive symptoms in people with schizophrenia (PWS) in rural Chaohu, China, and to further explore the role of depression severity in stigma and lifestyle quality. METHODS: Eight hundred twenty-one schizophrenia patients accomplished the entire scale, including the 9-item Patient Health Questionnaire (PHQ-9), the Social Impact Scale (SIS), and the World Health Organization on Quality of Life Brief Scale(WHOQOL-BREF). A straightforward mediation model was employed to determine if the intensity of the depression could act as a mediator between stigma and QOL. RESULTS: Two hundred seventy-nine schizophrenia patients (34%) had depressive symptoms (PHQ ≥ 10), and 542 patients (66%) did not (PHQ < 10). Logistic regression showed that marital status, job status, physical exercise, standard of living, and stigma contributed to the depressed symptoms of schizophrenia. Depression severity partially mediated the effect between stigma and QOL, with a mediating effect of 48.3%. CONCLUSIONS: This study discovered a significant incidence of depressed symptoms associated with schizophrenia, with depression severity serving as a mediator variable connecting stigma and QOL and partially moderating the association.

A double-cycle echo state network topology for time series prediction.

Echo state network (ESN) has gained wide acceptance in the field of time series prediction, relying on sufficiently complex reservoir connections to remember the historical features of the data and using these features to obtain the outputs by a simple linear readout. However, the randomness of its input and reservoir connections pose negative impacts on the prediction performance and performance stability of the models, the complexity of reservoir connections brings high time consumption during network computing, and the presence of randomness and complexity makes the hardware implementation of the ESN difficult. In response, we propose a double-cycle ESN (DCESN) based on the Li-ESN model, which has fixed weights to improve prediction performance and performance stability and simpler reservoir connections compared to the classical ESN to reduce the time consumption. The existence of both greatly reduces the difficulty of hardware implementation of the ESN and provides many conveniences for the future application of the ESN. Experimental results on many widely used time series datasets show that the DCESN has comparable or even better prediction performance than the ESN and good robustness against noise and parameter fluctuations.

Control Algorithm Design of a Force-Balance Accelerometer.

The force-balanced accelerometer (FBA), unlike other types of sensors, incorporates a closed-loop control. The efficacy of the system is contingent not solely on the hardware, but more critically on the formulation of the control algorithm. Conventional control strategies are usually designed for the purpose of response minimization of the sensitive elements, which limits the measurement accuracy and applicable frequency bandwidth of FBAs. In this paper, based on the model predictive control (MPC), a control algorithm of a force-balance accelerometer considering time delay is designed. The variable augmentation method is proposed to convert the force-balance control into an easy-handed measurement error minimization control problem. The discretization method is applied to deal with the time delay problem in the closed loop. The control algorithm is integrated into a practical FBA. The effectiveness of the proposed control is demonstrated through experiments conducted in an ultra-quiet chamber, as well as simulations. The results show that the closed loop in the FBA has a time delay 10 times of the control period, and, utilizing the proposed control, the acceleration signals can be accurately measured with a frequency range larger than 500 Hz. Meanwhile, the vibration response of the sensitive element of the controlled FBA is maintained at the level of microns, which guarantees a large measurement range of the FBA.

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Chloroplast Pan-Genomes and Comparative Transcriptomics Reveal Genetic Variation and Temperature Adaptation in the Cucumber.

Although whole genome sequencing, genetic variation mapping, and pan-genome studies have been done on a large group of cucumber nuclear genomes, organelle genome information is largely unclear. As an important component of the organelle genome, the chloroplast genome is highly conserved, which makes it a useful tool for studying plant phylogeny, crop domestication, and species adaptation. Here, we have constructed the first cucumber chloroplast pan-genome based on 121 cucumber germplasms, and investigated the genetic variations of the cucumber chloroplast genome through comparative genomic, phylogenetic, haplotype, and population genetic structure analysis. Meanwhile, we explored the changes in expression of cucumber chloroplast genes under high- and low-temperature stimulation via transcriptome analysis. As a result, a total of 50 complete chloroplast genomes were successfully assembled from 121 cucumber resequencing data, ranging in size from 156,616-157,641 bp. The 50 cucumber chloroplast genomes have typical quadripartite structures, consisting of a large single copy (LSC, 86,339-86,883 bp), a small single copy (SSC, 18,069-18,363 bp), and two inverted repeats (IRs, 25,166-25,797 bp). Comparative genomic, haplotype, and population genetic structure results showed that there is more genetic variation in Indian ecotype cucumbers compared to other cucumber cultivars, which means that many genetic resources remain to be explored in Indian ecotype cucumbers. Phylogenetic analysis showed that the 50 cucumber germplasms could be classified into 3 types: East Asian, Eurasian + Indian, and Xishuangbanna + Indian. The transcriptomic analysis showed that matK were significantly up-regulated under high- and low-temperature stresses, further demonstrating that cucumber chloroplasts respond to temperature adversity by regulating lipid metabolism and ribosome metabolism. Further, accD has higher editing efficiency under high-temperature stress, which may contribute to the heat tolerance. These studies provide useful insight into genetic variation in the chloroplast genome, and established the foundation for exploring the mechanisms of temperature-stimulated chloroplast adaptation.