Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Awareness and preparedness level of medical workers for radiation and nuclear emergency response.

Radiological science and nuclear technology have made great strides in the twenty-first century, with wide-ranging applications in various fields, including energy, medicine, and industry. However, those developments have been accompanied by the inherent risks of exposure to nuclear radiation, which is a source of concern owing to its potentially adverse effects on human health and safety and which is of particular relevance to medical personnel who may be exposed to certain cancers associated with low-dose radiation in their working environment. While medical radiation workers have seen a decrease in their occupational exposure since the 1950s thanks to improved measures for radiation protection, a concerning lack of understanding and awareness persists among medical professionals regarding these potential hazards and the required safety precautions. This issue is further compounded by insufficient capabilities in emergency response. This highlights the urgent need to strengthen radiation safety education and training to ensure the well-being of medical staff who play a critical role in radiological and nuclear emergencies. This review examines the health hazards of nuclear radiation to healthcare workers and the awareness and willingness and education of healthcare workers on radiation protection, calling for improved training programs and emergency response skills to mitigate the risks of radiation exposure in the occupational environment, providing a catalyst for future enhancement of radiation safety protocols and fostering of a culture of safety in the medical community.

Efficient non-line-of-sight tracking with computational neuromorphic imaging.

Non-line-of-sight (NLOS) sensing is an emerging technique that is capable of detecting objects hidden behind a wall, around corners, or behind other obstacles. However, NLOS tracking of moving objects is challenging due to signal redundancy and background interference. Here, we demonstrate computational neuromorphic imaging with an event camera for NLOS tracking, unaffected by the relay surface, which can efficiently obtain non-redundant information. We show how this sensor, which responds to changes in luminance within dynamic speckle fields, allows us to capture the most relevant events for direct motion estimation. The experimental results confirm that our method has superior performance in terms of efficiency, and accuracy, which greatly benefits from focusing on well-defined NLOS object tracking.

Neonatal Resuscitation Online Registry in Shenzhen: protocol for a prospective, multicentre, open, observational cohort study.

INTRODUCTION: Preterm birth complications and neonatal asphyxia are the leading causes of neonatal mortality worldwide. Surviving preterm and asphyxiated newborns can develop neurological sequelae; therefore, timely and appropriate neonatal resuscitation is important to decrease neonatal mortality and disability rates. There are very few systematic studies on neonatal resuscitation in China, and its prognosis remains unclear. We established an online registry for neonatal resuscitation in Shenzhen based on Utstein's model and designed a prospective, multicentre, open, observational cohort study to address many of the limitations of existing studies. The aim of this study is to explore the implementation and management, risk factors and outcomes of neonatal resuscitation in Shenzhen. METHODS AND ANALYSIS: This prospective, multicentre, open, observational cohort study will be conducted between January 2024 and December 2026 and will include >1500 newborns resuscitated at birth by positive pressure ventilation at five hospitals in Shenzhen, located in the south-central coastal area of Guangdong province, China. Maternal and infant information, resuscitation information, hospitalisation information and follow-up information will be collected. Maternal and infant information, resuscitation information and hospitalisation information will be collected from the clinical records of the patients. Follow-up information will include the results of follow-up examinations and outcomes, which will be recorded using the WeChat applet 'Resuscitation Follow-up'. These data will be provided by the neonatal guardians through the applet on their mobile phones. This study will provide a more comprehensive understanding of the implementation and management, risk factors and outcomes of neonatal resuscitation in Shenzhen; the findings will ultimately contribute to the reduction of neonatal mortality and disability rates in Shenzhen. ETHICS AND DISSEMINATION: Our protocol has been approved by the Medical Ethics Committee of Shenzhen Luohu People's Hospital (2023-LHQRMYY-KYLL-048). We will present the study results at academic conferences and peer-reviewed paediatrics journals. TRIAL REGISTRATION NUMBER: ChiCTR2300077368.

A comprehensive exploration of astrocytes in migraine: a bibliometric and visual analysis.

BACKGROUND: Migraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology. METHODS: On November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers. RESULTS: As of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences. CONCLUSIONS: Future investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Ferulic Acid Inhibits Arsenic-Induced Colon Injury by Improving Intestinal Barrier Function.

The prolonged exposure to arsenic results in intestinal barrier dysfunction, which is strongly concerned with detrimental processes such as oxidative stress and the inflammatory response. Ferulic acid (FA), as a phenolic acid, possesses the capability to mitigate arsenic-induced liver damage and cardiotoxic effects dependent on inhibition of oxidative stress and inflammatory responses. FA can mitigate testicular tissue damage and alveolar epithelial dysfunction, the mechanism of which may rely on nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) activation and nuclear factor-kappa B (NF-κB) pathway blocking. Based on the antioxidant and anti-inflammatory properties of FA, we speculated that FA might have the potential to inhibit arsenic-induced intestinal damage. To confirm this scientific hypothesis, mice exposed to sodium arsenite were treated with FA to observe colonic histopathology and TJ protein levels, and oxidative stress and TJ protein levels in Caco-2 cells exposed to sodium arsenite were assessed after FA intervention. In addition, molecular levels of NF-κB and Nrf2/HO-1 pathway in colon and Caco-2 cells were also detected. As shown in our data, FA inhibited arsenic-induced colon injury, which was reflected in the improvement of mucosal integrity, the decrease of down-regulated expression of tight junction (TJ) proteins (Claudin-1, Occludin, and ZO-1) and the inhibition of oxidative stress. Similarly, treatment with FA attenuated the inhibitory effect of arsenic on TJ protein expression in Caco-2 cells. In addition to suppressing the activation of NF-κB pathway, FA retrieved the activation of Nrf2/HO-1 pathway in colon and intestinal epithelial cells induced by arsenic. In summary, our findings propose that FA has the potential to mitigate arsenic-induced intestinal damage by preserving the integrity of intestinal epithelial TJs and suppressing oxidative stress. These results lay the groundwork for the potential use of FA in treating colon injuries caused by arsenic.

A qualitative exploration of e-cigarette prevention advertisements' effectiveness among college students in China.

INTRODUCTION: The rapid growth of e-cigarette usage among youth and young people has emerged as a significant public health concern. It is imperative to initiate effective vaping prevention campaigns and undertake relevant research to address this pressing issue. This research seeks to identify effective video advertisements to deter young people from starting to use e-cigarettes. It aims to offer evidence-based insights and recommendations for creating communication materials and designing messages for youth e-cigarette prevention efforts. METHODS: College students aged 18-24 years (n=40) participated in focus groups within this qualitative study. After viewing four stimulus videos, participants discussed what they perceived as effective and ineffective video characteristics, as well as suggestions for future videos. RESULTS: Effective video characteristics included the use of real-life testimonials, displaying specific health hazards, revealing harmful chemical ingredients and the deceptive nature of flavors, and positively perceived effectiveness. Participants generally found that videos with strong visual impact and graphics were more engaging and that approaches using fear and emotion were more effective. Ineffective characteristics included complex and exaggerated information, lack of empathy and irrelevance, insufficiently specific information, extreme and death-themed content, industry messages, as well as preachy tones, animations, metaphors, dull formats, excessive length, and scenes of e-cigarette use. CONCLUSIONS: Developing anti-e-cigarette campaign materials for youth necessitates target audience-focused qualitative research. This helps in deeply exploring and identifying effective themes and messages, as well as video characteristics and details while avoiding ineffective or even misleading messages and themes from young people's perspectives outside the United States. Future development of e-cigarette prevention videos for Chinese college students may consider incorporating localized real-life testimonial cases to convey specific harms, including self-efficacy information, and utilizing fear and emotional appeals.

Radiomics-Based Machine Learning Classification Strategy for Characterization of Hepatocellular Carcinoma on Contrast-Enhanced Ultrasound in High-Risk Patients with LI-RADS Category M Nodules.

Objective Accurate differentiation within the LI-RADS category M (LR-M) between hepatocellular carcinoma (HCC) and non-HCC malignancies (mainly intrahepatic cholangiocarcinoma [CCA] and combined hepatocellular and cholangiocarcinoma [cHCC-CCA]) is an area of active investigation. We aimed to use radiomics-based machine learning classification strategy for differentiating HCC from CCA and cHCC-CCA on contrast-enhanced ultrasound (CEUS) images in high-risk patients with LR-M nodules. Methods A total of 159 high-risk patients with LR-M nodules (69 HCC and 90 CCA/cHCC-CCA) who underwent CEUS within 1 month before pathologic confirmation from January 2006 to December 2019 were retrospectively included (111 patients for training set and 48 for test set). The training set was used to build models, while the test set was used to compare models. For each observation, six CEUS images captured at predetermined time points (T1, peak enhancement after contrast injection; T2, 30 seconds; T3, 45 seconds; T4, 60 seconds; T5, 1-2 minutes; and T6, 2-3 minutes) were collected for tumor segmentation and selection of radiomics features, which included seven types of features: first-order statistics, shape (2D), gray-level co-occurrence matrix, gray-level size zone matrix, gray-level run length matrix, neighboring gray tone difference matrix, and gray-level dependence matrix. Clinical data and key radiomics features were employed to develop the clinical model, radiomics signature (RS), and combined RS-clinical (RS-C) model. The RS and RS-C model were built using the machine learning framework. The diagnostic performance of these three models was calculated and compared. Results Alpha-fetoprotein (AFP), CA19-9, enhancement pattern, and time of washout were included as independent factors for clinical model (all p < 0.05). Both the RS and RS-C model performed better than the clinical model in the test set (area under the curve [AUC] of 0.698 [0.571-0.812] for clinical model, 0.903 [0.830-0.970] for RS, and 0.912 [0.838-0.977] for the RS-C model; both p < 0.05). Conclusions Radiomics-based machine learning classifiers may be competent for differentiating HCC from CCA and cHCC-CCA in high-risk patients with LR-M nodules.

Dynamic immune status analysis of peripheral blood mononuclear cells in patients with Klebsiella pneumoniae bloodstream infection sepsis using single-cell RNA sequencing.

Background: Klebsiella pneumoniae is a common Gram-negative bacterium. Blood infection caused by K. pneumoniae is one of the most common causes of human sepsis, which seriously threatens the life of patients. The immune status of peripheral blood mononuclear cells (PBMCs) based on single-cell RNA sequencing (scRNA-seq) in acute stage and recovery stage of sepsis caused by K. pneumoniae bloodstream infection has not been studied. Methods: A total of 13 subjects were included in this study, 3 healthy controls, 7 patients with K. pneumoniae bloodstream infection in the acute stage (4 patients died), and 3 patients in the recovery stage. Peripheral blood of all patients was collected and PBMCs were isolated for scRNA-seq analysis. We studied the changes of PBMCs components, signaling pathways, differential genes, and cytokines in acute and recovery stages. Results: During K. pneumoniae acute infection we observed a decrease in the proportion of T cells, most probably due to apoptosis and the function of T cell subtypes was disorder. The proportion of monocytes increased in acute stage. Although genes related to their phagocytosis function were upregulated, their antigen presentation capacity-associated genes were downregulated. The expression of IL-1ß, IL-18, IFNGR1 and IFNGR2 genes was also increased in monocytes. The proportion of DCs was depleted during the acute stage and did not recover during sepsis recovery. DCs antigen presentation was weakened during the acute stage but recovered fast during the recovery stage. pDCs response to MCP-1 chemokine was weakened, they recovered it quickly during the recovery stage. B cells showed apoptosis both in the acute stage and recovery stage. Their response to complement was weakened, but their antigen presentation function was enhanced. The proportion of NK cells stable during all disease's stages, and the expression of IFN-γ gene was upregulated. Conclusion: The proportion of PBMCs and their immune functions undergo variations throughout the course of the disease, spanning from the acute stage to recovery. These findings provide new insights into the mechanism of PBMCs immune function during K. pneumoniae bloodstream infection sepsis and recovery and sets the basis for further understanding and treatment.

Autotetraploidy of rice does not potentiate the tolerance to drought stress in the seedling stage.

Polyploid is considered an advantage that has evolved to be more environmentally adaptable than its diploid. To understand if doubled chromosome of diploid rice can improve drought tolerance, we evaluated the diploid (2X) and autotetraploid (4X) plants of three indica and three japonica varieties. Drought stress in the plastic bucket of four-leaf stage revealed that the drought tolerance of 4X plants was lower than that of its diploid donor plants. The assay of photosynthetic rate of all varieties showed that all 4X varieties had lower rates than their diploid donors. The capacity for reactive oxygen species production and scavenging varied among different 2X and 4X varieties. Further, transcriptomic analysis of 2X and 4X plants of four varieties under normal and drought condition showed that the wide variation of gene expression was caused by difference of varieties, not by chromosome ploidy. However, weighted gene co-expression network analysis (WGCNA) revealed that the severe interference of photosynthesis-related genes in tetraploid plants under drought stress is the primary reason for the decrease of drought tolerance in autotetraploid lines. Consistently, new transcripts analysis in autotetraploid revealed that the gene transcription related with mitochondrion and plastid of cell component was influenced most significantly. The results indicated that chromosome doubling of diploid rice weakened their drought tolerance, primarily due to disorder of photosynthesis-related genes in tetraploid plants under drought stress. Maintain tetraploid drought tolerance through chromosome doubling breeding in rice needs to start with the selection of parental varieties and more efforts.

Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II clinical trial.

OBJECTIVE: To evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC). METHODS: Eligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes. RESULTS: (1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4-5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively. CONCLUSIONS: The combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).

Recent selection and introgression facilitated high-altitude adaptation in cattle.

During the past 3000 years, cattle on the Qinghai-Xizang Plateau have developed adaptive phenotypes under the selective pressure of hypoxia, ultraviolet (UV) radiation, and extreme cold. The genetic mechanism underlying this rapid adaptation is not yet well understood. Here, we present whole-genome resequencing data for 258 cattle from 32 cattle breeds/populations, including 89 Tibetan cattle representing eight populations distributed at altitudes ranging from 3400 m to 4300 m. Our genomic analysis revealed that Tibetan cattle exhibited a continuous phylogeographic cline from the East Asian taurine to the South Asian indicine ancestries. We found that recently selected genes in Tibetan cattle were related to body size (HMGA2 and NCAPG) and energy expenditure (DUOXA2). We identified signals of sympatric introgression from yak into Tibetan cattle at different altitudes, covering 0.64%-3.26% of their genomes, which included introgressed genes responsible for hypoxia response (EGLN1), cold adaptation (LRP11), DNA damage repair (LATS1), and UV radiation resistance (GNPAT). We observed that introgressed yak alleles were associated with noncoding variants, including those in present EGLN1. In Tibetan cattle, three yak introgressed SNPs in the EGLN1 promoter region reduced the expression of EGLN1, suggesting that these genomic variants enhance hypoxia tolerance. Taken together, our results indicated complex adaptation processes in Tibetan cattle, where recently selected genes and introgressed yak alleles jointly facilitated rapid adaptation to high-altitude environments.

Controlling factors for the global meridional overturning circulation: A lesson from the Paleozoic.

The global meridional overturning circulation (GMOC) is important for redistributing heat and, thus, determining global climate, but what determines its strength over Earth's history remains unclear. On the basis of two sets of climate simulations for the Paleozoic characterized by a stable GMOC direction, our research reveals that GMOC strength primarily depends on continental configuration while climate variations have a minor impact. In the mid- to high latitudes, the volume of continents largely dictates the speed of westerly winds, which in turn controls upwelling and the strength of the GMOC. At low latitudes, open seaways also play an important role in the strength of the GMOC. An open seaway in one hemisphere allows stronger westward ocean currents, which support higher sea surface heights (SSH) in this hemisphere than that in the other. The meridional SSH gradient drives a stronger cross-equatorial flow in the upper ocean, resulting in a stronger GMOC. This latter finding enriches the current theory for GMOC.

Emergence of chimeralike oscillation modes in excitable complex networks with preferentially cutting-rewiring operation.

In this paper, the preferentially cutting-rewiring operation (PCRO) consisting of the cutting procedure and the rewiring procedure is proposed and is applied on an excitable Erdös-Rényi random network (EERRN), by which the structure of the initially homogeneous network changes dramatically, and lots of common leaves (CLs) are formed between the two hubs. Subsequently, besides the single-mode oscillations that can be usually observed in homogeneous excitable systems, a new kind of multi-mode oscillations composed of synchronous and asynchronous parts can self-organize to emerge, which are similar to the coherent and incoherent clusters in traditional chimera states and are consequently named as the chimeralike oscillation modes (CLOMs). Importantly, by utilizing the dominant phase-advanced driving method, both the mechanisms for the formation and the emergence of CLOMs in EERRNs with PCRO are well explained, among which the CL is exposed to play a key role in forming the CLOMs. Furthermore, the PCRO-induced CLOM phenomena can also be observed in other paradigmatic network models or with other paradigmatic excitable dynamics, which definitely confirms that the PCRO is an universal method in inducing the CLOMs in excitable complex networks. Our contributions may shed lights on a new perspective of the emergence of CLOMs in complex systems and would have great impacts in related fields.

Virulent Fusarium isolates with diverse morphologies show similar invasion and colonization strategies in alfalfa.

Root rot is a major disease that causes decline of alfalfa production, and Fusarium is a major pathogen associated with root rot. In this study, 13 Fusarium isolates were obtained from alfalfa with root rot in Gansu Province, the major alfalfa production region in China. The isolates were characterized by molecular genotyping (ITS, TEF 1-α and RPB2 fragments) and identified as six species, which included the F. acuminatum, F. incarnatum, F. oxysporum, F. proliferatum, F. redolens, and F. solani. We found that their morphology varied significantly at both the macro- and micro-levels, even for those from the same species. We developed a low cost and fast pathogenicity test and revealed that all isolates were pathogenic to alfalfa with typical root rot symptoms such as leaf yellowing and brown lesions on the root and stem. However, the virulence of the isolates differed. We also found that the conidia of all isolates germinated as early as 24 hours post inoculation (hpi), while hyphae colonized the root extensively and invaded the xylem vessel by 48 hpi. Together our results reveal that different virulent Fusarium isolates use a similar invasion strategy in alfalfa. This natural plant-fungus pathosystem is intriguing and warrants further examination, particularly with regard to efforts aimed at mitigating the impact of multiple similar vascular pathogens on infected alfalfa plants.

Spatial metabolomics reveals key features of hippocampal lipid changes in rats with postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery. Numerous evidence suggest that dysregulation of lipid metabolism is associated with cognitive impairment; however, its precise role in the development of POCD is still obscure. In this study, we established a cardiopulmonary bypass (CPB) model in rats and employed the Barnes maze to assess cognitive function, selecting POCD rats for subsequent experimentation. Utilizing mass spectrometry imaging, we detected plenty of lipids accumulates within the hippocampal CA1in the POCD group. Immunofluorescence staining revealed a significant reduction in the fluorescence intensity of calcium-independent phospholipases A2 (iPLA2) in the POCD group compared to the control, while serine palmitoyl transferase (SPT) was markedly increased in the POCD group. Transmission electron microscopy revealed that the number of synapses in hippocampal CA1decreased significantly and postsynaptic density became thinner in POCD group. Furthermore, after reversing the metabolic disorders of iPLA2 and SPT in the rat brain with docosahexaenoic acid and myriocin, the incidence of POCD after CPB was significantly reduced and the disrupted lipid metabolism in the hippocampus was also normalized. These findings may offer a novel perspective for exploring the etiology and prevention strategies of POCD after CPB.

Prediagnosis recognition of acute ischemic stroke by artificial intelligence from facial images.

Stroke is a major threat to life and health in modern society, especially in the aging population. Stroke may cause sudden death or severe sequela-like hemiplegia. Although computed tomography (CT) and magnetic resonance imaging (MRI) are standard diagnosis methods, and artificial intelligence models have been built based on these images, shortage in medical resources and the time and cost of CT/MRI imaging hamper fast detection, thus increasing the severity of stroke. Here, we developed a convolutional neural network model by integrating four networks, Xception, ResNet50, VGG19, and EfficientNetb1, to recognize stroke based on 2D facial images with a cross-validation area under curve (AUC) of 0.91 within the training set of 185 acute ischemic stroke patients and 551 age- and sex-matched controls, and AUC of 0.82 in an independent data set regardless of age and sex. The model computed stroke probability was quantitatively associated with facial features, various clinical parameters of blood clotting indicators and leukocyte counts, and, more importantly, stroke incidence in the near future. Our real-time facial image artificial intelligence model can be used to rapidly screen and prediagnose stroke before CT scanning, thus meeting the urgent need in emergency clinics, potentially translatable to routine monitoring.

LINC00982-encoded protein PRDM16-DT regulates CHEK2 splicing to suppress colorectal cancer metastasis and chemoresistance.

Metastasis is one of the key factors of treatment failure in late-stage colorectal cancer (CRC). Metastatic CRC frequently develops resistance to chemotherapeutic agents. This study aimed to identify the novel regulators from "hidden" proteins encoded by long noncoding RNAs (lncRNAs) involved in tumor metastasis and chemoresistance. Methods: CRISPR/Cas9 library functional screening was employed to identify the critical suppressor of cancer metastasis in highly invasive CRC models. Western blotting, immunofluorescence staining, invasion, migration, wound healing, WST-1, colony formation, gain- and loss-of-function experiments, in vivo experimental metastasis models, multiplex immunohistochemical staining, immunohistochemistry, qRT-PCR, and RT-PCR were used to assess the functional and clinical significance of FOXP3, PRDM16-DT, HNRNPA2B1, and L-CHEK2. RNA-sequencing, co-immunoprecipitation, qRT-PCR, RT-PCR, RNA affinity purification, RNA immunoprecipitation, MeRIP-quantitative PCR, fluorescence in situ hybridization, chromatin immunoprecipitation and luciferase reporter assay were performed to gain mechanistic insights into the role of PRDM16-DT in cancer metastasis and chemoresistance. An oxaliplatin-resistant CRC cell line was established by in vivo selection. WST-1, colony formation, invasion, migration, Biacore technology, gain- and loss-of-function experiments and an in vivo experimental metastasis model were used to determine the function and mechanism of cimicifugoside H-1 in CRC. Results: The novel protein PRDM16-DT, encoded by LINC00982, was identified as a cancer metastasis and chemoresistance suppressor. The down-regulated level of PRDM16-DT was positively associated with malignant phenotypes and poor prognosis of CRC patients. Transcriptionally regulated by FOXP3, PRDM16-DT directly interacted with HNRNPA2B1 and competitively decreased HNRNPA2B1 binding to exon 9 of CHEK2, resulting in the formation of long CHEK2 (L-CHEK2), subsequently promoting E-cadherin secretion. PRDM16-DT-induced E-cadherin secretion inhibited fibroblast activation, which in turn suppressed CRC metastasis by decreasing MMP9 secretion. Cimicifugoside H-1, a natural compound, can bind to LEU89, HIS91, and LEU92 of FOXP3 and significantly upregulated PRDM16-DT expression to repress CRC metastasis and reverse oxaliplatin resistance. Conclusions: lncRNA LINC00982 can express a new protein PRDM16-DT to function as a novel regulator in cancer metastasis and drug resistance of CRC. Cimicifugoside H-1 can act on the upstream of the PRDM16-DT signaling pathway to alleviate cancer chemoresistance.