Enhancing MAUDE Database Utility by GPT-4 and Cause-Effect Visualization.

The MAUDE database is a valuable public resource for understanding malfunctions and adverse events related to medical devices and health IT. However, its extensive data and complex structure pose challenges. To overcome this, we have developed an automated analytical pipeline using GPT-4, a cutting-edge large language model. This pipeline is intended to efficiently extract, categorize, and visualize safety events with minimal human annotation. In our analysis of 4,459 colonoscopy reports from MAUDE (2011-2021), the events were categorized into operational, human factor, and device-related. Ishikawa diagrams visualized a subset stored in a vector database for easy retrieval and comparison through a similarity search. This innovative approach streamlines access to vital safety insights, reducing the workload on human annotators, and holds promise to enhance the utility of the MAUDE database.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

BACKGROUND: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. METHODS: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. RESULTS: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs, short-term HSCs, and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. CONCLUSION: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. This novel and robust deep learning-based platform will provide a basis for the future development of a new generation stem cell identification and separation system. It may also provide new insight into the molecular mechanisms underlying stem cell self-renewal.

OsBCAT2, a gene responsible for the degradation of branched-chain amino acids, positively regulates salt tolerance by promoting the synthesis of vitamin B5.

Salt stress negatively affects rice growth, development and yield. Metabolic adjustments contribute to the adaptation of rice under salt stress. Branched-chain amino acids (BCAA) are three essential amino acids that cannot be synthesized by humans or animals. However, little is known about the role of BCAA in response to salt stress in plants. Here, we showed that BCAAs may function as scavengers of reactive oxygen species (ROS) to provide protection against damage caused by salinity. We determined that branched-chain aminotransferase 2 (OsBCAT2), a protein responsible for the degradation of BCAA, positively regulates salt tolerance. Salt significantly induces the expression of OsBCAT2 rather than BCAA synthesis genes, which indicated that salt mainly promotes BCAA degradation and not de novo synthesis. Metabolomics analysis revealed that vitamin B5 (VB5) biosynthesis pathway intermediates were higher in the OsBCAT2-overexpressing plants but lower in osbcat2 mutants under salt stress. The salt stress-sensitive phenotypes of the osbcat2 mutants are rescued by exogenous VB5, indicating that OsBCAT2 affects rice salt tolerance by regulating VB5 synthesis. Our work provides new insights into the enzymes involved in BCAAs degradation and VB5 biosynthesis and sheds light on the molecular mechanism of BCAAs in response to salt stress.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

Background: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. Methods: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. Results: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. Conclusion: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. With ongoing advancements in model algorithms and their integration into various imaging systems, deep learning stands poised to become an invaluable tool, significantly impacting stem cell research.

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases.

OsMDH12: A Peroxisomal Malate Dehydrogenase Regulating Tiller Number and Salt Tolerance in Rice.

Salinity is an important environmental factor influencing crop growth and yield. Malate dehydrogenase (MDH) catalyses the reversible conversion of oxaloacetate (OAA) to malate. While many MDHs have been identified in various plants, the biochemical function of MDH in rice remains uncharacterised, and its role in growth and salt stress response is largely unexplored. In this study, the biochemical function of OsMDH12 was determined, revealing its involvement in regulating tiller number and salt tolerance in rice. OsMDH12 localises in the peroxisome and is expressed across various organs. In vitro analysis confirmed that OsMDH12 converts OAA to malate. Seedlings of OsMDH12-overexpressing (OE) plants had shorter shoot lengths and lower fresh weights than wild-type (WT) plants, while osmdh12 mutants displayed the opposite. At maturity, OsMDH12-OE plants had fewer tillers than WT, whereas osmdh12 mutants had more, suggesting OsMDH12's role in tiller number regulation. Moreover, OsMDH12-OE plants were sensitive to salt stress, but osmdh12 mutants showed enhanced salt tolerance. The Na+/K+ content ratio increased in OsMDH12-OE plants and decreased in osmdh12 mutants, suggesting that OsMDH12 might negatively affect salt tolerance through influencing the Na+/K+ balance. These findings hint at OsMDH12's potential as a genetic tool to enhance rice growth and salt tolerance.

Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments.

Cell migration occurs in confined microenvironments, which plays a vital role in the process of tumor metastasis. However, it is challenging to study their behaviors in vivo. Here we developed a cell squeeze system that can be scaled down to micrometers to mimic native physical confined microenvironments, wherein degrees of surface adhesion and mechanical constraints could be manipulated in order to investigate cell-migrating behaviors. Based on the microscale cell squeeze system, we found the synergistic role of lamin A/C and vimentin in cell transition and migration under strong confinement. The dynamic variations in lamin A/C and vimentin expression establish a positive feedback loop in response to confinement, effectively promoting amoeboid migration by modulating nuclear deformability while ensuring cell viability. This work shed light on modulating cell response to microenvironments by altering the expression of lamin A/C and/or vimentin, which may be a more efficient way of inhibiting cancer metastasis.

A new peptide, VD11, promotes structural and functional recovery after spinal cord injury.

The regenerative capacity of the central nervous system is very limited and few effective treatments are currently available for spinal cord injury. It is therefore a priority to develop new drugs that can promote structural and functional recovery after spinal cord injury. Previous studies have shown that peptides can promote substantial repair and regeneration of injured tissue. While amphibians have a pronounced ability to regenerate the spinal cord, few studies have investigated the effect of amphibian spinal cord-derived peptides on spinal cord injury. Here we report for the first time the successful identification and isolation of a new polypeptide, VD11 (amino acid sequence: VDELWPPWLPC), from the spinal cord of an endemic Chinese amphibian (Odorrana schmackeri). In vitro experiments showed that VD11 promoted the secretion of nerve growth factor and brain-derived neurotrophic factor in BV2 cells stimulated with lipopolysaccharide, as well as the proliferation and synaptic elongation of PC12 cells subjected to hypoxia. In vivo experiments showed that intravertebral injection of VD11 markedly promoted recovery of motor function in rats with spinal cord injury, alleviated pathological damage, and promoted axonal regeneration. Furthermore, RNA sequencing and western blotting showed that VD11 may affect spinal cord injury through activation of the AMPK and AKT signaling pathways. In summary, we discovered a novel amphibian-derived peptide that promotes structural and functional recovery after spinal cord injury.

Natural variations of OsAUX5, a target gene of OsWRKY78, control the neutral essential amino acid content in rice grains.

Grain essential amino acid (EAA) levels contribute to rice nutritional quality. However, the molecular mechanisms underlying EAA accumulation and natural variation in rice grains remain unclear. Here we report the identification of a previously unrecognized auxin influx carrier subfamily gene, OsAUX5, which encodes an amino acid transporter that functions in uptake of multiple amino acids. We identified an elite haplotype of Pro::OsAUX5Hap2 that enhances grain EAA accumulation without an apparent negative effect on agronomic traits. Natural variations of OsAUX5 occur in the cis elements of its promoter, which are differentially activated because of the different binding affinity between OsWRKY78 and the W-box, contributing to grain EAA variation among rice varieties. The two distinct haplotypes were shown to have originated from different Oryza rufipogon progenitors, which contributed to the divergence between japonica and indica. Introduction of the indica-type Pro::OsAUX5Hap2 genotype into japonica could significantly increase EAA levels, indicating that indica-type Pro::OsAUX5Hap2 can be utilized to increase grain EAAs of japonica varieties. Collectively, our study uncovers an WRKY78-OsAUX5-based regulatory mechanism controlling grain EAA accumulation and provides a potential target for breeding EAA-rich rice.

Translation and validation of the Chinese version of Patient-completed Asthma Knowledge Questionnaire and its implementation in patient education.

Background: Poor control of asthma results from many factors, partly due to inadequate knowledge towards asthma among patients. It is necessary to know patients' knowledge level before education. However, there is no accepted instrument to evaluate knowledge of asthma in Chinese patients with asthma. The study aims to develop a Chinese version of Patient-completed Asthma Knowledge Questionnaire (PAKQ) to assess its reliability, validity, and responsiveness for testing its clinical application in Chinese adult patients with asthma. Methods: After translation, back-translation, and cross-cultural adaptation of the PAKQ into Chinese version, a survey of patients with asthma (n=464) in China was conducted. Demographics and clinical data were collected in addition to questionnaires concerning cognition of asthma, education, history, and asthma control test score. The PAKQ was then completed. 14±4 days after the initial assessment, the participants completed the retested questionnaire and again completed the questionnaire immediately after education. The reliability and the construct validity were evaluated. The optimal cut-off points for predicting disease knowledge among asthma patients were determined using the Youden index method. Results: The Chinese version of PAKQ showed high internal consistency (Cronbach's alpha =0.888) at baseline and an acceptable 2-week test-retest reliability (ICC =0.932, r=0.874). On the basis of large modification indices (>10), this four-factor questionnaire was found to fit the data satisfactorily (χ2/df =1.695, RMSEA =0.039, GFI =0.856, CFI =0.885, and SRMR =0.058). Paired t-tests showed significant changes on pre-educational and post-educational tests (t=22.83, df=463, P<0.0001). The optimal cut-off value of the PAKQ total score for assessing patients' knowledge level was 35 points (AUC =0.757). Conclusions: The Chinese version of the PAKQ questionnaire was developed and validated in terms of reliability and validity as an effective instrument for the insight into asthma knowledge of adult patients with asthma in China. Future research will evaluate the utility of the instrument in clinical practice.

OsbZIP18, a Positive Regulator of Serotonin Biosynthesis, Negatively Controls the UV-B Tolerance in Rice.

Serotonin (5-hydroxytryptamine) plays an important role in many developmental processes and biotic/abiotic stress responses in plants. Although serotonin biosynthetic pathways in plants have been uncovered, knowledge of the mechanisms of serotonin accumulation is still limited, and no regulators have been identified to date. Here, we identified the basic leucine zipper transcription factor OsbZIP18 as a positive regulator of serotonin biosynthesis in rice. Overexpression of OsbZIP18 strongly induced the levels of serotonin and its early precursors (tryptophan and tryptamine), resulting in stunted growth and dark-brown phenotypes. A function analysis showed that OsbZIP18 activated serotonin biosynthesis genes (including tryptophan decarboxylase 1 (OsTDC1), tryptophan decarboxylase 3 (OsTDC3), and tryptamine 5-hydroxylase (OsT5H)) by directly binding to the ACE-containing or G-box cis-elements in their promoters. Furthermore, we demonstrated that OsbZIP18 is induced by UV-B stress, and experiments using UV-B radiation showed that transgenic plants overexpressing OsbZIP18 exhibited UV-B stress-sensitive phenotypes. Besides, exogenous serotonin significantly exacerbates UV-B stress of OsbZIP18_OE plants, suggesting that the excessive accumulation of serotonin may be responsible for the sensitivity of OsbZIP18_OE plants to UV-B stress. Overall, we identified a positive regulator of serotonin biosynthesis and demonstrated that UV-B-stress induced serotonin accumulation, partly in an OsbZIP18-dependent manner.

Integration of rhythmic metabolome and transcriptome provides insights into the transmission of rhythmic fluctuations and temporal diversity of metabolism in rice.

Various aspects of the organisms adapt to cyclically changing environmental conditions via transcriptional regulation. However, the role of rhythmicity in altering the global aspects of metabolism is poorly characterized. Here, we subjected four rice (Oryza sativa) varieties to a range of metabolic profiles and RNA-seq to investigate the temporal relationships of rhythm between transcription and metabolism. More than 40% of the rhythmic genes and a quarter of metabolites conservatively oscillated across four rice accessions. Compared with the metabolome, the transcriptome was more strongly regulated by rhythm; however, the rhythm of metabolites had an obvious opposite trend between day and night. Through association analysis, the time delay of rhythmic transmission from the transcript to the metabolite level was ∼4 h under long-day conditions, although the transmission was nearly synchronous for carbohydrate and nucleotide metabolism. The rhythmic accumulation of metabolites maintained highly coordinated temporal relationships in the metabolic network, whereas the correlation of some rhythmic metabolites, such as branched-chain amino acids (BCAAs), was significantly different intervariety. We further demonstrated that the cumulative diversity of BCAAs was due to the differential expression of branched-chain aminotransferase 2 at dawn. Our research reveals the flexible pattern of rice metabolic rhythm existing with conservation and diversity.

Rice metabolic regulatory network spanning the entire life cycle.

As one of the most important crops in the world, rice (Oryza sativa) is a model plant for metabolome research. Although many studies have focused on the analysis of specific tissues, the changes in metabolite abundance across the entire life cycle have not yet been determined. In this study, combining both targeted and nontargeted metabolite profiling methods, a total of 825 annotated metabolites were quantified in rice samples from different tissues covering the entire life cycle. The contents of metabolites in different tissues of rice were significantly different, with various metabolites accumulating in the plumule and radicle during seed germination. Combining these data with transcriptome data obtained from the same time period, we constructed the Rice Metabolic Regulation Network. The metabolites and co-expressed genes were further divided into 12 clusters according to their accumulation patterns, with members within each cluster displaying a uniform and clear pattern of abundance across development. Using this dataset, we established a comprehensive metabolic profile of the rice life cycle and used two independent strategies to identify novel transcription factors-namely the use of known regulatory genes as bait to screen for new networks underlying lignin metabolism and the unbiased identification of new glycerophospholipid metabolism regulators on the basis of tissue specificity. This study thus demonstrates how guilt-by-association analysis of metabolome and transcriptome data spanning the entire life cycle in cereal crops provides novel resources and tools to aid in understanding the mechanisms underlying important agronomic traits.

Deep learning driven colorectal lesion detection in gastrointestinal endoscopic and pathological imaging.

Colorectal cancer has the second highest incidence of malignant tumors and is the fourth leading cause of cancer deaths in China. Early diagnosis and treatment of colorectal cancer will lead to an improvement in the 5-year survival rate, which will reduce medical costs. The current diagnostic methods for early colorectal cancer include excreta, blood, endoscopy, and computer-aided endoscopy. In this paper, research on image analysis and prediction of colorectal cancer lesions based on deep learning is reviewed with the goal of providing a reference for the early diagnosis of colorectal cancer lesions by combining computer technology, 3D modeling, 5G remote technology, endoscopic robot technology, and surgical navigation technology. The findings will supplement the research and provide insights to improve the cure rate and reduce the mortality of colorectal cancer.

MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis.

Mitochondrial antiviral signaling protein (MAVS) functions as a "switch" in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

ESM1/HIF­1α pathway modulates chronic intermittent hypoxia­induced non­small­cell lung cancer proliferation, stemness and epithelial­mesenchymal transition.

Obstructive sleep apnea (OSA) is a sleep­related disorder characterized by chronic intermittent hypoxia (CIH). Previous studies have found that intermittent hypoxia promotes drug resistance, cell proliferation, migration and invasion in non­small cell lung cancer (NSCLC). Endothelial cell­specific molecule­1 (ESM1) is a molecule shown to be overexpressed in several types of tumors. The purpose of this study was to investigate the correlation between CIH and ESM1 and their potential roles in the progression of NSCLC. Tumorspheres, cell viability and colony formation assays were used to evaluate cell proliferation. The expression levels of cancer stem cell (CSC) markers CD44, CD133, OCT4 and SOX2 were measured with western blotting and/or RT­qPCR. Transwell assays were applied to assess cell migration and invasion. Changes in the expression levels of epithelial­mesenchymal transition (EMT)­associated proteins were also detected by western blotting. The results indicated that CIH enhanced lung cancer stem cell (LCSC) NSCLC progression by promoting stemness, drug resistance, cell proliferation, migration and invasion via the ESM1/HIF­1α pathway. Unexpectedly, inhibition of ESM1 reversed the CIH­involved negative effects on LCSCs and in a mouse model. ESM1 therefore appears to be crucial mediator of CIH­mediated lung cancer progression.

SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO.

Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor κB (NF-κB) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IκB kinase alpha (IKKα)/ß/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.