Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function.

The folding and misfolding mechanism of multidomain proteins remains poorly understood. Although thermodynamic instability of the first nucleotide-binding domain (NBD1) of ΔF508 CFTR (cystic fibrosis transmembrane conductance regulator) partly accounts for the mutant channel degradation in the endoplasmic reticulum and is considered as a drug target in cystic fibrosis, the link between NBD1 and CFTR misfolding remains unclear. Here, we show that ΔF508 destabilizes NBD1 both thermodynamically and kinetically, but correction of either defect alone is insufficient to restore ΔF508 CFTR biogenesis. Instead, both ΔF508-NBD1 energetic and the NBD1-MSD2 (membrane-spanning domain 2) interface stabilization are required for wild-type-like folding, processing, and transport function, suggesting a synergistic role of NBD1 energetics and topology in CFTR-coupled domain assembly. Identification of distinct structural deficiencies may explain the limited success of ΔF508 CFTR corrector molecules and suggests structure-based combination corrector therapies. These results may serve as a framework for understanding the mechanism of interface mutation in multidomain membrane proteins.

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA.

Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG trinucleotide repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (ARE). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker ß-III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a pathway implicated in this pathology. These findings suggest that in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington's disease and spinocerebellar ataxias.

DDID: a comprehensive resource for visualization and analysis of diet-drug interactions.

Diet-drug interactions (DDIs) are pivotal in drug discovery and pharmacovigilance. DDIs can modify the systemic bioavailability/pharmacokinetics of drugs, posing a threat to public health and patient safety. Therefore, it is crucial to establish a platform to reveal the correlation between diets and drugs. Accordingly, we have established a publicly accessible online platform, known as Diet-Drug Interactions Database (DDID, https://bddg.hznu.edu.cn/ddid/), to systematically detail the correlation and corresponding mechanisms of DDIs. The platform comprises 1338 foods/herbs, encompassing flora and fauna, alongside 1516 widely used drugs and 23 950 interaction records. All interactions are meticulously scrutinized and segmented into five categories, thereby resulting in evaluations (positive, negative, no effect, harmful and possible). Besides, cross-linkages between foods/herbs, drugs and other databases are furnished. In conclusion, DDID is a useful resource for comprehending the correlation between foods, herbs and drugs and holds a promise to enhance drug utilization and research on drug combinations.

Blocking the dimerization of polyglutamine-expanded androgen receptor protects cells from DHT-induced toxicity by increasing AR turnover.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. This work seeks to investigate this mechanism by interrogating the role of AR homodimerization- a unique form of the N/C-interaction- in SBMA. We show that, although the AR N/C-interaction is reduced by polyglutamine-expansion, homodimers of 5α-dihydrotestosterone (DHT)-bound AR are increased. Additionally, blocking homodimerization results in decreased AR aggregation and toxicity in cell models. Blocking homodimerization results in the increased degradation of AR, which likely plays a role in the protective effects of this mutation. Overall, this work identifies a novel mechanism in SBMA pathology that may represent a novel target for the development of therapeutics for this disease.

CovInter: interaction data between coronavirus RNAs and host proteins.

Coronavirus has brought about three massive outbreaks in the past two decades. Each step of its life cycle invariably depends on the interactions among virus and host molecules. The interaction between virus RNA and host protein (IVRHP) is unique compared to other virus-host molecular interactions and represents not only an attempt by viruses to promote their translation/replication, but also the host's endeavor to combat viral pathogenicity. In other words, there is an urgent need to develop a database for providing such IVRHP data. In this study, a new database was therefore constructed to describe the interactions between coronavirus RNAs and host proteins (CovInter). This database is unique in (a) unambiguously characterizing the interactions between virus RNA and host protein, (b) comprehensively providing experimentally validated biological function for hundreds of host proteins key in viral infection and (c) systematically quantifying the differential expression patterns (before and after infection) of these key proteins. Given the devastating and persistent threat of coronaviruses, CovInter is highly expected to fill the gap in the whole process of the 'molecular arms race' between viruses and their hosts, which will then aid in the discovery of new antiviral therapies. It's now free and publicly accessible at: https://idrblab.org/covinter/.

Fluorogen-Functionalized Mesoporous Silica Hybrid Sensing Materials: Applications in Cu2+ Detection.

Since Cu2+ ions play a pivotal role in both ecosystems and human health, the development of a rapid and sensitive method for Cu2+ detection holds significant importance. Fluorescent mesoporous silica materials (FMSMs) have garnered considerable attention in the realm of chemical sensing, biosensing, and bioimaging due to their distinctive structure and easily functionalized surfaces. As a result, numerous Cu2+ sensors based on FMSMs have been devised and extensively applied in environmental and biological Cu2+ detection over the past few decades. This review centers on the recent advancements in the methodologies for preparing FMSMs, the mechanisms underlying sensing, and the applications of FMSMs-based sensors for Cu2+ detection. Lastly, we present and elucidate pertinent perspectives concerning FMSMs-based Cu2+ sensors.

A Mean Field to Capture Asynchronous Irregular Dynamics of Conductance-Based Networks of Adaptive Quadratic Integrate-and-Fire Neuron Models.

Mean-field models are a class of models used in computational neuroscience to study the behavior of large populations of neurons. These models are based on the idea of representing the activity of a large number of neurons as the average behavior of mean-field variables. This abstraction allows the study of large-scale neural dynamics in a computationally efficient and mathematically tractable manner. One of these methods, based on a semianalytical approach, has previously been applied to different types of single-neuron models, but never to models based on a quadratic form. In this work, we adapted this method to quadratic integrate-and-fire neuron models with adaptation and conductance-based synaptic interactions. We validated the mean-field model by comparing it to the spiking network model. This mean-field model should be useful to model large-scale activity based on quadratic neurons interacting with conductance-based synapses.

Superlubricity Achieved by a Transparent Poly(vinylpyrrolidone) Composite Hydrogel with Glycerol Ethoxylate in Ocular Conditions.

Efficient and stable ocular lubrication is pivotal in safeguarding eye tissues from wear, especially under repetitive strain due to frequent blinking. Hydrogels have been reported to possess adjustable mechanical properties, biocompatibility, durability, and elevated water content and extensive utilization in medical fields. In this work, a kind of visible photo-cross-linking poly(vinylpyrrolidone) (PVP) hydrogel was designed and synthesized using 1-vinyl-2-pyrrolidone (NVP) and poly(ethylene glycol) diacrylate (PEGDA). To optimize the structure and improve the lubrication performance of hydrogels, we prepared and investigated glycerol ethoxylate (GE)-introduced composite hydrogels (GE/PVP). The results show that the addition of 3 wt % GE helped the hydrogel to form a uniform and dense porous matrix and reduce the frictional coefficient (COF) by over 50%, achieving superlubricity (COF ≈ 0.005). However, with the excessive increase of GE (6 wt %), the structure of the hydrogel is destroyed, inducing pore walls to thin and expand. After that, a lubrication mechanism of the GE/PVP composite hydrogel was proposed, in which the addition of GE reduced the surface tension of the hydrogel, enhanced the hydration ability of the hydrogel, and thus decreased the friction between sliding surfaces. Besides, the cytotoxicity tests show that the composite hydrogels possess good biocompatibility. Overall, the as-synthesized hydrogels hold great potential as lubricating medium for use in ocular applications.

Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

Development and evaluation of genomics informed real-time PCR assays for the detection and strain typing of Mycobacterium avium subsp. paratuberculosis.

AIMS: This study aimed to identify specific genomic targets for the detection and strain typing of Map and analyse their sensitivity and specificity, and detect Map directly from faeces. METHODS AND RESULTS: A comparative genomics approach was used to identify specific genomic targets for the detection and strain typing of Map. A Map specific qPCR using the primer pair 7132 that targets a DNA segregation ATPase protein was able to detect all strains of Map and is more sensitive than the current Johne's disease PCR assays with a sensitivity of 0.0002 fg µl-1. A strain specific qPCR using the Atsa primer pair that targets the arylsulfase gene was able to differentiate between Type S and Type C strains of Map and was more sensitive than the IS1311 PCR and REA with a sensitivity of 40 fg µl-1 and was specific for Type S Map. Both assays successfully detected Map directly from faeces. CONCLUSION: This study developed and validated two genomics informed qPCR assays, 7132B Map and Atsa Type S and found both assays to be highly specific and sensitive for the detection of Map from culture and directly from faeces. This is the first time that a probe-based qPCR has been designed and developed for Map strain typing, which will greatly improve the response time during outbreak investigations.

Association between systemic immune inflammatory/inflammatory response index and hypertension: A cohort study of functional community.

BACKGROUND AND AIMS: In prospective studies, there is limited evidence of the association between inflammation and hypertension. We aimed to explore the relationship between systemic immune inflammatory index (SII)/systemic inflammatory response index (SIRI) and hypertension in a prospective cohort study to identify the best inflammatory cell markers that predict hypertension. METHODS AND RESULTS: This study was conducted in a functional community cohort in Beijing. In 2015, a total of 6003 individuals without hypertension were recruited and followed up until 2021. Using a restriction cubic spline with baseline SII/SIRI as a continuous variable, the dose-response relationship between hypertension and SII/SIRI was explored. Logistic regression was used to analyze the correlation between hypertension and SII/SIRI trajectory groups. At a mean follow-up of 6 years, 970 participants developed hypertension. SII showed a significant nonlinear dose-response relationship with hypertension (P < 0.05). Higher SII/SIRI was associated with an increased risk of hypertension (SII: RR = 1.003, 95%CI: 1.001-1.004; SIRI: RR = 1.228, 95%CI: 1.015-1.486). Both SII and SIRI were more predictive in males than females (SII: 0.698 vs. 0.695; SIRI: 0.686 vs. 0.678). CONCLUSION: Both systemic immune inflammatory index (SII) and systemic inflammatory response Index (SIRI) independently increased the risk of hypertension, and both were effective inflammatory cell indicators that predict the risk of hypertension.

Comparative study on the efficacy of PRP gel and UC-MSCs gel as adjuvant therapies in the treatment of DFU wounds.

BACKGROUND: Diabetic foot ulcer (DFU) is a common and serious complication of diabetes, and its treatment is challenging. Platelet-rich plasma (PRP) gel and umbilical cord mesenchymal stem cells (UC-MSCs) gel have been concerned as new therapies for DFU in recent years, and comparative studies on the efficacy and mechanisms of these methods, however, are rarely reported. METHODS: Thirty patients with DFU were selected and divided into the PRP group and the UC-MSCs group, and wound healing, foot blood vessels (ABI index), infection index (CRP), neuropathy symptoms (TCSS score), and foot skin temperature before and after treatment were compared between the two groups. SPSS 21.0 was used for statistical analysis. RESULTS: The results showed that the efficacy of the UC-MSCs gel group was significantly better than that of the PRP group in terms of wound healing rate, time to complete wound closure, ABI index, CRP level and TCSS score. No statistically significant difference in foot skin temperature was observed between the two groups. CONCLUSION: The efficacy of UC-MSCs gel is significantly superior to that of PRP gel in the treatment of DFU, with shortened time to complete wound closure, increased wound healing rate, better pain and infection control, and improved vascular and neurological symptoms.

Association of variability in metabolic parameters with the incidence of type 2 diabetes: evidence from a functional community cohort.

BACKGROUND: To investigate the association of variability in metabolic parameters such as total cholesterol concentrations (TC), uric acid (UA), body mass index (BMI), visceral adiposity index (VAI) and systolic blood pressure (SBP) with incident type 2 diabetes (T2D) and whether variability in these metabolic parameters has additive effects on the risk of T2D. METHODS: Based on the Beijing Functional Community Cohort, 4392 participants who underwent three health examinations (2015, 2016, and 2017) were followed up for incident T2D until the end of 2021. Variability in metabolic parameters from three health examinations were assessed using the coefficient of variation, standard deviation, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability index. Participants were grouped according to the number of high-variability metabolic parameters. Cox proportional hazards models were performed to assess the hazard ratio (HR) and 95% confidence interval (CI) for incident T2D. RESULTS: During a median follow-up of 3.91 years, 249 cases of incident T2D were identified. High variability in TC, BMI, VAI and SBP was significantly associated with higher risks of incident T2D. As for UA, significant multiplicative interaction was found between variability in UA and variability in other four metabolic parameters for incident T2D. The risk of T2D significantly increased with the increasing numbers of high-variability metabolic parameters. Compared with the group with low variability for 5 parameters, the HR (95% CI) for participants with 1-2, 3, 4-5 high-variability metabolic parameters were 1.488 (1.051, 2.107), 2.036 (1.286, 3.222) and 3.017 (1.549, 5.877), respectively. Similar results were obtained in various sensitivity analyses. CONCLUSIONS: High variability of TC, BMI, VAI and SBP were independent predictors of incident T2D, respectively. There was a graded association between the number of high-variability metabolic parameters and incident T2D.

Systematic Description of the Content Variation of Natural Products (NPs): To Prompt the Yield of High-Value NPs and the Discovery of New Therapeutics.

Natural products (NPs) have long been associated with human production and play a key role in the survival of species. Significant variations in NP content may severely affect the "return on investment" of NP-based industries and render ecological systems vulnerable. Thus, it is crucial to construct a platform that relates variations in NP content to their corresponding mechanisms. In this study, a publicly accessible online platform, NPcVar (http://npcvar.idrblab.net/), was developed, which systematically described the variations of NP contents and their corresponding mechanisms. The platform comprises 2201 NPs and 694 biological resources, including plants, bacteria, and fungi, curated using 126 diverse factors with 26,425 records. Each record contains information about the species, NP, and factors involved, as well as NP content data, parts of the plant that produce NPs, the location of the experiment, and reference information. All factors were manually curated and categorized into 42 classes which belong to four mechanisms (molecular regulation, species factor, environmental condition, and combined factor). Additionally, the cross-links of species and NP to well-established databases and the visualization of NP content under various experimental conditions were provided. In conclusion, NPcVar is a valuable resource for understanding the relationship between species, factors, and NP contents and is anticipated to serve as a promising tool for improving the yield of high-value NPs and facilitating the development of new therapeutics.

Di- and Triterpenoids from the Rhizomes of Isodon amethystoides and Their Anti-inflammatory Activities.

Amethystoidesic acid (1), a triterpenoid with an unprecedented 5/6/6/6 tetracyclic skeleton, and six undescribed diterpenoids, amethystoidins A-F (2-7), were isolated from the rhizomes of Isodon amethystoides along with 31 known di- and triterpenoids (8-38). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of a triterpenoid possessing a rare ring system (5/6/6/6) derived from a contracted A-ring and the 18,19-seco-E-ring of ursolic acid. Compounds 6, 16, 21, 22, 24, and 27 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which could be partly mediated by the downregulation of LPS-induced inducible nitric oxide synthase (iNOS) protein expression.

Significant roles of core prokaryotic microbiota across soil profiles in an organic contaminated site: Insight into microbial assemblage, co-occurrence patterns, and potentially key ecological functions.

Extreme environmental disturbances induced by organic contaminated sites impose serious impacts on soil microbiomes. However, our understanding of the responses of the core microbiota and its ecological roles in organic contaminated sites is limited. In this study, we took a typical organic contaminated site as an example and investigated the composition and structure, assembly mechanisms of core taxa and their roles in key ecological functions across soil profiles. Results presented that core microbiota with a considerably lower number of species (7.93%) than occasional taxa presented comparatively high relative abundances (38.04%) yet, which was mainly comprised of phyla Proteobacteria (49.21%), Actinobacteria (12.36%), Chloroflexi (10.63%), and Firmicutes (8.21%). Furthermore, core microbiota was more influenced by geographical differentiation than environmental filtering, which possessed broader niche widths and stronger phylogenetic signals for ecological preferences than occasional taxa. Null modelling suggested that stochastic processes dominated the assembly of the core taxa and maintained a stable proportion along soil depths. Core microbiota had a greater impact on microbial community stability and possessed higher functional redundancy than occasional taxa. Additionally, the structural equation model illustrated that core taxa played pivotal roles in degrading organic contaminants and maintaining key biogeochemical cycles potentially. Overall, this study deepens our knowledge of the ecology of core microbiota under complicated environmental conditions in organic contaminated sites, and provides a fundamental basis for preserving and potentially utilizing core microbiota to maintain soil health.

Long-term effect of submicronic particulate matter (PM1) and intermodal particulate matter (PM1-2.5) on incident dyslipidemia in China: A nationwide 5-year cohort study.

BACKGROUND: There is insufficient evidence of associations between incident dyslipidemia with PM1 (submicronic particulate matter) and PM1-2.5 (intermodal particulate matter) in the middle-aged and elderly. We aimed to determine the long-term effects of PM1 and PM1-2.5 on incident dyslipidemia respectively. METHODS: We studied 6976 individuals aged ≥45 from the China Health and Retirement Longitudinal Study from 2013 to 2018. The concentrations of particular matter (PM) for every individual's address were evaluated using a satellite-based spatiotemporal model. Dyslipidemia was evaluated by self-reported. The generalized linear mixed model was applied to quantify the correlations between PM and incident dyslipidemia. RESULTS: After a 5-year follow-up, 333 (4.77%) participants developed dyslipidemia. Per 10 µg/m³ uptick in four-year average concentrations of PMs (PM1 and PM1-2.5) corresponded to 1.11 [95% confidence interval (CI): 1.01-1.23)] and 1.23 (95% CI: 1.06-1.43) fold risks of incident dyslipidemia. Nonlinear exposure-response curves were observed between PM and incident dyslipidemia. The effect size of PM1 on incident dyslipidemia was slightly higher in males [1.14 (95% CI: 0.98-1.32) vs. 1.04 (95% CI: 0.89-1.21)], the elderly [1.23 (95% CI: 1.04-1.45) vs. 1.03 (95% CI: 0.91-1.17)], people with less than primary school education [1.12 (95% CI: 0.94-1.33) vs. 1.08 (95% CI: 0.94-1.23)], and solid cooking fuel users [1.17 (95% CI: 1.00-1.36) vs. 1.06 (95% CI: 0.93-1.21)], however, the difference was not statistically significant (Z = -0.82, P = 0.413; Z = -1.66, P = 0.097; Z = 0.32, P = 0.752; Z = -0.89, P = 0.372). CONCLUSIONS: Long-term exposure to PM1 and PM1-2.5 were linked with an increased morbidity of dyslipidemia in the middle-aged and elderly population. Males, the elderly, and solid cooking fuel users had higher risk. Further studies would be warranted to establish an accurate reference value of PM to mitigate growing dyslipidemia.

Tuberculosis in older adults: case studies from four countries with rapidly ageing populations in the western pacific region.

BACKGROUND: The Western Pacific Region has one of the fastest-growing populations of older adults (≥ 65 years) globally, among whom tuberculosis (TB) poses a particular concern. This study reports country case studies from China, Japan, the Republic of Korea, and Singapore reflecting on their experiences in managing TB among older adults. FINDINGS: Across all four countries, TB case notification and incidence rates were highest among older adults, but clinical and public health guidance focused on this population was limited. Individual country reports illustrated a range of practices and challenges. Passive case finding remains the norm, with limited active case finding (ACF) programs implemented in China, Japan, and the Republic of Korea. Different approaches have been trialled to assist older adults in securing an early diagnosis, as well as adhering to their TB treatment. All countries emphasised the need for person-centred approaches that include the creative application of new technology and tailored incentive programs, as well as reconceptualisation of how we provide treatment support. The use of traditional medicines was found to be culturally entrenched among older adults, with a need for careful consideration of their complementary use. TB infection testing and the provision of TB preventive treatment (TPT) were underutilised with highly variable practice. CONCLUSION: Older adults require specific consideration in TB response policies, given the burgeoning aging population and their high TB risk. Policymakers, TB programs and funders must invest in and develop locally contextualised practice guidelines to inform evidence-based TB prevention and care practices for older adults.

Significance of platelets in the early warning of new-onset AKI in the ICU by using supervise learning: a retrospective analysis.

OBJECTIVE: To explore a machine learning model for the early prediction of acute kidney injury (AKI) and to screen the related factors affecting new-onset AKI in the ICU. METHODS: A retrospective analysis was performed used the MIMIC-III data source. New onset of AKI defined based on the serum creatinine changed. We included 19 variables for AKI assessment using four machine learning models: support vector machines, logistic regression, and random forest. and XGBoost, using accuracy, specificity, precision, recall, F1 score, and AUROC (area under the ROC curve) to evaluate model performance. The four models predicted new-onset AKI 3-6-9-12 h ahead. The SHapley Additive exPlanation (SHAP) value is used to evaluate the feature importance of the model. RESULTS: We finally respectively extracted 1130 AKI patients and non-AKI patients from the MIMIC-III database. With the extension of the early warning time, the prediction performance of each model showed a downward trend, but the relative performance was consistent. The prediction performance comparison of the four models showed that the XGBoost model performed the best in all evaluation indicators in all the time point at new-onset AKI 3-6-9-12 h ahead (accuracy 0.809 vs 0.78 vs 0.744 vs 0.741, specificity 0.856 vs 0.826 vs 0.797 vs 0.787, precision 0.842 vs 0.81 vs 0.775 vs 0.766, recall 0.759 vs 0.734 vs 0.692 vs 0.694, Fl score 0.799 vs 0.769 vs 0.731 vs 0.729, AUROC 0.892 vs 0.857 vs 0.827 vs 0.818). In the prediction of AKI 6, 9 and 12 h ahead, the importance of creatinine, platelets, and height was the most important based on SHapley. CONCLUSIONS: The machine learning model described in this study can predict AKI 3-6-9-12 h before the new-onset of AKI in ICU. In particular, platelet plays an important role.

The new-onset of AKI in ICU is a common and important problem, which early be identified the risk of AKI can improve patients' outcomes.We explored MIMIC-III and determined the exact time point of occurrence of AKI as the basis for the new-onset of AKI in ICU.XGBoost model performed the best prediction in all the time point at new-onset AKI 3­6­9­12 h ahead.For patients with the new-onset of AKI in ICU, platelets become an important factor associated with AKI.

A novel oxoisoaporphine-type alkaloid from the rhizome of Menispermum dauricum.

A phytochemical investigation of Menispermum dauricum led to the isolation of five oxoisoaporphine-type alkaloids (1-5) and five aporphine-type alkaloids (6-10), including a novel oxoisoaporphine-type alkaloid: menispeimin A (1). Their structures were elucidated by spectroscopic studies including MS, 1 D and 2 D NMR, and confirmed by comparing with literature data. Among them, alkaloids 4-10 were obtained for the first time from Menispermum genus. Natural products 2, 4 and 6 exhibited significant cytotoxic activity against A549, Bel-7402 and MCF-7 cell lines.