Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development.

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.

LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

The chromosome-level assembly of the wild diploid alfalfa genome provides insights into the full landscape of genomic variations between cultivated and wild alfalfa.

Alfalfa (Medicago sativa L.) is one of the most important forage legumes in the world, including autotetraploid (M. sativa ssp. sativa) and diploid alfalfa (M. sativa ssp. caerulea, progenitor of autotetraploid alfalfa). Here, we reported a high-quality genome of ZW0012 (diploid alfalfa, 769 Mb, contig N50 = 5.5 Mb), which was grouped into the Northern group in population structure analysis, suggesting that our genome assembly filled a major gap among the members of M. sativa complex. During polyploidization, large phenotypic differences occurred between diploids and tetraploids, and the genetic information underlying its massive phenotypic variations remains largely unexplored. Extensive structural variations (SVs) were identified between ZW0012 and XinJiangDaYe (an autotetraploid alfalfa with released genome). We identified 71 ZW0012-specific PAV genes and 1296 XinJiangDaYe-specific PAV genes, mainly involved in defence response, cell growth, and photosynthesis. We have verified the positive roles of MsNCR1 (a XinJiangDaYe-specific PAV gene) in nodulation using an Agrobacterium rhizobia-mediated transgenic method. We also demonstrated that MsSKIP23_1 and MsFBL23_1 (two XinJiangDaYe-specific PAV genes) regulated leaf size by transient overexpression and virus-induced gene silencing analysis. Our study provides a high-quality reference genome of an important diploid alfalfa germplasm and a valuable resource of variation landscape between diploid and autotetraploid, which will facilitate the functional gene discovery and molecular-based breeding for the cultivars in the future.

ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing intracellular glycine biosynthesis.

BACKGROUND: Zinc finger SWIM-type containing 4 (ZSWIM4) induces drug resistance in breast cancer cells. However, its role in epithelial ovarian cancer (EOC) remains unknown. In this study, we aimed to investigate the clinical significance of ZSWIM4 expression in EOC and develop new clinical therapeutic strategies for EOC. METHODS: ZSWIM4 expression in control and EOC tumor tissues was examined using immunohistochemistry. Lentiviral transduction, Cell Counting Kit-8 assay, tumorsphere formation assay, flow cytometry, western blotting, and animal xenograft model were used to assess the role of ZSWIM4 in chemotherapy. Cleavage Under Targets and Tagmentation (CUT&Tag) assays, chromatin immunoprecipitation assays, and luciferase reporter assays were used to confirm FOXK1-mediated upregulation of ZSWIM4 expression. The mechanism by which ZSWIM4 inhibition improves chemosensitivity was evaluated using RNA-sequencing. A ZSWIM4-targeting inhibitor was explored by virtual screening and surface plasmon resonance analysis. Patient-derived organoid (PDO) models were constructed from EOC tumor tissues with ZSWIM4 expression. RESULTS: ZSWIM4 was overexpressed in EOC tumor tissues and impaired patient prognoses. Its expression correlated positively with EOC recurrence. ZSWIM4 expression was upregulated following carboplatin treatment, which, in turn, contributed to chemoresistance. Silencing ZSWIM4 expression sensitized EOC cells to carboplatin treatment in vitro and in vivo. FOXK1 could bind to the GTAAACA sequence of the ZSWIM4 promoter region to upregulate ZSWIM4 transcriptional activity and FOXK1 expression increased following carboplatin treatment, leading to an increase in ZSWIM4 expression. Mechanistically, ZSWIM4 knockdown downregulated the expression of several rate-limiting enzymes involved in glycine synthesis, causing a decrease in intracellular glycine levels, thus enhancing intracellular reactive oxygen species production induced by carboplatin treatment. Compound IPN60090 directly bound to ZSWIM4 protein and exerted a significant chemosensitizing effect in both EOC cells and PDO models. CONCLUSIONS: ZSWIM4 inhibition enhanced EOC cell chemosensitivity by ameliorating intracellular glycine metabolism reprogramming, thus providing a new potential therapeutic strategy for EOC.

Diastereodivergent and Regioselective Synthesis of Tetrahydrofuro[2,3-b]furans with Four Consecutive Stereocenters.

Base-catalyzed diastereodivergent and regioselective domino processes of triketone enones with arylacetaldehydes for the synthesis of tetrahydrofuro[2,3-b]furans with four consecutive stereocenters are reported. Good yields and diastereoselectivities are obtained when DBU is employed as a catalyst; in contrast, Et3N delivers a different diastereomer in excellent diastereoselectivity. This work offers many advantages, including switchable diastereoselectivity, cheap base catalysts, and a simple operation.

Establishment of a real-time fluorescent quantitative PCR detection method and phylogenetic analysis of BoAHV-1.

BACKGROUND: Infectious bovine rhinotracheitis (IBR), caused by Bovine alphaherpesvirus-1 (BoAHV-1), is an acute, highly contagious disease primarily characterized by respiratory tract lesions in infected cattle. Due to its severe pathological damage and extensive transmission, it results in significant economic losses in the cattle industry. Accurate detection of BoAHV-1 is of paramount importance. In this study, we developed a real-time fluorescent quantitative PCR detection method for detecting BoAHV-1 infections. Utilizing this method, we tested clinical samples and successfully identified and isolated a strain of BoAHV-1.1 from positive samples. Subsequently, we conducted a genetic evolution analysis on the isolate strain's gC, TK, gG, gD, and gE genes. RESULTS: The study developed a real-time quantitative PCR detection method using SYBR Green II, achieving a detection limit of 7.8 × 101 DNA copies/µL. Specificity and repeatability analyses demonstrated no cross-reactivity with other related pathogens, highlighting excellent repeatability. Using this method, 15 out of 86 clinical nasal swab samples from cattle were found to be positive (17.44%), which was higher than the results obtained from conventional PCR detection (13.95%, 12/86). The homology analysis and phylogenetic tree analysis of the gC, TK, gG, gD, and gE genes of the isolated strain indicate that the JL5 strain shares high homology with the BoAHV-1.1 reference strains. Amino acid sequence analysis revealed that gC, gE, and gG each had two amino acid mutations, while the TK gene had one synonymous mutation and one H to Y mutation, with no amino acid mutations observed in the gD gene. Phylogenetic tree analysis indicated that the JL5 strain belongs to the BoAHV-1.1 genotype and is closely related to American strains such as C33, C14, and C28. CONCLUSIONS: The established real-time fluorescent quantitative PCR detection method exhibits good repeatability, specificity, and sensitivity. Furthermore, genetic evolution analysis of the isolated BoAHV-1 JL-5 strain indicates that it belongs to the BoAHV-1.1 subtype. These findings provide a foundation and data for the detection, prevention, and control Infectious Bovine Rhinotracheitis.

Platinum-ruthenium-iron embedded in nitrogen-doped ordered mesoporous carbon for adrenaline electrochemical sensing study.

A novel nitrogen-doped ordered mesoporous carbon (OMC) pore-embedded growth Pt-Ru-Fe nanoparticles (Pt1-Ru7.5-Fex@N-OMCs) composite was designed and synthesized for the first time. SBA-15 was used as a template, and dopamine was used as a carbon and nitrogen source and metal linking reagent. The oxidative self-polymerization reaction of dopamine was utilized to polymerize dopamine into two-dimensional ordered SBA-15 template pores. Iron porphyrin was introduced as an iron source at the same time as polymerization of dopamine, which was introduced inside and outside the pores using dopamine-metal linkage. Carbonization of polydopamine, nitrogen doping and iron nanoparticle formation were achieved by one-step calcination. Then the templates were etched to form Fex@N-OMCs, and finally the Pt1-Ru7.5-Fex@N-OMCs composites were stabilized by the successful introduction of platinum-ruthenium nanoparticles through the substitution reaction. The composite uniformly embeds the transition metal nanoparticles inside the OMC pores with high specific surface area, which limits the size of the metal nanoparticles inside the pores. At the same time, the metal nanoparticles are also loaded onto the surface of the OMCs, realizing the uniform loading of metal nanoparticles both inside and outside the pores. This enhances the active sites of the composite, promotes the mass transfer process inside and outside the pores, and greatly enhances the electrocatalytic performance of the catalyst. The material shows high electrocatalytic performance for adrenaline, which is characterized by a wide linear range, high sensitivity and low detection limit, and can realize the detection of actual samples.

Summer heatwaves promote harmful algal blooms in the Fuchunjiang Reservoir, an important drinking water source.

Extensive outbreaks of harmful algal blooms (HABs) occurred in the Fuchunjiang Reservoir in 2022, a crucial urban drinking water source, coinciding with extreme summer heatwaves. We hypothesize that these heatwaves contributed to HABs formation and expansion. Leveraging Landsat 8 and Sentinel-2 data, we employed clustering and machine learning methods to quantify the HABs distribution and area. Concurrent meteorological and water quality data aided in uncovering the effects of heatwave on HABs. When applying different methods to extract HABs from remote sensing images, random forest (RF) analyses indicated accuracies of 99.3% and 99.8% for Landsat 8 and Sentinel-2 data, respectively, while classification and regression tree (CART) analyses indicated 99.1% and 99.7% accuracies, respectively. Support vector machine (SVM) exhibited lower accuracies (83.5% and 97.4%). Thus RF, given its smaller differences between satellites and high accuracy, was selected for further analysis. Both satellites detected extensive HABs in 2022, with Sentinel-2 recording a peak area of 24.13 km2 (44.6% of cloud-free water area) on August 11, 2022. Increasing trends with amplified durations were observed for summer heatwaves in Jiande and Tonglu around the Fuchunjiang Reservoir. Notably, these areas experienced extreme heatwaves for 63 and 58 days in 2022, respectively, more than double the 1980-2022 average. From June 1 to October 8, 2022, water temperature peaks significantly coincided with expansive HABs and elevated chlorophyll a (Chl-a) concentration from 4.8 µg/L to 119.2 µg/L during the summer heatwaves. Our findings indicated that the reservoir became more HAB-prone during heatwave events, escalating the drinking water safety risk. These results emphasize the challenges faced by reservoir managers in dealing with climate-induced extreme heatwaves and underscore the urgency for heightened attention from water source management departments.

An alfalfa MYB-like transcriptional factor MsMYBH positively regulates alfalfa seedling drought resistance and undergoes MsWAV3-mediated degradation.

Drought is a major threat to alfalfa (Medicago sativa L.) production. The discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa cultivars. Here, we report a genome-wide association study of drought resistance in alfalfa. We identified and functionally characterized an MYB-like transcription factor gene (MsMYBH), which increases the drought resistance in alfalfa. Compared with the wild-types, the biomass and forage quality were enhanced in MsMYBH overexpressed plants. Combined RNA-seq, proteomics and chromatin immunoprecipitation analysis showed that MsMYBH can directly bind to the promoters of MsMCP1, MsMCP2, MsPRX1A and MsCARCAB to improve their expression. The outcomes of such interactions include better water balance, high photosynthetic efficiency and scavenge excess H2O2 in response to drought. Furthermore, an E3 ubiquitin ligase (MsWAV3) was found to induce MsMYBH degradation under long-term drought, via the 26S proteasome pathway. Furthermore, variable-number tandem repeats in MsMYBH promoter were characterized among a collection of germplasms, and the variation is associated with promoter activity. Collectively, our findings shed light on the functions of MsMYBH and provide a pivotal gene that could be leveraged for breeding drought-resistant alfalfa. This discovery also offers new insights into the mechanisms of drought resistance in alfalfa.

Functional and phylogenetic relationships link predators to plant diversity via trophic and non-trophic pathways.

Human-induced biodiversity loss negatively affects ecosystem function, but the interactive effects of biodiversity change across trophic levels remain insufficiently understood. We sampled arboreal spiders and lepidopteran larvae across seasons in 2 years in a subtropical tree diversity experiment, and then disentangled the links between tree diversity and arthropod predator diversity by deconstructing the pathways among multiple components of diversity (taxonomic, phylogenetic and functional) with structural equation models. We found that herbivores were major mediators of plant species richness effects on abundance, species richness, functional and phylogenetic diversity of predators, while phylogenetic, functional and structural diversity of trees were also important mediators of this process. However, the strength and direction differed between functional, structural and phylogenetic diversity effects, indicating different underlying mechanisms for predator community assembly. Abundance and multiple diversity components of predators were consistently affected by tree functional diversity, indicating that the variation in structure and environment caused by plant functional composition might play key roles in predator community assembly. Our study highlights the importance of an integrated approach based on multiple biodiversity components in understanding the consequences of biodiversity loss in multitrophic communities.

Urbanization shifts long-term phenology and severity of phytoplankton blooms in an urban lake through different pathways.

Climate change can induce phytoplankton blooms (PBs) in eutrophic lakes worldwide, and these blooms severely threaten lake ecosystems and human health. However, it is unclear how urbanization and its interaction with climate impact PBs, which has implications for the management of lakes. Here, we used multi-source remote sensing data and integrated the Virtual-Baseline Floating macroAlgae Height (VB-FAH) index and OTSU threshold automatic segmentation algorithm to extract the area of PBs in Lake Dianchi, China, which has been subjected to frequent PBs and rapid urbanization in its vicinity. We further explored long-term (2000-2021) trends in the phenological and severity metrics of PBs and quantified the contributions from urbanization, climate change, and also nutrient levels to these trends. When comparing data from 2011-2021 to 2000-2010, we found significantly advanced initiation of PBs (28.6 days) and noticeably longer duration (51.9 days) but an insignificant trend in time of disappearance. The enhancement of algal nutrient use efficiency, likely induced by increased water temperature and reduced nutrient concentrations, presumably contributed to an earlier initiation and longer duration of PBs, while there was a negative correlation between spring wind speed and the initiation of PBs. Fortunately, we found that both the area of the PBs and the frequency of severe blooms (covering more than 19.8 km2 ) demonstrated downward trends, which could be attributed to increased wind speed and/or reduced nutrient levels. Moreover, the enhanced land surface temperature caused by urbanization altered the thermodynamic characteristics between the land and the lake, which, in turn, possibly caused an increase in local wind speed and water temperature, suggesting that urbanization can differently regulate the phenology and severity of PBs. Our findings have significant implications for the understanding of the impacts of urbanization on PB dynamics and for improving lake management practices to promote sustainable urban development under global change.

Virtual screening of carboxylic acid reductases for biocatalytic synthesis of 6-aminocaproic acid and 1,6-hexamethylenediamine.

The key precursors for nylon synthesis, that is, 6-aminocaproic acid (6-ACA) and 1,6-hexamethylenediamine (HMD), are produced from petroleum-based feedstocks. A sustainable biocatalytic alternative method from bio-based adipic acid has been demonstrated recently. However, the low efficiency and specificity of carboxylic acid reductases (CARs) used in the process hampers its further application. Herein, we describe a highly accurate protein structure prediction-based virtual screening method for the discovery of new CARs, which relies on near attack conformation frequency and the Rosetta Energy Score. Through virtual screening and functional detection, five new CARs were selected, each with a broad substrate scope and the highest activities toward various di- and ω-aminated carboxylic acids. Compared with the reported CARs, KiCAR was highly specific with regard to adipic acid without detectable activity to 6-ACA, indicating a potential for 6-ACA biosynthesis. In addition, MabCAR3 had a lower Km with regard to 6-ACA than the previously validated CAR MAB4714, resulting in twice conversion in the enzymatic cascade synthesis of HMD. The present work highlights the use of structure-based virtual screening for the rapid discovery of pertinent new biocatalysts.

Tree dissimilarity determines multi-dimensional beta-diversity of herbivores and carnivores via bottom-up effects.

Global biodiversity decline and its cascading effects through trophic interactions pose a severe threat to human society. Establishing the impacts of biodiversity decline requires a more thorough understanding of multi-trophic interactions and, more specifically, the effects that loss of diversity in primary producers has on multi-trophic community assembly. Within a synthetic conceptual framework for multi-trophic beta-diversity, we tested a series of hypotheses on neutral and niche-based bottom-up processes in assembling herbivore and carnivore communities in a subtropical forest using linear models, hieratical variance partitioning based on linear mixed-effects models (LMMs) and simulation. We found that the observed taxonomic, phylogenetic and functional beta-diversity of both herbivorous caterpillars and carnivorous spiders were significantly and positively related to tree dissimilarity. Linear models and variance partitioning for LMMs jointly suggested that as a result of bottom-up effects, producer dissimilarities were predominant in structuring consumer dissimilarity, the strength of which highly depended on the trophic dependencies on producers, the diversity facet examined, and data quality. Importantly, linear models for standardized beta-diversities against producer dissimilarities implied a transition between niche-based processes such as environmental filtering and competitive exclusion, which supports the role of bottom-up effect in determining consumer community assembly. These findings enrich our mechanistic understanding of the 'Diversity Begets Diversity' hypothesis and the complexity of higher-trophic community assembly, which is fundamental for sustainable biodiversity conservation and ecosystem management.

A case report of isolated right ventricular noncompaction with mutation of ACVRL1: a new cause of noncompaction of ventricular myocardium?

BACKGROUND: Noncompaction of ventricular myocardium(NVM) is a rare kind of cardiomyopathy associated with genetic mutations and nongenetic factors, among which the isolated right ventricular noncompaction (iRVNC) is the most rare type. ACVRL1 is the pathogenic gene of type 2 hereditary hemorrhagic telangiectasia (HHT2), and there's no NVM reported to be associated with ACVRL1 mutation. CASE PRESENTATION: This is a rare case diagnosed as iRVNC and pulmonary hypertention with ACVRL1 mutation detected. CONCLUSION: iRVNC in this case may be due to ACVRL1 mutation, secondary to pulmonary hypertention and right ventricular failure caused by ACVRL1 mutation, or they happened in the same case coincidently.

Syncope as the initial symptom in a patient with nasopharyngeal carcinoma: a case report.

BACKGROUND: A high prevalence of nasopharyngeal carcinoma (NPC) has been found in China, but it rarely occurs with syncope. Studies have demonstrated that syncope due to NPC may be related to carotid sinus syndrome, glossopharyngeal irritation, and parapharyngeal and retropharyngeal space lesions. Such patients require evaluation by nasopharyngoscopy and head magnetic resonance imaging/computed tomography. There is no known single effective treatment for these patients. Various interventions may be considered in an effort to relieve syncope, including vasoconstrictive drugs, cardiac pacemaker implantation, radiotherapy and chemotherapy, and surgical resection. CASE PRESENTATION: This case report describes a 56-year-old man who developed recurrent syncope with atrial fibrillation, a long RR interval, and hypotension. A single chamber pacemaker was fitted, but it failed to relieve the symptom. Cranial magnetic resonance imaging and pathological tests led to a final diagnosis of NPC. After six courses of chemotherapy and 35 sessions of radiotherapy, the patient became asymptomatic. However, he died from a massive uncontrolled hemorrhage in the nasopharynx two years later. CONCLUSIONS: This case brings attention to the fact that syncope can be a symptom of NPC. Due to the insidiously malignant nature of this cancer, when a patient presents with syncope, clinicians should bear in mind this connection, albeit a rare one. There are at least two ways of treating NPC-associated syncope, but there is disagreement about which is the most effective.

LncRNA RPPH1 acts as a molecular sponge for miR-122 to regulate Wnt1/ß-catenin signaling in hepatocellular carcinoma.

This study aimed to explore the role of lncRNA RPPH1 in hepatocellular carcinoma. The expression of RPPH1 and miR-122 was determined by Real-time PCR. Cell proliferation and colony formation assays were employed to monitor cell growth in vitro. Wound healing and Transwell assays were applied to detect cell migration and invasion. A dual-luciferase reporter assay was used to verify the interaction between RPPH1 and miR-122. The in vivo function of RPPH1 was illustrated by xenograft tumor models. The results showed that the expression of RPPH1 was markedly upregulated in human HCC specimens and cell lines compared to normal controls. However, the trend of miR-122 was the opposite. RPPH1 facilitates the proliferation, migration, and invasion of HCC cells and synchronously suppresses cell apoptosis. The dual-luciferase assay confirmed the relationship between RPPH1 and miR-122. Rescue experiments showed that RPPH1 acted as a competing endogenous RNA (ceRNA) by sponging miR-122 in HCC cells. Moreover, RPPH1 positively regulated the expression of Wnt1 and its downstream targets through miR-122. Our study demonstrates for the first time that RPPH1 promotes HCC progression via the miR-122/Wnt1/ß-catenin axis, which may represent a valuable therapeutic target for patients with HCC.

The novel left atrial appendage strain parameters are associated with thrombosis risk in patients with non-valvular atrial fibrillation.

OBJECTIVES: We sought to explore a novel left atrial appendage (LAA) strain parameter which could represent the cumulative adverse impact of chronic Atrial fibrillation (AF) on the LAA function, and the relationship between the LAA strain parameter and thrombosis risk in patients with non-valvular AF. METHODS: We enrolled 268 patients with non-valvular AF and 58 sinus rhythm subjects who underwent transesophageal echocardiography in the study. LAA longitudinal strain amplitude (LAA LSA) was defined as the sum of the value of the maximum positive peak strain (LAA PLS) and the absolute value of the minimum negative peak strain (LAA NLS). Dense spontaneous echo contrast (SEC) was defined as grade 3 or 4 SEC. RESULTS: Compared to sinus rhythm group, the global LAA strain parameters were significantly lower in paroxysmal AF (n = 148), and the lowest of them were found in persistent AF (n = 120), which suggested that the global LAA strain parameters could evaluate LAA function in sinus rhythm, paroxysmal AF and persistent AF. Compared with patients in AF without SEC/thrombus (n = 113), the regional and global LAA strain parameters were significantly depressed in AF with SEC/thrombus (n = 155). Multivariate logistic regression analyses showed that LAA global LSA (OR 0.768; 95% CI:0.569, 0.970; p = 0.027) was an independent predicter of the SEC/thrombus. Compared with patients in AF without dense SEC or thrombus (n = 210), the regional and global LAA strain parameters were significantly impaired in the patients with dense SEC/thrombus(n = 58). LAA global LSA (AUC 0.884) had the best predictable accuracy for dense SEC or thrombus, and outperformed LAA PLS, LAA NLS, CHA2DS2-VASc score and conventional LAA functional parameters that have been used in the evaluation blood flow stasis in LAA. LAA LSA showed excellent interobserver and intra-observer agreement beyond LAA PLS and LAA NLS. CONCLUSION: The novel LAA strain parameters, which were feasible and reproducible parameters for evaluation LAA mechanic function, had good predictive accuracy for blood flow stasis in LAA beyond conventional LAA functional parameters.

Machine Learning-Based Prediction of Acute Kidney Injury Following Pediatric Cardiac Surgery: Model Development and Validation Study.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication following pediatric cardiac surgery, which is associated with increased morbidity and mortality. The early prediction of CSA-AKI before and immediately after surgery could significantly improve the implementation of preventive and therapeutic strategies during the perioperative periods. However, there is limited clinical information on how to identify pediatric patients at high risk of CSA-AKI. OBJECTIVE: The study aims to develop and validate machine learning models to predict the development of CSA-AKI in the pediatric population. METHODS: This retrospective cohort study enrolled patients aged 1 month to 18 years who underwent cardiac surgery with cardiopulmonary bypass at 3 medical centers of Central South University in China. CSA-AKI was defined according to the 2012 Kidney Disease: Improving Global Outcomes criteria. Feature selection was applied separately to 2 data sets: the preoperative data set and the combined preoperative and intraoperative data set. Multiple machine learning algorithms were tested, including K-nearest neighbor, naive Bayes, support vector machines, random forest, extreme gradient boosting (XGBoost), and neural networks. The best performing model was identified in cross-validation by using the area under the receiver operating characteristic curve (AUROC). Model interpretations were generated using the Shapley additive explanations (SHAP) method. RESULTS: A total of 3278 patients from one of the centers were used for model derivation, while 585 patients from another 2 centers served as the external validation cohort. CSA-AKI occurred in 564 (17.2%) patients in the derivation cohort and 51 (8.7%) patients in the external validation cohort. Among the considered machine learning models, the XGBoost models achieved the best predictive performance in cross-validation. The AUROC of the XGBoost model using only the preoperative variables was 0.890 (95% CI 0.876-0.906) in the derivation cohort and 0.857 (95% CI 0.800-0.903) in the external validation cohort. When the intraoperative variables were included, the AUROC increased to 0.912 (95% CI 0.899-0.924) and 0.889 (95% CI 0.844-0.920) in the 2 cohorts, respectively. The SHAP method revealed that baseline serum creatinine level, perfusion time, body length, operation time, and intraoperative blood loss were the top 5 predictors of CSA-AKI. CONCLUSIONS: The interpretable XGBoost models provide practical tools for the early prediction of CSA-AKI, which are valuable for risk stratification and perioperative management of pediatric patients undergoing cardiac surgery.

Two new alkaloids produced by Dothideomycetes sp. BMC-101 isolated from the Magnolia grandiflora.

AbstactA total of 16 fungal strains were isolated from fresh leaves and flowers of Magnolia grandiflora and the EtOAc extracts of them were assayed for antitumor activities. Among these, the fungus Dothideomycetes sp. BMC-101 with broad spectrum inhibition was selected for further study. Four alkaloids (1-4) including two new compounds (2-(hydroxyimino)-3-phenylpropanoyl)-L-phenylalanine (1) and 8-Acetyl-bisdethiobis(methylsulfanyl)apoaranotin (4)) were isolated from Dothideomycetes sp. BMC-101. The structure of 1 was characterized with an oxime moiety formed by the condensation of two phenylalanines. To our knowledge, this is the first report on a fungal phenylalanine derivative with an oxime moiety.

Optimizing payment for ecosystem services in a drinking water source watershed by quantifying the supply and demand of soil retention service.

Payment for ecosystem services (PES) plays a vital role in coordinating the relationship between ecosystem services supply and demand sides in watersheds. The upstream soil retention service brings significant off-site benefits to the downstream stakeholders. To fill gaps in the supply and demand of soil retention services for PES, we developed an approach that combined long-term observation data, hydrological model, and cost-benefit analysis. We applied and demonstrated the approach in a typical drinking water source watershed. By constructing the relationship between water clarity and the demanded trophic state, we identified the demand for soil retention as the suspended sediment concentration ≤4.4 mg L-1 at a transboundary station. Then, a well-calibrated hydrological model was applied to simulate the downstream sediment reduction under 36 upstream reforestation scenarios. Results showed that cropland reforestation effectively reduced downstream sediment loads by up to 37.8%. However, the efficiency of cropland reforestation for soil retention supply was influenced by its area, slope, and location. The cost-benefit analysis revealed that the feasible sediment reduction was 11,000 t per year, and the market-equilibrium price was 5800 CNY (Chinese Yuan, 7 CNY equaled 1 USD in 2020) per ton. The downstream side should pay 64 million CNY annually for soil retention provided by reforesting at upstream sloping cropland of 8° or above. This study suggested that the approach was helpful for integrating soil retention service supply and demand at a watershed scale to support PES decision-making.