SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis.

BACKGROUND: Angiogenesis, which plays a critical role in embryonic development and tissue repair, is controlled by a set of angiogenic signaling pathways. As a TF (transcription factor) belonging to the basic helix-loop-helix family, HEY (hairy/enhancer of split related with YRPW motif)-1 (YRPW motif, abbreviation of 4 highly conserved amino acids in the motif) has been identified as a key player in developmental angiogenesis. However, the precise mechanisms underlying HEY1's actions in angiogenesis remain largely unknown. Our previous studies have suggested a potential role for posttranslational SUMOylation in the dynamic regulation of vascular development and organization. METHODS: Immunoprecipitation, mass spectrometry, and bioinformatics analysis were used to determine the biochemical characteristics of HEY1 SUMOylation. The promoter-binding capability of HEY1 was determined by chromatin immunoprecipitation, dual luciferase, and electrophoretic mobility shift assays. The dimerization pattern of HEY1 was determined by coimmunoprecipitation. The angiogenic capabilities of endothelial cells were assessed by CCK-8 (cell counting kit-8), 5-ethynyl-2-deoxyuridine staining, wound healing, transwell, and sprouting assays. Embryonic and postnatal vascular growth in mouse tissues, matrigel plug assay, cutaneous wound healing model, oxygen-induced retinopathy model, and tumor angiogenesis model were used to investigate the angiogenesis in vivo. RESULTS: We identified intrinsic endothelial HEY1 SUMOylation at conserved lysines by TRIM28 (tripartite motif containing 28) as the unique E3 ligase. Functionally, SUMOylation facilitated HEY1-mediated suppression of angiogenic RTK (receptor tyrosine kinase) signaling and angiogenesis in primary human endothelial cells and mice with endothelial cell-specific expression of wild-type HEY1 or a SUMOylation-deficient HEY1 mutant. Mechanistically, SUMOylation facilitates HEY1 homodimer formation, which in turn preserves HEY1's DNA-binding capability via recognition of E-box promoter elements. Therefore, SUMOylation maintains HEY1's function as a repressive TF controlling numerous angiogenic genes, including RTKs and Notch pathway components. Proangiogenic stimuli induce HEY1 deSUMOylation, leading to heterodimerization of HEY1 with HES (hairy and enhancer of split)-1, which results in ineffective DNA binding and loss of HEY1's angiogenesis-suppressive activity. CONCLUSIONS: Our findings demonstrate that reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine-tuning the transcriptional activity of HEY1. Specifically, SUMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA-binding capability in endothelial cells.

FGFR1 SUMOylation coordinates endothelial angiogenic signaling in angiogenesis.

Angiogenesis contributes fundamentally to embryonic development, tissue homeostasis, and wound healing. Basic fibroblast growth factor (FGF2) is recognized as the first proangiogenic molecule discovered, and it facilitates angiogenesis by activating FGF receptor 1 (FGFR1) signaling in endothelial cells. However, the precise roles of FGFR and the FGF/FGFR signaling axis in angiogenesis remain unclear, especially because of the contradictory phenotypes of in vivo FGF and FGFR gene deficiency models. Our previous study results suggested a potential role of posttranslational small ubiquitin-like modifier modification (SUMOylation), with highly dynamic regulatory features, in vascular development and disorder. Here, we identified SENP1-regulated endothelial FGFR1 SUMOylation at conserved lysines responding to proangiogenic stimuli, while SENP1 functioned as the deSUMOylase. Hypoxia-enhanced FGFR1 SUMOylation restricted the tyrosine kinase activation of FGFR1 by modulating the dimerization of FGFR1 and FGFR1 binding with its phosphatase PTPRG. Consequently, it facilitated the recruitment of FRS2α to VEGFR2 but limited additional recruitment of FRS2α to FGFR1, supporting the activation of VEGFA/VEGFR2 signaling in endothelial cells. Furthermore, SUMOylation-defective mutation of FGFR1 resulted in exaggerated FGF2/FGFR1 signaling but suppressed VEGFA/VEGFR2 signaling and the angiogenic capabilities of endothelial cells, which were rescued by FRS2α overexpression. Reduced angiogenesis and endothelial sprouting in mice bearing an endothelial-specific, FGFR1 SUMOylation-defective mutant confirmed the functional significance of endothelial FGFR1 SUMOylation in vivo. Our findings identify the reversible SUMOylation of FGFR1 as an intrinsic fine-tuned mechanism in coordinating endothelial angiogenic signaling during neovascularization; SENP1-regulated FGFR1 SUMOylation and deSUMOylation controls the competitive recruitment of FRS2α by FGFR1 and VEGFR2 to switch receptor-complex formation responding to hypoxia and normoxia angiogenic environments.

Research of Pulmonary Fibrosis Lesions Based on FLIM and SHG Imaging Microscopy.

Two-photon fluorescence lifetime microscopy (TP-FLIM) is a powerful quantitative imaging technique that characterizes and analyzes the structure and function of biological samples through a combination of intensity and lifetime imaging. Because TP-FLIM is independent of the fluorescence signal intensity and the fluorophore concentration, it is widely used in high-throughput, high-content drug screening and clinical diagnostics. Second harmonic generation (SHG) imaging technology has the advantages of high spatial resolution and imaging depth inherent to nonlinear optical imaging. Second harmonics often appear in noncentrosymmetric structures. Collagen tissue in biological organisms is a good example of these structures, showing strong harmonic effects. Therefore, SHG has been widely used for imaging of specific tissue structure imaging. TP-FLIM technology is highly sensitive for quantitatively detecting changes in microenvironments. The objective of this study is to examine pathological pulmonary fibrosis slices using a combined approach of TP-FLIM and SHG technology. The fluorescence lifetime data of pulmonary collagen fibers are analyzed by using phasor plot analysis methods, and normal collagen fibers and fibrotic collagen fibers are distinguished by calculating the aspect ratio from the SHG images formed by the collagen fibers. Our study provides a new method for a deeper understanding of the pathological mechanisms and clinical diagnosis of pulmonary fibrosis and other collagen fiber-related disorders.

Cardiogenic shock in a 28-year-old woman associated with sibutramine use.

A 28-year-old woman collapsed in her home, and her companion rushed to call emergency services. Upon arrival, a physician performed CPR and endotracheal intubation, successfully restoring her voluntary heart rhythm. However, while en route to the hospital, ventricular fibrillation recurred. Despite the restoration of her voluntary rhythm through electrical defibrillation, she remained in a comatose state, which eventually led to multiple organ failures. Family members revealed that she had a 2-month history of taking diet pills. Histological examination revealed cardiomyocyte necrosis, contraction band necrosis, interstitial hemorrhage, collagen deposition, interstitial fiber proliferation, and myofiber remodeling. Analysis of blood and urine using GC-MS and LC-MS detected sibutramine and its primary metabolites, M1 and M2, which were consistent with the composition of the medication she was taking. The deceased was in good health with no underlying heart disease. The above information confirmed that the cause of her death was sibutramine.

Transformer-Based Molecular Generative Model for Antiviral Drug Design.

Since the Simplified Molecular Input Line Entry System (SMILES) is oriented to the atomic-level representation of molecules and is not friendly in terms of human readability and editable, however, IUPAC is the closest to natural language and is very friendly in terms of human-oriented readability and performing molecular editing, we can manipulate IUPAC to generate corresponding new molecules and produce programming-friendly molecular forms of SMILES. In addition, antiviral drug design, especially analogue-based drug design, is also more appropriate to edit and design directly from the functional group level of IUPAC than from the atomic level of SMILES, since designing analogues involves altering the R group only, which is closer to the knowledge-based molecular design of a chemist. Herein, we present a novel data-driven self-supervised pretraining generative model called "TransAntivirus" to make select-and-replace edits and convert organic molecules into the desired properties for design of antiviral candidate analogues. The results indicated that TransAntivirus is significantly superior to the control models in terms of novelty, validity, uniqueness, and diversity. TransAntivirus showed excellent performance in the design and optimization of nucleoside and non-nucleoside analogues by chemical space analysis and property prediction analysis. Furthermore, to validate the applicability of TransAntivirus in the design of antiviral drugs, we conducted two case studies on the design of nucleoside analogues and non-nucleoside analogues and screened four candidate lead compounds against anticoronavirus disease (COVID-19). Finally, we recommend this framework for accelerating antiviral drug discovery.

Explore drug-like space with deep generative models.

The process of design/discovery of drugs involves the identification and design of novel molecules that have the desired properties and bind well to a given disease-relevant target. One of the main challenges to effectively identify potential drug candidates is to explore the vast drug-like chemical space to find novel chemical structures with desired physicochemical properties and biological characteristics. Moreover, the chemical space of currently available molecular libraries is only a small fraction of the total possible drug-like chemical space. Deep molecular generative models have received much attention and provide an alternative approach to the design and discovery of molecules. To efficiently explore the drug-like space, we first constructed the drug-like dataset and then performed the generative design of drug-like molecules using a Conditional Randomized Transformer approach with the molecular access system (MACCS) fingerprint as a condition and compared it with previously published molecular generative models. The results show that the deep molecular generative model explores the wider drug-like chemical space. The generated drug-like molecules share the chemical space with known drugs, and the drug-like space captured by the combination of quantitative estimation of drug-likeness (QED) and quantitative estimate of protein-protein interaction targeting drug-likeness (QEPPI) can cover a larger drug-like space. Finally, we show the potential application of the model in design of inhibitors of MDM2-p53 protein-protein interaction. Our results demonstrate the potential application of deep molecular generative models for guided exploration in drug-like chemical space and molecular design.

High flow nasal cannula oxygen therapy versus non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease with acute-moderate hypercapnic respiratory failure: a randomized controlled non-inferiority trial.

BACKGROUND: Although cumulative studies have demonstrated a beneficial effect of high-flow nasal cannula oxygen (HFNC) in acute hypercapnic respiratory failure, randomized trials to compare HFNC with non-invasive ventilation (NIV) as initial treatment in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients with acute-moderate hypercapnic respiratory failure are limited. The aim of this randomized, open label, non-inferiority trial was to compare treatment failure rates between HFNC and NIV in such patients. METHODS: Patients diagnosed with AECOPD with a baseline arterial blood gas pH between 7.25 and 7.35 and PaCO2 ≥ 50 mmHg admitted to two intensive care units (ICUs) at a large tertiary academic teaching hospital between March 2018 and December 2022 were randomly assigned to HFNC or NIV. The primary endpoint was the rate of treatment failure, defined as endotracheal intubation or a switch to the other study treatment modality. Secondary endpoints were rates of intubation or treatment change, blood gas values, vital signs at one, 12, and 48 h, 28-day mortality, as well as ICU and hospital lengths of stay. RESULTS: 225 total patients (113 in the HFNC group and 112 in the NIV group) were included in the intention-to-treat analysis. The failure rate of the HFNC group was 25.7%, while the NIV group was 14.3%. The failure rate risk difference between the two groups was 11.38% (95% CI 0.25-21.20, P = 0.033), which was higher than the non-inferiority cut-off of 9%. In the per-protocol analysis, treatment failure occurred in 28 of 110 patients (25.5%) in the HFNC group and 15 of 109 patients (13.8%) in the NIV group (risk difference, 11.69%; 95% CI 0.48-22.60). The intubation rate in the HFNC group was higher than in the NIV group (14.2% vs 5.4%, P = 0.026). The treatment switch rate, ICU and hospital length of stay or 28-day mortality in the HFNC group were not statistically different from the NIV group (all P > 0.05). CONCLUSION: HFNC was not shown to be non-inferior to NIV and resulted in a higher incidence of treatment failure than NIV when used as the initial respiratory support for AECOPD patients with acute-moderate hypercapnic respiratory failure. TRIAL REGISTRATION: chictr.org (ChiCTR1800014553). Registered 21 January 2018, http://www.chictr.org.cn.

Polymeric nanoparticles (PNPs) for oral delivery of insulin.

Successful oral insulin administration can considerably enhance the quality of life (QOL) of diabetes patients who must frequently take insulin injections. Oral insulin administration, on the other hand, is seriously hampered by gastrointestinal enzymes, wide pH range, mucus and mucosal layers, which limit insulin oral bioavailability to ≤ 2%. Therefore, a large number of technological solutions have been proposed to increase the oral bioavailability of insulin, in which polymeric nanoparticles (PNPs) are highly promising for oral insulin delivery. The recently published research articles chosen for this review are based on applications of PNPs with strong future potential in oral insulin delivery, and do not cover all related work. In this review, we will summarize the controlled release mechanisms of oral insulin delivery, latest oral insulin delivery applications of PNPs nanocarrier, challenges and prospect. This review will serve as a guide to the future investigators who wish to engineer and study PNPs as oral insulin delivery systems.

The cardiovascular toxicity of clozapine in embryonic zebrafish and RNA sequencing-based transcriptome analysis.

Clozapine (CLZ) is the most prescribed medication for treating refractory schizophrenia but is associated with significant cardiovascular toxicity. This study aimed to investigate the cardiovascular toxicity induced by CLZ using zebrafish as a model animal. For this purpose, zebrafish developed to 80-h post-fertilization were exposed to different CLZ concentration solutions for 24 h followed by cardiac morphological observations in yolk sac edema, pericardial edema, and blood coagulation, in addition to increased SV-BA distance, functionally manifested as bradycardia, and decreased cardiac ejection fraction using the untreated embryos as control. At the same time, RNA sequencing was used to study the possible molecular mechanism of CLZ-induced cardiovascular toxicity. The results indicated that compared to the control group, the experimental groups possessed a total of 5888 differentially expressed genes (DEGs), where gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of analysis indicated that DEGs were mainly enriched in the pathways related to ion channels. These findings may provide new insights and directions for the subsequent in-depth study of the molecular mechanism of CLZ-induced cardiovascular toxicity.

Association Between Red Cell Distribution Width and Liver Injury after Cardiac and Aortic Aneurysm Surgery with Cardiopulmonary Bypass.

OBJECTIVES: This study aimed to investigate the association between preoperative red blood cell distribution width (RDW) levels and liver injury (LI) after cardiac surgery, to highlight RDW's usefulness in the early identification and intervention for patients at high risk of LI. DESIGN: A retrospective observational study. SETTING: A university-affiliated teaching hospital and tertiary referral center. PARTICIPANTS: Adult patients who underwent cardiac and aortic aneurysm surgery at Changhai Hospital in 2021. INTERVENTIONS: Postoperative LI was defined by increased liver enzyme levels and/or hyperbilirubinemia, noted from the time of surgery to discharge. Logistic regression analyses were conducted to examine the RDW-LI relationship, with stratified analyses based on age, gender, and anemia. Survival within 30 days was assessed using the Kaplan-Meier method, with survival curve differences analyzed via the log-rank test. The study included 3 sets of sensitivity analyses. MEASUREMENTS AND MAIN RESULTS: Postoperative LI was observed in 75 patients (10%). Multivariate regression analysis showed a significant association between high RDW levels and postoperative LI (adjusted odds ratio, 3.25; p = 0.033; 95% confidence intefal, 1.10-9.63), even after adjusting for all covariates. This association remained consistent across 3 sets of sensitivity analyses. Subgroup analysis showed men had a higher correlation with LI (p for interaction = 0.041). Kaplan-Meier analysis indicated a significantly lower survival rate in the LI group (76%) compared with the non-LI group (99.6%; p < 0.001). CONCLUSIONS: Preoperative RDW levels are significantly associated with postoperative LI. RDW could serve as a significant useful marker for early detection and intervention in patients at high risk of LI, thereby potentially improving patient outcomes.

A serial analysis of hydrogen sulfide poisoning: three group accidents.

Hydrogen sulfide (H2S) is a powerful toxic gas in workplace incidents, and it poses a threat to colleagues or family members involved in rescues, leading to a "domino effect" of multiple deaths. In this report, we describe three incidents in which 10 people died, and we present the results of the analyses performed in different incidents, including paper pulp pit, sewer, and sewage well. We provide the macroscopic and morphological findings of ten victims, which include conjunctival hemorrhage, corneal erosion, pulmonary edema, and pulmonary hemorrhage. Additionally, we observed large amounts of waste paper pulp or black sludge in the upper and lower respiratory tracts or upper and lower gastrointestinal tracts of six victims. Furthermore, we conducted a toxicological examination of the victims' blood sulfide using an alkylation extraction approach combined with gas chromatography/mass spectrometry. The sulfide concentrations in the 10 victims ranged from 0.06 to 6.72 mg/L.

Development and validation of a nomogram for predicting overall survival in patients with early-onset endometrial cancer.

BACKGROUND: This study aimed to investigate the differences in the clinicopathological characteristics of younger and older patients with endometrial cancer (EC) and develop a nomogram to assess the prognosis of early onset EC in terms of overall survival. METHODS: Patients diagnosed with EC from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were selected. Clinicopathological characteristics were compared between younger and older patients, and survival analysis was performed for both groups. Prognostic factors affecting overall survival in young patients with EC were identified using Cox regression. A nomogram was created and internal validation was performed using the consistency index, decision curve analysis, receiver operating characteristic curves, and calibration curves. External validation used data from 70 patients with early onset EC. Finally, Kaplan-Meier curves were plotted to compare survival outcomes across the risk subgroups. RESULTS: A total of 1042 young patients and 12,991 older patients were included in this study. Younger patients were divided into training (732) and validation (310) cohorts in a 7:3 ratio. Cox regression analysis identified age, tumorsize, grade, FIGO stage(International Federation of Gynecology and Obstetrics) and surgery as independent risk factors for overall survival, and a nomogram was constructed based on these factors. Internal and external validations demonstrated the good predictive power of the nomogram. In particular, the C-index for the overall survival nomogram was 0.832 [95% confidence interval (0.797-0.844)] in the training cohort and 0.839 (0.810-0.868) in the internal validation cohort. The differences in the Kaplan-Meier curves between the different risk subgroups were statistically significant. CONCLUSIONS: In this study, a nomogram for predicting overall survival of patients with early onset endometrial cancer based on the SEER database was developed to help assess the prognosis of patients and guide clinical treatment.

Temporal coexistence mechanisms contribute to the latitudinal gradient in forest diversity.

The tropical forests of Borneo and Amazonia may each contain more tree species diversity in half a square kilometre than do all the temperate forests of Europe, North America, and Asia combined. Biologists have long been fascinated by this disparity, using it to investigate potential drivers of biodiversity. Latitudinal variation in many of these drivers is expected to create geographic differences in ecological and evolutionary processes, and evidence increasingly shows that tropical ecosystems have higher rates of diversification, clade origination, and clade dispersal. However, there is currently no evidence to link gradients in ecological processes within communities at a local scale directly to the geographic gradient in biodiversity. Here, we show geographic variation in the storage effect, an ecological mechanism that reduces the potential for competitive exclusion more strongly in the tropics than it does in temperate and boreal zones, decreasing the ratio of interspecific-to-intraspecific competition by 0.25% for each degree of latitude that an ecosystem is located closer to the Equator. Additionally, we find evidence that latitudinal variation in climate underpins these differences; longer growing seasons in the tropics reduce constraints on the seasonal timing of reproduction, permitting lower recruitment synchrony between species and thereby enhancing niche partitioning through the storage effect. Our results demonstrate that the strength of the storage effect, and therefore its impact on diversity within communities, varies latitudinally in association with climate. This finding highlights the importance of biotic interactions in shaping geographic diversity patterns, and emphasizes the need to understand the mechanisms underpinning ecological processes in greater detail than has previously been appreciated.

A prognostic risk model for ovarian cancer based on gene expression profiles from gene expression omnibus database.

This study explored prognostic genes of ovarian cancer and built a prognostic model based on these genes to predict patient's survival, which is of great significance for improving treatment of ovarian cancer. GSE26712 dataset was downloaded from Gene Expression Omnibus database as training set, while OV-AU dataset was downloaded from ICGC website as validation set. All genes in GSE26712 were analyzed by univariate Cox regression, Lasso regression, and multivariate Cox regression analyses. Then prognosis-related feature genes were screened to construct a multivariate risk model. Meanwhile, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed on samples in the high/low-risk groups using Gene Set Enrichment Analysis (GSEA) software. Finally, survival curve and receiver operating characteristic curve were drawn to verify the validity of the model. Ten feature genes related to prognosis of ovarian cancer were obtained: CMTM6, COLGALT1, F2R, GPR39, IGFBP3, RNF121, MTMR9, ORAI2, SNAI2, ZBTB16. GSEA enrichment analysis showed that there were notable differences in biological pathways such as gap junctions and homologous recombination between the high/low-risk groups. Through further verification of training set and validation set, the 10-gene prognostic model was found to be effective for the prognosis of ovarian cancer patients. In this study, we constructed a 10-gene prognostic model which predicted the prognosis of ovarian cancer patients well by integrating clinical prognostic parameters. It may have certain reference value for subsequent clinical treatment research of ovarian cancer patients and help in clinical treatment decision-making.

Synthesis and Evaluation of 2-Amine-4-oxyphosaniline Pyrimidine Derivatives as EGFR L858R/T790M/C797S Mutant Inhibitors.

Epidermal growth factor receptor (EGFR) C797S mutation leads to Osimertinib drug resistance by disturbing the covalent biding of Michael acceptor group to the Cys797 residue in the ATP biding cleft. In this manuscript, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were designed, synthesized and evaluated as new noncovalent reversible EGFR inhibitors against L858R/T790M/C797S (CTL) triple mutant. The kinases inhibitiory activity evaluation showed that four compounds exhibited significant inhibitory activities against CTL (IC50 < 30 nM). In particularly, the most promising compound 7a showed excellent enzymatic inhibitory activity against CTL with IC50 value of 9.9 nM, which was more potent than control compound Osimertinib. Moreover, cell proliferation assays indicated that 7a effectively inhibited H1975-EGFR L858R/T790M/C797S with IC50 value of 0.33 µM. Furthermore, compound 7a displayed good metabolic stabilities in human, rat and mouse liver microsomes, and the putative biding mode of compound 7a with ATP was revealed by molecular docking study. These findings strongly indicated that compound 7a was a promising L858R/T790M/C797S mutant EGFR inhibitor.

Experimental investigation and modeling on the supersaturated total dissolved gas (TDG) dissipation in aeration.

Supersaturated total dissolved gas (TDG) generation in rivers poses great harm to aquatic organisms. In this paper, 30 groups of supersaturated TDG dissipation experiments with aeration were carried out. These results showed that aeration actively promoted the dissipation of supersaturated TDG. The aeration rate decreased by 34.94% from 1.0 m3/h to 5.0 m3/h, the reduced proportion of aeration aperture was 35.51% from 215 mm to 260 mm, whereas the aeration depth increased by 16.93% from 0.4 m to 1.2 m for the TDG dissipation time required, resulting in corresponding the variation of TDG dissipation coefficients were 86.26%, 23.74% and -5.39%, respectively. In general, the effect on TDG dissipation is that the aeration rate is the largest, followed by the aeration aperture, and the aeration depth is the smallest. A quantitative relationship was established between TDG dissipation coefficient and aeration conditions, and followed a power function, while the aeration depth inhibited its dissipation. Moreover, what matters was that a numerical model was presented for predicting the TDG dissipation in Eulerian-Eulerian. When the parameter was ß = 10.52, the error between the original experimental data and the simulated of a multiphase TDG dissipation model was 0.2%. The study provides essential scientific data for mitigating the harms of supersaturated TDG.

The Application of Computer Technology to Clinical Practice Guideline Implementation: A Scoping Review.

Implementation of clinical practice guidelines (CPG) is a complex and challenging task. Computer technology, including artificial intelligence (AI), has been explored to promote the CPG implementation. This study has reviewed the main domains where computer technology and AI has been applied to CPG implementation. PubMed, Embase, Web of science, the Cochrane Library, China National Knowledge Infrastructure database, WanFang DATA, VIP database, and China Biology Medicine disc database were searched from inception to December 2021. Studies involving the utilization of computer technology and AI to promote the implementation of CPGs were eligible for review. A total of 10429 published articles were identified, 117 met the inclusion criteria. 21 (17.9%) focused on the utilization of AI techniques to classify or extract the relative content of CPGs, such as recommendation sentence, condition-action sentences. 47 (40.2%) focused on the utilization of computer technology to represent guideline knowledge to make it understandable by computer. 15 (12.8%) focused on the utilization of AI techniques to verify the relative content of CPGs, such as conciliation of multiple single-disease guidelines for comorbid patients. 34 (29.1%) focused on the utilization of AI techniques to integrate guideline knowledge into different resources, such as clinical decision support systems. We conclude that the application of computer technology and AI to CPG implementation mainly concentrated on the guideline content classification and extraction, guideline knowledge representation, guideline knowledge verification, and guideline knowledge integration. The AI methods used for guideline content classification and extraction were pattern-based algorithm and machine learning. In guideline knowledge representation, guideline knowledge verification, and guideline knowledge integration, computer techniques of knowledge representation were the most used.

Antiaromatic Sapphyrin Isomer: Transformation into Contracted Porphyrinoids with Variable Aromaticity.

Sapphyrin is a pentapyrrolic expanded porphyrin with a 22π aromatic character. Herein, we report the synthesis of a 20π antiaromatic sapphyrin isomer 1 by oxidative cyclization of a pentapyrrane precursor P5 with a terminal ß-linked pyrrole. The resulting isomer 1, containing a mis-linked bipyrrole unit in the skeleton, exhibits a reactivity for further oxidation due to the distinct antiaromatic electronic structure, affording a fused macrocycle 2, possessing a spiro-carbon-containing [5.6.5.6]-tetracyclic structure. Subsequent treatment with an acid afforded a weakly aromatic pyrrolone-appended N-confused corrole 3, and thermal fusion gave a [5.6.5.7]-tetracyclic-ring-embedded 14π aromatic triphyrin(2.1.1) analog 4. The cyclization at the mis-linked pyrrole moiety of P5 played a crucial role in synthesizing the antiaromatic porphyrinoid susceptible to facile transformation to novel porphyrinoids with variable aromaticity.

The Effect of Cognitive Intervention on Cognitive Function in Older Adults With Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Cognitive intervention includes cognitive stimulation, cognitive training, and cognitive rehabilitation. This systematic review was performed to re-assess the efficacy of cognitive intervention for the patients with Alzheimer's disease (AD). Twenty studies (2012 participants) were eventually included. For global cognitive function, the combined mean difference (MD) in eight studies was 1.67 (95% Confidence Interval: 0.45, 2.89, p = 0.007; Q = 33.28, df = 8, p < 0.0001, τ2 = 2.17, I2 = 76%) for the short term. The pooled standardized mean difference (SMD) of six RCTs was 1.61 (95% Confidence Interval: 0.65, 2.56, p = 0.0009; Q = 127.66, df = 6, p < 0.00001, τ2 = 1.56, I2 = 95%) for the medium term. The pooled SMD of seven studies was 0.79 (95% Confidence Interval: 0.33, 1.25, p = 0.0008; Q = 35.10, df = 7, p < 0.0001, τ2 = 0.33, I2 = 80%) for the long term. For depression, the pooled SMD of two trials was -0.48 (95% Confidence Interval: -0.71, -0.24; p < 0.0001, I2 = 4%) for the short term. Cognitive training may show obvious improvements in global cognitive function whether after short, medium, or long-term interventions and in depression after short term intervention. However, the positive effect of the intervention on general cognitive function or depression did not seem to persist after intervention ended. There is still a lack of reliable and consistent conclusions relevant to the effect of cognitive stimulation and cognitive rehabilitation on observed outcomes, cognitive training for memory or other non-cognitive outcomes. PROSPERO registration number: CRD42019121768.

Structural insights into histone chaperone Chz1-mediated H2A.Z recognition and histone replacement.

Chz1 is a specific chaperone for the histone variant H2A.Z in budding yeast. The ternary complex formed by Chz1 and H2A.Z-H2B dimer is the major in vivo substrate of Swi2/snif2-related 1 (SWR1), the ATP-dependent chromatin remodeling enzyme that deposits H2A.Z into chromatin. However, the structural basis for the binding preference of Chz1 for H2A.Z over H2A and the mechanism by which Chz1 modulates the histone replacement remain elusive. Here, we show that Chz1 utilizes 2 distinct structural domains to engage the H2A.Z-H2B dimer for optimal and specific recognition of H2A.Z. The middle region of Chz1 (Chz1-M) directly interacts with 2 highly conserved H2A.Z-specific residues (Gly98 and Ala57) and dictates a modest preference for H2A.Z-H2B. In addition, structural and biochemical analysis show that the C-terminal region of Chz1 (Chz1-C) harbors a conserved DEF/Y motif, which reflects the consecutive D/E residues followed by a single aromatic residue, to engage an arginine finger and a hydrophobic pocket in H2A.Z-H2B, enhancing the binding preference for H2A.Z-H2B. Furthermore, Chz1 facilitates SWR1-mediated H2A.Z deposition by alleviating inhibition caused by aggregation of excess free histones, providing insights into how Chz1 controls the bioavailability of H2A.Z to assist SWR1 in promoter-specific installation of a histone mark. Our study elucidates a novel H2A.Z-recognition mechanism and uncovers a molecular rationale for binding of free histone by specialized histone chaperones in vivo.