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Small ubiquitin-like modifiers (SUMOs) are tiny but important protein regulators involved in orchestrating a broad spectrum of biological processes, either by covalently modifying protein substrates or by noncovalently interacting with other proteins. Here, we report an updated server, GPS-SUMO 2.0, for the prediction of SUMOylation sites and SUMO-interacting motifs (SIMs). For predictor training, we adopted three machine learning algorithms, penalized logistic regression (PLR), a deep neural network (DNN), and a transformer, and used 52 404 nonredundant SUMOylation sites in 8262 proteins and 163 SIMs in 102 proteins. To further increase the accuracy of predicting SUMOylation sites, a pretraining model was first constructed using 145 545 protein lysine modification sites, followed by transfer learning to fine-tune the model. GPS-SUMO 2.0 exhibited greater accuracy in predicting SUMOylation sites than did other existing tools. For users, one or multiple protein sequences or identifiers can be input, and the prediction results are shown in a tabular list. In addition to the basic statistics, we integrated knowledge from 35 public resources to annotate SUMOylation sites or SIMs. The GPS-SUMO 2.0 server is freely available at https://sumo.biocuckoo.cn/. We believe that GPS-SUMO 2.0 can serve as a useful tool for further analysis of SUMOylation and SUMO interactions.
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Internet , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina , Software , Sumoilação , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Aprendizado de Máquina , Motivos de Aminoácidos , Humanos , Algoritmos , Sítios de LigaçãoRESUMO
In cellular contexts, the oscillation of calcium ions (Ca2+) is intricately linked to various physiological processes, such as cell proliferation, metabolism, and survival. Stromal interaction molecule 1 (STIM1) proteins form a crucial regulatory component in the store-operated calcium entry (SOCE) process. The structural attributes of STIM1 are vital for its functionality, encompassing distinct domains situated in the endoplasmic reticulum (ER) lumen and the cytoplasm. The intraluminal domain enables the timely detection of diminishing Ca2+ concentrations, prompting structural modifications that activate the cytoplasmic domain. This activated cytoplasmic domain undergoes conformational alterations and engages with membrane components, opening a channel that facilitates the influx of Ca2+ from the extracellular environment. Given its multiple domains and interaction mechanisms, STIM1 plays a foundational role in cellular biology. This review focuses on the design of optogenetic tools inspired by the structure and function of STIM1. These tools offer a groundbreaking approach for studying and manipulating intracellular Ca2+ signaling with precisely spatiotemporal control. We further explore the practical applications of these tools, spanning fundamental scientific research, clinical studies, and their potential for translational research.
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Supported ionic liquid membranes (SILMs), owing to their capacities in harnessing physicochemical properties of ionic liquid for exceptional CO2 solubility, have emerged as a promising platform for CO2 extraction. Despite great achievements, existing SILMs suffer from poor structural and performance stability under high-pressure or long-term operations, significantly limiting their applications. Herein, a one-step and in situ interfacial polymerization strategy is proposed to elaborate a thin, mechanically-robust, and highly-permeable polyamide armor on the SILMs to effectively protect ionic liquid within porous supports, allowing for intensifying the overall stability of SILMs without compromising CO2 separation performance. The armored SILMs have a profound increase of breakthrough pressure by 105% compared to conventional counterparts without armor, and display high and stable operating pressure exceeding that of most SILMs previously reported. It is further demonstrated that the armored SILMs exhibit ultrahigh ideal CO2/N2 selectivity of about 200 and excellent CO2 permeation of 78 barrers upon over 150 h operation, as opposed to the full failure of CO2 separation performance within 36 h using conventional SILMs. The design concept of armor provides a flexible and additional dimension in developing high-performance and durable SILMs, pushing the practical application of ionic liquids in separation processes.
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OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.
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Ferroptosis has been shown to be involved in carbon tetrachloride (CCl4)-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl4-induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl4-induced mice. In vitro, CCl4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl4-evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl4-induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl4-exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl4-induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl4-exposed human hepatocytes. Moreover, CCl4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl4-evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl4 exposure. Finally, MitoQ pretreatment alleviated CCl4-induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl4-induced ALI via the mtROS-ACSL4 pathway.
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Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Coenzima A Ligases , Ferroptose , Hepatócitos , Camundongos Endogâmicos C57BL , Compostos Organofosforados , Espécies Reativas de Oxigênio , Regulação para Cima , Animais , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Regulação para Cima/efeitos dos fármacos , Células Hep G2 , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ferroptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Masculino , Compostos Organofosforados/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
A high-performance 5-junction cascade quantum dot (QD) vertical cavity surface-emitting laser (VCSEL) with 1.3â µm wavelength was designed. The characteristics of the QD as active regions and tunnel junctions are combined to effectively increase output power. The photoelectric characteristics of single-junction, 3-junction cascade, and 5-junction cascade QD VCSELs are compared at continuous-wave conditions. Results indicate that the threshold current gradually decreases, and the output power and slope efficiency exponential increase with the increase of the number of active regions. The peak power conversion efficiency of 58.4% is achieved for the 5-junction cascade individual QD VCSEL emitter with 10â µm oxide aperture. The maximum slope efficiency of the device is 6.27â W/A, which is approximately six times than that of the single-junction QD VCSEL. The output power of the 5-junction cascade QD VCSEL reaches 188.13â mW at injection current 30â mA. High-performance multi-junction cascade 1.3-µm QD VCSEL provides data and theoretical support for the preparation of epitaxial materials.
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Palladium-catalyzed dipolar cycloaddition reactions represent an efficient strategy for the construction of cyclic compounds, with the development of novel dipolar precursors being a key focus. In this study, a new type of dipolar precursor was synthesized through the assembly of the vinylethylene carbonate unit and the tetrahydronaphthalene skeleton. This dipolar precursor can undergo [3 + 2], [5 + 4], and [5 + 2] cycloaddition reactions, leading to the construction of tetrahydronaphthalene-fused oxazolidin-2-ones, 1,5-oxazonines, and tetrahydrooxepines. In general, all of these reactions exhibited good reaction efficiency and functional group tolerance.
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Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.
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Increasing evidences implicate vital role of neuronal damage in the development of hepatic encephalopathy (HE). Neurofilament light chain (NfL) is the main frame component of neurons and is closely related to axonal radial growth and neuronal structural stability. We hypothesized that NfL as a biomarker of axonal injury may contribute to early diagnosis of HE. This study recruited 101 patients with liver cirrhosis, 10 healthy individuals, and 7 patients with Parkinson's disease. Minimal hepatic encephalopathy (MHE) was diagnosed using psychometric hepatic encephalopathy score. Serum NfL levels were measured by the electrochemiluminescence immunoassay. Serum NfL levels in cirrhotic patients with MHE were significantly higher than cirrhotic patients without MHE, and increased accordingly with the aggravation of HE. Serum NfL levels were associated with psychometric hepatic encephalopathy score, Child-Pugh score, model for end-stage liver disease score, and days of hospitalization. Additionally, serum NfL was an independent predictor of MHE (odds ratio of 1.020 (95% CI 1.005-1.034); P = 0.007). The discriminative abilities of serum NfL were high for identifying MHE (AUC of 0.8134 (95% CI 0.7130-0.9219); P Ë 0.001) and OHE (AUC of 0.8852 (95% CI 0.8117-0.9587); P Ë 0.001). Elevated serum NfL levels correlated with the presence of MHE and associated with the severity of HE, are expected to be a biomarker in patients with cirrhosis. Our study suggested that neuronal damage may play a critical role in the development of HE.
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OBJECTIVE: This case series study investigated the outcomes of an innovative approach, ansa cervicalis nerve (ACN)-to-recurrent laryngeal nerve (RLN) low-tension anastomosis. METHODS: Patients who received laryngeal nerve anastomosis between May 2015 and September 2021 at the facility were enrolled. The inclusion criteria were patients with RLN dissection and anastomosis immediately during thyroid surgery. Exclusion criteria were cases with anastomosis other than cervical loop-RLN anastomosis or pronunciation recovery time > 6 months. Patients admitted before January 2020 were assigned to group A which underwent the conventional tension-free anastomosis, and patients admitted after January 2020 were group B and underwent the innovative low-tension anastomosis (Dong's method). RESULTS: A total of 13 patients were included, 11 patients received unilateral surgery, and 2 underwent bilateral surgery. For patients who underwent unilateral anastomosis, group B had a significantly higher percentage of normal pronunciation via GRBAS scale (83.3 % vs. 0 %, p = 0.015) and voice handicap index (66.7 % vs. 0 %, p = 0.002), and shorter recovery time in pronunciation (median: 1-day vs. 4 months, p = 0.001) than those in group A after surgery. CONCLUSIONS: ACNs-to-RLN low-tension anastomosis with a laryngeal segment ≤1 cm (Dong's method) significantly improves postoperative pronunciation and recovery time. The results provide clinicians with a new strategy for ACN -to-RLN anastomosis during thyroid surgery.
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Anastomose Cirúrgica , Fonação , Nervo Laríngeo Recorrente , Tireoidectomia , Humanos , Anastomose Cirúrgica/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Nervo Laríngeo Recorrente/cirurgia , Tireoidectomia/métodos , Fonação/fisiologia , Adulto , Recuperação de Função Fisiológica , Traqueotomia/métodos , Resultado do Tratamento , Idoso , Plexo Cervical/cirurgia , Traumatismos do Nervo Laríngeo Recorrente/prevenção & controle , Traumatismos do Nervo Laríngeo Recorrente/etiologiaRESUMO
BACKGROUND: Virtual simulation and face-to-face simulation are effective for clinical judgment training. Rare studies have tried to improve clinical judgment ability by applying virtual simulation and face-to-face simulation together. This study aimed to evaluate the effect of an integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program on enhancing nursing students' clinical judgment ability and understanding of nursing students' experiences of the combined simulation. METHODS: A sequential exploratory mixed-methods study was conducted in a nursing simulation center of a university in Central China. Third-year nursing students (n = 122) taking clinical training in ICUs were subsequentially assigned to the integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program arm (n = 61) or the face-to-face simulation-only arm (n = 61) according to the order in which they entered in ICU training. Clinical judgment ability was measured by the Lasater Clinical Judgment Rubric (LCJR). Focus group interviews were conducted to gather qualitative data. RESULTS: Students in both arms demonstrated significant improvement in clinical judgment ability scores after simulation, and students in the integrated arm reported more improvement than students in the face-to-face simulation-only arm. The qualitative quotes provided a context for the quantitative improvement measured by the LJCR in the integrated arm. Most of the quantitative findings were confirmed by qualitative findings, including the domains and items in the LJCR. The findings verified and favored the effect of the combination of non-immersive virtual simulation and high-fidelity face-to-face simulation integrated program on enhancing nursing students' clinical judgment ability. CONCLUSIONS: The integrated virtual simulation and face-to-face simulation program was feasible and enhanced nursing students' self-reported clinical judgment ability. This integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program may benefit nursing students and newly graduated nurses in the ICU more than face-to-face simulation only.
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Bacharelado em Enfermagem , Estudantes de Enfermagem , Humanos , Julgamento , China , Raciocínio ClínicoRESUMO
In this experiment, the micro-precipitation method was used to prepare self-assembled nanoparticles of Herpetospermum caudigerum Wall.(MP-SAN). The process was optimized using average particle size and polydispersity index(PDI)as evaluation indexes. The mean particle size, PDI,zeta potential, and microstructure of MP-SAN were characterized. The intestinal absorption mechanism of dehydrodiconiferyl alcohol(DA)and herpetrione(Her)in MP-SAN was investigated through single-pass intestinal perfusion in rats. The optimized process parameters for producing MP-SAN were a stirring speed of 800 r·min~(-1),stirring time of 5 min, and rotary evaporation temperature of 40â. The resulting MP-SAN exhibited a spherical-like structure and uniform morphology, with a mean particle size of(267.63±13.27) nm, a PDI of 0.062 0±0.043 9,and a zeta potential of(-46.18±3.66) mV. The absorption rate constant(K_a)and apparent permeability coefficient(P_(app))of DA in the ileal segment were significantly higher than those in the jejunal segment(P<0.05). However, there was no significant difference in the absorption of Her between the ileal and jejunal segments. Intestinal absorption parameters of DA and Her tended to increase with increasing drug concentration. Specifically, the K_a and P_(app) of DA in MP-SAN in the high-concentration group were significantly higher than those in the low-concentration group(P<0.01). The addition of verapamil, a P-glycoprotein inhibitor, did not significantly affect the intestinal absorption of DA and Her. However, the absorption of both DA and Her in MP-SAN was significantly increased by the addition of indomethacin(P<0.05),suggesting that DA and Her may be substrates for multidrug resistance-associated protein 2.
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Absorção Intestinal , Nanopartículas , Tamanho da Partícula , Animais , Nanopartículas/química , Ratos , Masculino , Ratos Sprague-Dawley , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Cucurbitaceae/químicaRESUMO
OBJECTIVES: To investigate the clinical characteristics of Ureaplasma urealyticum (UU) infection and colonization in extremely preterm infants and its impact on the incidence of bronchopulmonary dysplasia (BPD). METHODS: A retrospective analysis was conducted on 258 extremely preterm infants who were admitted to the Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, from September 2018 to September 2022. According to the results of UU nucleic acid testing and the evaluation criteria for UU infection and colonization, the subjects were divided into three groups: UU-negative group (155 infants), UU infection group (70 infants), and UU colonization group (33 infants). The three groups were compared in terms of general information and primary and secondary clinical outcomes. RESULTS: Compared with the UU-negative group, the UU infection group had significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay (P<0.05), while there were no significant differences in the incidence rates of BPD and moderate/severe BPD between the UU colonization group and the UU-negative group (P>0.05). CONCLUSIONS: The impact of UU on the incidence of BPD in extremely preterm infants is associated with the pathogenic state of UU (i.e., infection or colonization), and there are significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay in extremely preterm infants with UU infection. UU colonization is not associated with the incidence of BPD and moderate/severe BPD in extremely preterm infants.
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Displasia Broncopulmonar , Lactente Extremamente Prematuro , Infecções por Ureaplasma , Ureaplasma urealyticum , Humanos , Infecções por Ureaplasma/epidemiologia , Infecções por Ureaplasma/complicações , Ureaplasma urealyticum/isolamento & purificação , Recém-Nascido , Estudos Retrospectivos , Feminino , Masculino , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/microbiologia , Displasia Broncopulmonar/etiologia , Tempo de InternaçãoRESUMO
Background: Valvular heart disease (VHD) is a major precipitating factor of atrial fibrillation (AF) that contributes to decreased cardiac function, heart failure, and stroke. Stroke induced by VHD combined with atrial fibrillation (AF-VHD) is a much more serious condition in comparison to VHD alone. The aim of this study was to explore the molecular mechanism governing VHD progression and to provide candidate treatment targets for AF-VHD. Methods: Four public mRNA microarray datasets were downloaded and differentially expressed genes (DEGs) screening was performed. Weighted gene correlation network analysis was carried out to detect key modules and explore their relationships and disease status. Candidate hub signature genes were then screened within the key module using machine learning methods. The receiver operating characteristic curve and nomogram model analysis were used to determine the potential clinical significance of the hub genes. Subsequently, target gene protein levels in independent human atrial tissue samples were detected using western blotting. Specific expression analysis of the hub genes in the tissue and cell samples was performed using single-cell sequencing analysis in the Human Protein Atlas tool. Results: A total of 819 common DEGs in combined datasets were screened. Fourteen modules were identified using the cut tree dynamic function. The cyan and purple modules were considered the most clinically significant for AF-VHD. Then, 25 hub genes in the cyan and purple modules were selected for further analysis. The pathways related to dilated cardiomyopathy, hypertrophic cardiomyopathy, and heart contraction were concentrated in the purple and cyan modules of the AF-VHD. Genes of importance (CSRP3, MCOLN3, SLC25A5, and FIBP) were then identified based on machine learning. Of these, CSRP3 had a potential clinical significance and was specifically expressed in the heart tissue. Conclusions: The identified genes may play critical roles in the pathophysiological process of AF-VHD, providing new insights into VHD development to AF and helping to determine potential biomarkers and therapeutic targets for treating AF-VHD.
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Antígenos CD19 , Imunoterapia Adotiva , Humanos , Antígenos CD19/imunologia , Resultado do Tratamento , Imunoterapia Adotiva/métodos , Recidiva , Masculino , Feminino , Receptores de Antígenos Quiméricos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , AdultoRESUMO
This work focuses on the issue of observer-based resilient dissipativity control of discrete-time memristor-based neural networks (DTMBNNs) with unbounded or bounded time-varying delays. Firstly, the Luenberger observer is designed, and additionally based on the observed states, the observer-based resilient controller is proposed. An augmented system is presented by considering both the error system and the DTMBNNs with the controller. Secondly, a novel sufficient extended exponential dissipativity condition is obtained for the augmented system with unbounded time-varying delays by proposing a system solutions-based estimation approach. This method is based on system solutions and without constructing any Lyapunov-Krasovskii functionals (LKF), thereby reducing the complexity of theoretical derivation and computational workload. In addition, an algorithm is proposed to solve the nonlinear inequalities in the sufficient condition. Thirdly, the sufficient extended exponential dissipativity condition for the augmented system with bounded time-varying delays is also obtained. Finally, the effectiveness of the theoretical results is illustrated through two simulation examples.
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Algoritmos , Redes Neurais de Computação , Dinâmica não Linear , Fatores de Tempo , Simulação por ComputadorRESUMO
Phenotypic age acceleration (PAA) is a sensitive marker of biological aging. Circulating methylmalonic acid (MMA) is a novel biomarker of mitochondrial dysfunction and has been associated with age-related disorders. Our study aimed to investigate to what extent circulating MMA was associated with PAA, and whether the association was independent of vitamin B12 status and renal function in the general population. We analyzed cross-sectional data from 13,023 participants across a wide age range (mean age: 38.9 years, range: 12 - 85 years, 51.1% women) from the US National Health and Nutrition Examination Survey (NHANES). PAA was calculated based on the published algorithm. Linear regression models were performed to assess the association between circulating MAA and PAA. Only 31% of the variation in MMA levels was explained by age, sex, race/ethnicity, social economic status, vitamin B12 status, and renal function. Per unit increase in circulating MAA (1.0 nmol/L) was associated with 1.59 years increase in PAA (ß = 1.59, 95% CI: 1.17, 2.00, p < 0.001) after adjusting for multiple confounders. Importantly, PAA increased with circulating MMA levels independent of vitamin B12, creatine, and homocysteine levels. The association was more pronounced in subgroups of age ≥ 65 years, women, underweight, vitamin B12 < 400 µmol/L, and homocysteine ≥ 10 µmol/L. The association was much stronger among participants with cardiovascular diseases (CVDs) than without CVDs. In conclusion, our current population-based study showed that mitochondria-derived circulating MMA was associated with increased phenotypic age acceleration in the general population.
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Ácido Metilmalônico , Deficiência de Vitamina B 12 , Humanos , Feminino , Idoso , Masculino , Inquéritos Nutricionais , Estudos Transversais , Vitamina B 12 , Biomarcadores , HomocisteínaRESUMO
Neural architecture search (NAS) is a popular method that can automatically design deep neural network structures. However, designing a neural network using NAS is computationally expensive. This article proposes a gradient-guided evolutionary NAS (GENAS) to design convolutional neural networks (CNNs) for image classification. GENAS is a hybrid algorithm that combines evolutionary global and local search operators to evolve a population of subnets sampled from a supernet. Each candidate architecture is encoded as a table describing which operations are associated with the edges between nodes signifying feature maps. Besides, evolutionary optimization uses novel crossover and mutation operators to manipulate the subnets using the proposed tabular encoding. Every n generations, the candidate architectures undergo a local search inspired by differentiable NAS. GENAS is designed to overcome the limitations of both evolutionary and gradient descent NAS. This algorithmic structure enables the performance assessment of the candidate architecture without retraining, thus limiting the NAS calculation time. Furthermore, subnet individuals are decoupled during evaluation to prevent strong coupling of operations in the supernet. The experimental results indicate that the searched structures achieve test errors of 2.45%, 16.86%, and 23.9% on CIFAR-10/100/ImageNet datasets and it costs only 0.26 GPU days on a graphic card. GENAS can effectively expedite the training and evaluation processes and obtain high-performance network structures.
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Background: The optimal perioperative antithrombotic strategy for patients with acute coronary syndrome (ACS) during percutaneous coronary intervention (PCI) remains controversial. Objectives: To determine the safety and effectiveness of bivalirudin plus ticagrelor vs bivalirudin plus clopidogrel in patients with ACS undergoing PCI in the real world. Methods: Between March 2016 and March 2019, 7234 patients with ACS who had undergone PCI, received bivalirudin periprocedurally, and were prescribed ticagrelor or clopidogrel were enrolled in a single-center, all-comer, modern, retrospective cohort study. Incidence rates of 12-month ischemia (cardiac death, myocardial infarction, or stroke), all-cause death, Bleeding Academic Research Consortium (BARC) type 2,3,5 bleeding, and BARC type 3,5 bleeding were compared between different groups. Results: In total, 4960 patients received bivalirudin plus clopidogrel and 2274 patients received bivalirudin plus ticagrelor. Compared with bivalirudin plus clopidogrel, bivalirudin plus ticagrelor was associated with lower ischemic events (1.74% vs 2.84%; relative risk, 0.61; 95% CI, 0.41-0.91; P = .02) and stroke (0.05% vs 1.01%, P < .001) within 12 months after PCI without excessive risk of bleeding (BARC type 2,3,5 bleeding: 4.49% vs 3.76%, P = .22; BARC type 3,5 bleeding: 2.84% vs 2.02%, P = .08). The beneficial effects of bivalirudin plus ticagrelor were consistent among subgroups. Conclusion: As an initial treatment strategy, bivalirudin plus ticagrelor could reduce the 12-month risk of ischemic events compared with bivalirudin plus clopidogrel significantly without increasing the bleeding risk in ACS patients undergoing PCI.
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Objective: Atypical polypoid adenomyoma (APA) is a rare benign tumor frequently diagnosed in young women that may coexist with or progress to atypical endometrial hyperplasia (EAH) or endometrioid endometrial carcinoma (EEC). This study aimed to investigate which subset of patients with APA are prone to concurrent or subsequent EAH or EEC, evaluate the necessity of progestin treatment in patients with APA only after achieving a complete response (CR) through hysteroscopic lesion resection, and assess the impact of concurrent APA on the fertility-preserving treatment of EAH or EEC. Methods: This retrospective single-center study analyzed 86 patients with APA treated at the Obstetrics and Gynecology Hospital of Fudan University between January 2010 and October 2021. Patients with EAH or EEC only who underwent fertility-preserving treatment during the same period were matched in a 2:1 ratio with patients with concurrent APA and EAH or EEC. The clinicopathological characteristics, treatments, and prognosis were analyzed. Results: The median patient age was 31 years (range 21-47 years). Among the 86 included patients, nine underwent total hysterectomy, 62 received conservative treatment, and the remaining 15 were lost to follow-up. A comparison of the 16 patients with APA only versus the 58 patients with APA and concurrent or subsequent EAH or EEC revealed that a homeostasis model assessment of insulin resistance (HOMA-IR) of > 2.2 (P = 0.047) and high-density lipoprotein (HDL) concentration of < 1.2 mmol/L (P = 0.028) were independent risk factors for EAH or EEC in patients with APA. Among the 17 patients with APA only who received conservative treatment and achieved a CR after hysteroscopic lesion resection, 13 received hormone treatment for a median duration of 6.3 months. The median follow-up time for these 17 patients was 49.0 months, during which no recurrence of APA was observed, but six patients developed endometrial hyperplastic diseases. Regarding the impact of concurrent APA on fertility-preserving treatment for EAH or EEC, the median time to achieve a CR was 24.0 weeks (95% confidence interval [CI]: 23.0-40.4) in the APA group and 26.0 weeks (95% CI: 24.3-32.3) in the non-APA group (P = 0.424). There were no significant differences between the two groups in the outcomes of fertility-preserving treatment. Conclusion: Patients with APA only may still develop endometrial hyperplastic diseases after complete resection of the lesion under hysteroscopy to achieve a CR, particularly those with a HOMA-IR of > 2.2 or HDL concentration of < 1.2 mmol/L. Concurrent APA did not affect the efficacy of fertility-preserving treatment in patients with EAH or EEC.