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BACKGROUND: Certain patient subpopulations requiring dialysis initiation show varied survival rates and chances of ending renal replacement therapy (RRT). Consensus clustering can help identify these subgroups and their dialysis outcomes. METHODS: The study included patients who were over 18 years old with urine output above 400 ml per day and an estimated glomerular filtration rate over 15 ml/min/1.73 m2. They underwent acute RRT because of systemic demand-capacity imbalance. Using consensus clustering with 33 clinical variables and urea:creatinine ratio (UCR) to the variables to investigate the catabolic demand. Endpoints were all-cause mortality and being dialysis-free at 180-day follow-up after RRT initiation. RESULTS: Of 946 patients (mean 63 ± 17 years and 649 men, 68.6 %) three distinct phenotypes were identified. 509 (53.8%) patients died and 364 (38.5%) patients were weaned off dialysis. Cluster 2 showed better survival (60.23% vs. 53.18% [cluster 1] vs. 45.85% [cluster 3], P < 0.01) and higher possibility to be weaned off RRT (45.24% vs. 38.44% [cluster 1] vs. 31.62% [cluster 3], P < 0.01). High UCR had increased mortality (59.16% vs. 47.75%, P < 0.01) and a lower weaning rates (33.27%; 45.72%, P < .01). UCR with the clustering phenotype improved risk stratification. CONCLUSIONS: Among critical patients undergoing RRT due to systemic demand-capacity imbalance, more than half of the patients died. We identified distinct phenotypes in demand-capacity imbalance in a heterogeneous cohort of patients initializing RRT. Additionally, we found that pre-dialysis UCR as a novel predictor for mortality and the likelihood of being dialysis-free.
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To promote the growth of Casuarina equisetifolia and address the abnormalities in the structure and function of rhizosphere soil microbial community, we isolated eight strains with multiple functions from the root nodules of C. equisetifolia, including nitrogen fixation (N), production of cell wall-degrading enzymes (protease and cellulase), auxin (IAA) production, siderophore production, ammonia (NH3) production, and phosphate solubilization. Among these strains, LB08, LB18, LB19, LB42, LB46, LB63, and LB69 were identified as Paenibacillus species, while LQ10 was identified as a Brucella sp. Results of seed soaking experiments showed that all the eight strains promoted the growth of C. equisetifolia seedlings. Strain LB69 significantly increased the germination rate and seedling vigor by 19.7% and 28.3%, respectively. Strain LQ10 significantly enhanced root length and root vigor by 48.2% and 334.4%, respectively. Strains LB18 and LB42 had the strongest effects on early shoot length and biomass accumulation, with increases of 22.4% and 32.8%, respectively. After seed soaking, the number of isozymes bands of polyphenol oxidase, superoxide dismutase, and peroxidase increased, with some bands showing enhanced intensity and increased diversity of enzyme isoforms, thereby enhancing stress resistance. In summary, the addition of these eight strains promoted plant growth and antioxidant enzyme activity, indicating their potential role as biofertilizers.
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Germinación , Rizosfera , Plantones , Semillas , Microbiología del Suelo , Plantones/crecimiento & desarrollo , Plantones/microbiología , Semillas/crecimiento & desarrollo , Semillas/microbiología , Paenibacillus/crecimiento & desarrollo , Paenibacillus/fisiología , Paenibacillus/metabolismo , Raíces de Plantas/microbiología , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/crecimiento & desarrollo , Bacterias/aislamiento & purificaciónRESUMEN
The application of traditional isocyanate-based polyimide (PI) foams is highly hindered due to limited flame retardancy, poor mechanical properties, and relatively single functionality. Herein, we propose an effective method to fabricate dual cross-linked polyimide/bismaleimide (PI-BMI) foams with outstanding heat resistance and enhanced mechanical properties by incorporating bis(3-ethyl-5-methyl-4-maleimidophenyl)methane (ME-BMI) as the interpenetrating network. The results show that the prepared PI-BMI composite foams exhibit enhanced mechanical properties with lightweight characteristics (23-80 kg·m-3). When the ME-BMI loading reached 120 wt %, the tensile and compressive strength of PI-BMI composite foam can reach 1.9 and 7.8 MPa, which are 9.6 and 63.3 times higher than that of pure PI foam, respectively. In comparison with PIF-0, the 10% heat loss temperature (Td,10%) of PIF-90 improved by 156 °C. Moreover, the PI-BMI foam piezoelectric sensor containing fluorine groups presents a short response time (14.22 ms), high sensitivity (0.266 V/N), and outstanding stability (10 000 cycles). Besides, the sensor can accurately monitor human activity in different states. This work provides a promising strategy for designing multifunctional PI foams, making them suitable for applications in aerospace and microelectronics.
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Thin-film lithium niobate (TFLN) based integrated photonic devices have been intensively investigated due to their promising properties, enabling various on-chip applications. Grating couplers (GCs) are wildly used for their flexibility and high alignment tolerance for fiber-to-chip coupling. However, achieving high coupling efficiency (CE) in TFLN GCs often requires the use of reflectors, hybrid materials, or extremely narrow linewidths of the grating arrays, which significantly increases the fabrication difficulty. Therefore, there is a demand for high-CE GCs on TFLN with simple structure and easy fabrication processes. In this paper, combining process capabilities, we demonstrate a highly efficient apodized GC by linearly optimizing the period length and the fill factor on a 600-nm-thick TFLN platform. Without any reflector or hybrid material, we achieve a remarkable coupling loss of -2.97â dB at 1555â nm on the 600-nm-thick X-cut TFLN platform with only a single lithography and etching step. Our work sets a new benchmark for CE among GCs on the 600-nm-thick TFLN platform.
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ETHNOPHARMACOLOGICAL RELEVANCE: The use of lavender as sleep aid or hypnotic agent can be traced back as early as ancient Romans and Greeks. Yet, objective experimental data on whether and how lavender enhances sleep duration or/and sleep quality remain lacking. AIM OF THE STUDY: We aimed to characterize the sleep-wake regulating effects of lavender in the mouse and to demonstrate the brain targets and neural circuits involved. MATERIALS AND METHODS: A self-made precise odor delivery system combined with chronic polysomnographic recordings was employed to assess the sleep-wake effects of inhalation with lavender essential oil (LEO, extracted from lavender) and its different constituents during the light and dark phases in free-moving C57BL/6J mice. Neuroviral labeling, in situ hybridization and pharmacogenetics were combined to identify the neural circuits and targets involved. Finally, an insomniac model of DL-4-Chlorophenylalanine (PCPA)-treated mice was established to examine the sleep-inducing potential of LEO. RESULTS: We found that inhalation of LEO with a concentration at 25.0% during the light (inactive) phase significantly shortened the latency to non-rapid eye movement (NREM) sleep, increased the total amount of NREM sleep at the expense of wakefulness (W), and enhanced cortical EEG slow wave activities, notably delta power spectra density. We further identified linalool, d-limonene, 1,8-cineole, linalyl acetate and terpinene-4-ol as the major effective sleep-promoting monomer components. Importantly, we found that LEO no longer produced any of the above sleep-promoting effect following either nasal injection of zinc sulfate which interrupts the olfactory pathway, or pharmacogenetics silencing of central amygdala GABAergic neurons. Finally, LEO reestablished NREM sleep with short latency in PCPA-treated insomniac mice, effects comparable with those induced by a potent sedative diazepam. CONCLUSIONS: We have characterized the quantitative and qualitative sleep-promoting effects of LEO and its effective components via the olfactory pathway and central amygdala GABA neuronal targets. The hypnotic property of LEO is reinforced by its ability to restore sleep in insomnia. Our study thus establishes a neurobiological basis for aromatherapy of sleep disorders using lavender.
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OBJECTIVES: To evaluate the relationship between oral health and geriatric disorders, as well as its role in clinical outcomes among acutely admitted older patients. DESIGN: A retrospective observational study was conducted. SETTING: The study was conducted at a medical center in central Taiwan. PARTICIPANTS: A total of 1,141 patients (651 males and 490 females), aged 65 years or older, were admitted due to acute illness with geriatric syndromes from October 1, 2018, to March 31, 2023. MEASUREMENTS: A comprehensive geriatric assessment (CGA) was conducted, covering the comorbidity index, cognitive status, mood, physical function, nutritional status, mobility, health-related quality of life, frailty, and oral health condition. Oral health was evaluated using a bedside oral examination with scores ranging from 8 to 24, where scores of 8-10 indicated normal oral health, 11-14 indicated moderate impairment, and 15-24 indicated severe impairment. The primary outcome observed was in-hospital mortality. RESULTS: Among the participants, 40.5% experienced cognitive impairment, 24.8% exhibited depressive symptoms, 69.4% had low hand grip strength, 36.5% demonstrated low performance in mobility, and 78.9% were at risk of malnutrition. Severe impairment of oral health was found in 18.8% of the participants, while frailty was observed in 85.1%. Stratification of oral health severity revealed differences in various CGA parameters, including comorbidity, polypharmacy, cognitive impairment, depressive mood, physical activity, mobility, nutritional status, and quality of life, as well as clinical outcomes such as length of stay and in-hospital mortality between the groups. In univariable analysis, age, gender, frailty, oral health impairment, comorbidity index, nutritional status, and cognitive and physical functions were all significantly associated with in-hospital mortality. After adjusting for significant factors, severe oral health impairment remained significantly associated with mortality. CONCLUSION: In acutely admitted older patients, oral health was associated with geriatric disorders and was linked to in-hospital mortality. Early intervention in oral health may be necessary to improve outcomes.
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It is critical to identify and detect hazardous, flammable, explosive, and poisonous gases in the realms of industrial production and medical diagnostics. To detect and categorize a range of common hazardous gasses, we propose an attention-based Long Short term memory Full Convolutional network (ALSTM-FCN) in this paper. We adjust the network parameters of ALSTM-FCN using the Sparrow search algorithm (SSA) based on this, by comparison, SSA outperforms Particle Swarm Optimization (PSO) Algorithm, Genetic Algorithm (GA), Gray Wolf Optimization (GWO) Algorithm, Cuckoo Search (CS) Algorithm and other traditional optimization algorithms. We evaluate the model using University of California-Irvine (UCI) datasets and compare it with LSTM and FCN. The findings indicate that the ALSTM-FCN hybrid model has a better reliability test accuracy of 99.461% than both LSTM (89.471%) and FCN (96.083%). Furthermore, AdaBoost, logistic regression (LR), extra tree (ET), decision tree (DT), random forest (RF), K-nearest neighbor (KNN) and other models were trained. The suggested approach outperforms the conventional machine learning model in terms of gas categorization accuracy, according to experimental data. The findings indicate a potential for a broad range of polluting gas detection using the suggested ALSTM-FCN model, which is based on SSA optimization.
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Algoritmos , Gases , Gases/análisis , Redes Neurales de la Computación , Contaminantes Atmosféricos/análisisRESUMEN
Seasonal influenza A virus subtype H3N2 (A/H3N2) circulates globally and has been linked to higher hospitalization rates and summer outbreaks in temperate regions. Here, A/H3N2 circulation in Shanghai, China was systematically studied using data and materials generated by the Shanghai influenza surveillance network from 2005 to 2023. Time-series analysis of incidence and subtyping data showed that A/H3N2 co-circulated with other (sub)types and dominated in multiple seasonal influenza peaks, preferentially in summer. Whole genomes of 528 representative strains were sequenced, and spatiotemporal phylodynamic analysis using these and GISAID-archived sequences demonstrated that in the years before the COVID-19 pandemic, phylogenetically similar strains were circulating locally and elsewhere. However, clade 1a.1 (within 3C.2a.1b.2a), circulated in and only in Shanghai and domestically in 2022, while the sibling clade 2 predominated in other regions. Interestingly, clade 1a.1 was swiftly and completely replaced by clade 2, mostly 2a.3a.1, at the start of 2023. In hemagglutination inhibition and neutralization assays, sera from healthy donors collected in 2022 displayed higher or similar reactivity against 2a.3a.1 compared to 1a.1. By contrast, transcription and replication competence of 2a.3a.1 in MDCK cells was higher than 1a.1. These results indicated that instead of antigenicity differences enabling evasion of pre-existing immunity, higher replicative capability more likely contributed to 2a.3a.1 viruses achieving dominance in China. In addition to summarizing patterns of A/H3N2 local circulation in Shanghai, this work revealed an unusual episode in A/H3N2 global circulation and evolution dynamics in connection to the COVID-19 pandemic and explored possible mechanistic explanations.
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Genoma Viral , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana , Filogenia , Secuenciación Completa del Genoma , China/epidemiología , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/aislamiento & purificación , Subtipo H3N2 del Virus de la Influenza A/clasificación , Humanos , Gripe Humana/virología , Gripe Humana/epidemiología , COVID-19/epidemiología , COVID-19/virología , Estaciones del Año , SARS-CoV-2/genética , SARS-CoV-2/clasificación , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/inmunología , Células de Riñón Canino Madin Darby , Perros , AnimalesRESUMEN
INTRODUCTION: Informal caregiving is associated with mental disorders and reduced quality of life. The aim of this systematic review was to summarize the results of methodologically high-quality intervention studies on the effectiveness of non-pharmacological interventions on patient-relevant outcomes for family caregivers in Germany. METHOD: We searched three large scientific literature databases for intervention studies with a control group and a low or moderate risk of bias on the effectiveness of non-pharmacological interventions for family caregivers in Germany. RESULT: Among 4,376 publications reviewed, 10 intervention studies with good methodological quality were identified. These investigated multi-component interventions or cognitive behavioral therapy for family caregivers of people with dementia (8 studies), stroke (1 study) and with general care dependency (1 study). The control groups received information material as a minimal intervention or usual standard care. Meta-analyses showed a statistically significant slight reduction in depressive symptoms 3-6 months after the start of the study as a result of cognitive behavioral therapy (standardized mean difference -0.27; 95% confidence interval -0.44 - -0.10), but this no longer reached statistical significance after 9-12 months (-0.21; -0.51 - 0.09). Multi-component interventions showed no changes in depressive symptoms either after 3-6 or after 9-12 months (-0.18; -0.40 - 0.03 and -0.14; -0.47 - 0.14, respectively). In contrast, the mental component of quality of life of family caregivers improved statistically significantly in the multi-component intervention groups compared to the control groups: slightly after 3-6 months (0.28; 0.01 - 0.56) and moderately after 9-12 months (0.45; 0.09 - 0.82). The interventions had no effect on the physical component of quality of life. CONCLUSION: The reduction of depressive symptoms by behavioral therapy interventions for family caregivers appears to be only slight and not sustainable. The mental component of quality of life of people affected may be improved in the longer term by multi-component interventions. Current scientifically examined interventions for informal caregivers do not appear to have a sufficient and sustainable effect. Greater effects could possibly be achieved through more elaborate behavioral approaches, but also structural preventive measures.
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Introduction: This study aimed to explore the relationship between the trajectories of body weight (BW) z-scores at birth, discharge, and 6 months corrected age (CA) and neurodevelopmental outcomes at 24 months CA. Methods: Conducted as a population-based retrospective cohort study across 21 hospitals in Taiwan, we recruited 3,334 very-low-birth-weight (VLBW) infants born between 2012 and 2017 at 23-32 weeks of gestation. Neurodevelopmental outcomes were assessed at 24 months CA. Instances of neurodevelopmental impairment (NDI) were defined by the presence of at least one of the following criteria: cerebral palsy, severe hearing loss, profound vision impairment, or cognitive impairment. Group-based trajectory modeling was employed to identify distinct BW z-score trajectory groups. Multivariable logistic regression was used to assess the associations between these trajectories, postnatal comorbidity, and neurodevelopmental impairments. Results: The analysis identified three distinct trajectory groups: high-climbing, mid-declining, and low-declining. Significant associations were found between neurodevelopmental impairments and both cystic periventricular leukomalacia (cPVL) [with an adjusted odds ratio (aOR) of 3.59; p < 0.001] and belonging to the low-declining group (aOR: 2.59; p < 0.001). Discussion: The study demonstrated that a low-declining pattern in body weight trajectory from birth to 6 months CA, along with cPVL, was associated with neurodevelopmental impairments at 24 months CA. These findings highlight the importance of early weight trajectory and specific health conditions in predicting later neurodevelopmental outcomes in VLBW infants.
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Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5's tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA's regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.
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Neoplasias de la Boca , ARN Circular , Nexinas de Clasificación , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Nexinas de Clasificación/metabolismo , Nexinas de Clasificación/genética , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Ratones , Ratones Desnudos , MicroARNs/metabolismo , MicroARNs/genética , Masculino , Femenino , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismoRESUMEN
Adult zebrafish are able to heal large-sized cutaneous wounds in hours with little to no scarring. This rapid re-epithelialization is crucial for preventing infection and jumpstarting the subsequent regeneration of damaged tissues. Despite significant progress in understanding this process, it remains unclear how vast numbers of epithelial cells are orchestrated on an organismic scale to ensure the timely closure of millimeter-sized wounds. Here, we report an unexpected role of adult zebrafish appendages (fins) in accelerating the re-epithelialization process. Through whole-body monitoring of single-cell dynamics in live animals, we found that fin-resident epithelial cells (FECs) are highly mobile and migrate to cover wounds in nearby body regions. Upon injury, FECs readily undergo organ-level mobilization, allowing for coverage of body surfaces of up to 4.78 mm2 in less than 8 h. Intriguingly, long-term fate-tracking experiments revealed that the migratory FECs are not short-lived at the wound site; instead, the cells can persist on the body surface for more than a year. Our experiments on "fin-less" and "fin-gaining" individuals demonstrated that the fin structures are not only capable of promoting rapid re-epithelialization but are also necessary for the process. We further found that fin-enriched extracellular matrix laminins promote the active migration of FECs by facilitating lamellipodia formation. These findings lead us to conclude that appendage structures in regenerative vertebrates, such as fins, may possess a previously unrecognized function beyond serving as locomotor organs. The appendages may also act as a massive reservoir of healing cells, which speed up wound closure and tissue repair.
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Células Epiteliales , Cicatrización de Heridas , Pez Cebra , Animales , Pez Cebra/fisiología , Células Epiteliales/fisiología , Cicatrización de Heridas/fisiología , Repitelización/fisiología , Movimiento Celular , Aletas de Animales/fisiología , Aletas de Animales/lesionesRESUMEN
Background: Glove reuse poses risks, as chemicals can persist even after cleaning. Decontamination methods like thermal aeration, recommended by US OSHA, vary in effectiveness. Some studies show promising results, while others emphasize the importance of considering both permeation and tensile strength changes. This research advocates for informed glove reuse, emphasizing optimal thermal aeration temperatures and providing evidence to guide users in maintaining protection efficiency. Methods: The investigation evaluated Neoprene and Nitrile gloves (22 mils). Permeation tests with toluene and acetone adhered to American Society for Testing Materials (ASTM) F739 standards. Decontamination optimization involved aeration at various temperatures. The experiment proceeded with a maximum of 22 re-exposure cycles. Tensile strength and elongation were assessed following ASTM D 412 protocols. Breakthrough time differences were statistically analyzed using t-test and ANOVA. Results: At room temperature, glove residuals decreased, and standardized breakthrough time (SBT)2 was significantly lower than SBT1, indicating reduced protection. Higher temperature decontamination accelerated residual removal, with ΔSBT (SBT2/SBT1) exceeding 100%, signifying restored protection. Tensile tests showed stable neoprene properties postdecontamination. Results underscore thermal aeration's efficacy for gloves reuse, emphasizing temperature's pivotal role. Findings recommend meticulous management strategies, especially post-breakthrough, to uphold glove-protective performance. Conclusions: Thermal aeration at 100°C for 1 hour proves effective, restoring protection without compromising glove strength. The study, covering twenty cycles, suggests safe glove reuse with proper decontamination, reducing costs significantly. However, limitations in chemical-glove combinations and exclusive focus on specific gloves caution against broad generalization. The absence of regulatory directives on glove reuse highlight the importance of informed selection and rigorous decontamination validation for workplace safety practices.
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BACKGROUND: The present study compares the anatomical and functional outcomes (best-corrected visual acuity (BCVA) and central macular thickness (CMT)) among membrane peeling with or without SF6 tamponade in patients with epiretinal membrane. METHODS: We retrospectively reviewed patients diagnosed with macular pucker who underwent pars plana vitrectomy and membrane peeling in a tertiary center in Taiwan from January 2021 to December 2022. Subjects were categorized into with or without SF6 tamponade groups (SF6 group and BSS group). Postoperative intraocular pressure and complications were documented. Logistic regression analyses were performed to identify the prognostic factors during follow-up. RESULTS: A total of 89 eyes were enrolled, including 34 eyes in the BSS group and 55 eyes in the SF6 group. The mean age was 66 years old, and a female predilection was demonstrated. Both groups possessed statistically significant improvement in BCVA and CMT after the operation. There was no significant difference in CMT between the groups at any time of observation, yet we observed significant differences in baseline BCVA and BCVA at last follow-up among the two groups. Both groups yielded an approximate enhancement of LogMAR 0.3 in BCVA postoperatively. There was no significant difference noted in postoperative IOP between the two groups. CONCLUSION: Membrane peeling with or without SF6 tamponade yields comparable outcomes anatomically and functionally. This may indicate that SF6 tamponade for idiopathic macular pucker surgery may not provide extra benefit, and therefore warrants reconsideration as standard procedure.
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In the field of drug discovery, a proliferation of pre-trained models has surfaced, exhibiting exceptional performance across a variety of tasks. However, the extensive size of these models, coupled with the limited interpretative capabilities of current fine-tuning methods, impedes the integration of pre-trained models into the drug discovery process. This paper pushes the boundaries of pre-trained models in drug discovery by designing a novel fine-tuning paradigm known as the Head Feature Parallel Adapter (HFPA), which is highly interpretable, high-performing, and has fewer parameters than other widely used methods. Specifically, this approach enables the model to consider diverse information across representation subspaces concurrently by strategically using Adapters, which can operate directly within the model's feature space. Our tactic freezes the backbone model and forces various small-size Adapters' corresponding subspaces to focus on exploring different atomic and chemical bond knowledge, thus maintaining a small number of trainable parameters and enhancing the interpretability of the model. Moreover, we furnish a comprehensive interpretability analysis, imparting valuable insights into the chemical area. HFPA outperforms over seven physiology and toxicity tasks and achieves state-of-the-art results in three physical chemistry tasks. We also test ten additional molecular datasets, demonstrating the robustness and broad applicability of HFPA.
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The fucosylation of glycoproteins regulates diverse physiological processes. Inhibitors that can control cellular levels of protein fucosylation have consequently emerged as being of high interest. One area where inhibitors of fucosylation have gained significant attention is in the production of afucosylated antibodies, which exhibit superior antibody-dependent cell cytotoxicity as compared to their fucosylated counterparts. Here, we describe ß-carbafucose, a fucose derivative in which the endocyclic ring oxygen is replaced by a methylene group, and show that it acts as a potent metabolic inhibitor within cells to antagonize protein fucosylation. ß-carbafucose is assimilated by the fucose salvage pathway to form GDP-carbafucose which, due to its being unable to form the oxocarbenium ion-like transition states used by fucosyltransferases, is an incompetent substrate for these enzymes. ß-carbafucose treatment of a CHO cell line used for high-level production of the therapeutic antibody Herceptin leads to dose-dependent reductions in core fucosylation without affecting cell growth or antibody production. Mass spectrometry analyses of the intact antibody and N-glycans show that ß-carbafucose is not incorporated into the antibody N-glycans at detectable levels. We expect that ß-carbafucose will serve as a useful research tool for the community and may find immediate application for the rapid production of afucosylated antibodies for therapeutic purposes.
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Cricetulus , Fucosa , Fucosa/metabolismo , Animales , Células CHO , Glicosilación , Humanos , Trastuzumab/farmacología , Trastuzumab/metabolismo , Fucosiltransferasas/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacosRESUMEN
Understanding water splitting in pH-neutral media has important implications for hydrogen production from seawater. Despite their significance, electrochemical water oxidation and reduction in neutral electrolytes still face great challenges. This study focuses on designing efficient electrocatalysts capable of promoting the oxygen evolution reaction (OER) in neutral media by incorporating high-valence elements into transition-metal hydroxides. The as-prepared and optimized two-dimensional Mo-Co(OH)2 nanosheets, which undergo operando transformation into oxyhydroxide active species, demonstrated an overpotential of 550 mV at 10 mA cm-2 with a Tafel slope of 110.1 mV dec-1 in 0.5 M KHCO3. In situ X-ray absorption spectroscopy revealed that the incorporation of high-valence elements facilitates the generation of CoOOH active sites at low potential and enhances electron transfer kinetics by altering the electronic environment of the Co center. This study offers new insights for developing more efficient OER electrocatalysts and provides fresh ideas for seawater utilization through the study of the reaction mechanism of the near-neutral-pH OER.
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Our aim was to develop a machine learning-based predictor for early mortality and severe intraventricular hemorrhage (IVH) in very-low birth weight (VLBW) preterm infants in Taiwan. We collected retrospective data from VLBW infants, dividing them into two cohorts: one for model development and internal validation (Cohort 1, 2016-2021), and another for external validation (Cohort 2, 2022). Primary outcomes included early mortality, severe IVH, and early poor outcomes (a combination of both). Data preprocessing involved 23 variables, with the top four predictors identified as gestational age, birth body weight, 5-min Apgar score, and endotracheal tube ventilation. Six machine learning algorithms were employed. Among 7471 infants analyzed, the selected predictors consistently performed well across all outcomes. Logistic regression and neural network models showed the highest predictive performance (AUC 0.81-0.90 in both internal and external validation) and were well-calibrated, confirmed by calibration plots and the lowest two mean Brier scores (0.0685 and 0.0691). We developed a robust machine learning-based outcome predictor using only four accessible variables, offering valuable prognostic information for parents and aiding healthcare providers in decision-making.