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BACKGROUND: Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. METHODOLOGY/PRINCIPAL FINDINGS: Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. CONCLUSIONS/SIGNIFICANCE: Overall, the study and modelling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.
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Objective: To explore the reasonable dietary trajectory of elderly people in the community and to test the correlation between different dietary trajectories and body mass index (BMI) of the elderly people in the community to provide a reference for these individuals to formulate scientific interventions and cultivate healthy living habits. Methods: The data of The Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2011 to 2018 were used to evaluate the dietary status of elderly people in the community according to their diet, and body mass index was calculated according to height and weight. The latent variable growth mixed (LGMM) model was used to analyze the development trajectory of diet in elderly people, and the multivariate logistic regression model was used to test the relationship between different dietary development trajectories and BMI changes as well as to test the correlation between different dietary trajectories and BMI of the elderly people in the community. Results: The LGMM fit four dietary trajectories of elderly individuals: the continuous reasonable diet group (37.81%), the dietary behavior decline group (28.84%), the continuous unreasonable diet group (20.16%), and the dietary behavior improvement group (13.19%). The results showed that factors including male sex, rural setting, being spouseless, nonformal education status, not being wealthy, living alone, and having tooth loss were more likely to be classified as the "persistently unreasonable diet group" (p < 0.05). The logistic regression results showed that the "continuous reasonable diet group" and the "dietary behavior improvement group" were significantly correlated with the development of obesity to a normal BMI. Conclusion: The dietary behavior of the elderly was significantly correlated with BMI value, and improving the reasonable dietary behavior of the elderly could reduce the high BMI to the normal range, but could not restore the low BMI to the normal range, indicating that reasonable dietary behavior is an important measure to prevent and improve overweight or obesity in the elderly. There is significant heterogeneity in the dietary behavior of the elderly, and community medical staff should identify the risk factors of various dietary behaviors of other groups as soon as possible, and provide corresponding intervention strategies to help them change their poor dietary behaviors and improve their nutritional status.
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Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.
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Caspasa 1 , Hidrógeno , Memantina , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Ratas Sprague-Dawley , Agua , Animales , Memantina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hidrógeno/farmacología , Piroptosis/efectos de los fármacos , Ratas , Caspasa 1/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/prevención & control , Lesiones Encefálicas/patología , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Estrés Oxidativo/efectos de los fármacos , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/prevención & controlRESUMEN
Astatine-211 (211At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of 211At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview of the current strategies for 211At radiolabeling, including nucleophilic and electrophilic substitution reactions, as well as the recent advances in the development of novel bifunctional coupling agents and labeling approaches to enhance the stability of 211At-labeled compounds. The preclinical and clinical applications of 211At-labeled radiopharmaceuticals, including small molecules, peptides, and antibodies, are also discussed. Looking forward, the identification of new molecular targets, the optimization of 211At production and quality control methods, and the continued evaluation of 211At-labeled radiopharmaceuticals in preclinical and clinical settings will be the key to realizing the full potential of 211At-based targeted alpha therapy. With the growing interest and investment in this field, 211At-labeled radiopharmaceuticals are poised to play an increasingly important role in future cancer treatment.
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Porous graphene, including 2D and 3D porous graphene, is widely researched recently. One of the most attractive features is the proper utilization of graphene defects, which combine the advantages of both graphene and porous materials, greatly enriching the applications of porous graphene in biology, chemistry, electronics, and other fields. In this review, the defects of graphene are first discussed to provide a comprehensive understanding of porous graphene. Then, the latest advancements in the preparation of 2D and 3D porous graphene are presented. The pros and cons of these preparation methods are discussed in detail, providing a direction for the fabrication of porous graphene. Moreover, various superior properties of porous graphene are described, laying the foundation for their promising applications. Owing to its abundant morphology, wide distribution of pore size, and remarkable properties benefited from porous structure, porous graphene can not only promote molecular diffusion and electron transfer but also expose more active sites. Consequently, a serious of applications containing gas sieving, liquid separation, sensors, and supercapacitors, are presented. Finally, the challenges confronted during preparation and characterization of porous graphene are discussed, offering guidance for the future development of porous graphene in fabrication, characterization, properties, and applications.
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Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions (DMRs) were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors (TFs), including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions (NDRs) in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening the fetal gene reprogramming in HCM.
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Background: Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose: Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods: PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results: Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion: Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.
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Ovarian endometriosis is characterized by the growth of endometrial tissue within the ovary, causing infertility and chronic pain. However, its pathophysiology remains unclear. Utilizing high-precision single-cell RNA sequencing, we profile the normal, eutopic, and ectopic endometrium from 34 individuals across proliferative and secretory phases. We observe an increased proportion of ciliated cells in both eutopic and ectopic endometrium, characterized by a diminished expression of estrogen sulfotransferase, which likely confers apoptosis resistance. After translocating to ectopic lesions, endometrial epithelium upregulates nicotinamide N-methyltransferase expression that inhibits apoptosis by promoting deacetylation and subsequent nuclear exclusion of transcription factor forkhead box protein O1, thereby leading to the downregulation of the apoptotic gene BIM. Moreover, epithelial cells in ectopic lesions elevate HLA class II complex expression, which stimulates CD4+ T cells and consequently contributes to chronic inflammation. Altogether, our study provides a comprehensive atlas of ovarian endometriosis and highlights potential therapeutic targets for modulating apoptosis and inflammation.
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Endometriosis , Femenino , Humanos , Endometriosis/patología , Células Epiteliales/metabolismo , Epitelio/metabolismo , Endometrio/metabolismo , Análisis de la Célula Individual , Inflamación/patologíaRESUMEN
Long noncoding RNAs (lncRNAs) have significant regulatory roles in gene expression. Interactions with proteins are one of the ways lncRNAs play their roles. Since experiments to determine lncRNA-protein interactions (LPIs) are expensive and time-consuming, many computational methods for predicting LPIs have been proposed as alternatives. In the LPIs prediction problem, there commonly exists the imbalance in the distribution of positive and negative samples. However, there are few existing methods that give specific consideration to this problem. In this paper, we proposed a new clustering-based LPIs prediction method using segmented k-mer frequencies and multi-space clustering (LPI-SKMSC). It was dedicated to handling the imbalance of positive and negative samples. We constructed segmented k-mer frequencies to obtain global and local features of lncRNA and protein sequences. Then, the multi-space clustering was applied to LPI-SKMSC. The convolutional neural network (CNN)-based encoders were used to map different features of a sample to different spaces. It used multiple spaces to jointly constrain the classification of samples. Finally, the distances between the output features of the encoder and the cluster center in each space were calculated. The sum of distances in all spaces was compared with the cluster radius to predict the LPIs. We performed cross-validation on 3 public datasets and LPI-SKMSC showed the best performance compared to other existing methods. Experimental results showed that LPI-SKMSC could predict LPIs more effectively when faced with imbalanced positive and negative samples. In addition, we illustrated that our model was better at uncovering potential lncRNA-protein interaction pairs.
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Redes Neurales de la Computación , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Análisis por Conglomerados , Biología Computacional/métodos , Algoritmos , Proteínas/metabolismo , Proteínas/genética , HumanosRESUMEN
Twisted bilayer graphene (TBG) generates significant attention in the fundamental research of 2D materials due to its distinct twist-angle-dependent properties. Exploring the efficient production of TBG with a wide range of twist angles stands as one of the major frontiers in moiré materials. Here, the local space-confined chemical vapor deposition growth technique for high-quality single-crystal TBG with twist angles ranging from 0° to 30° on liquid copper substrates is reported. The clean surface, pristine interface, high crystallinity, and thermal stability of TBG are verified by using comprehensive characterization techniques including optical microscopy, electron microscopy, and secondary-ion mass spectrometry. The proportion of TBG in bilayer graphene reaches as high as 89%. In addition, the stacking structure and growth mechanism of TBG are investigated, revealing that the second graphene layer develops beneath the first one. A series of comparative experiments illustrates that the liquid copper surface, with its excellent fluidity, promotes the growth of TBG. Electrical measurements show the twist-angle-dependent electronic properties of as-grown TBG, achieving a room-temperature carrier mobility of 26640 cm2 V-1 s-1 . This work provides an approach for the in situ preparation of 2D twisted materials and facilitates the application of TBG in the fields of electronics.
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Empirical information about the transport properties of neonicotinoid pesticides through the soil as affected by the ubiquitous low molecular weight organic acids (LMWOAs) is lacking. Herein, the impacts of three LMWOAs with different molecular structures, including citric acid, acetic acid, and malic acid, on the mobility characteristics of two typical neonicotinoid pesticides (Dinotefuran (DTF) and Nitenpyram (NTP)) were explored. Interestingly, under acidic conditions, different mechanisms were involved in transporting DTF and NTP by adding exogenous LMWOAs. Concretely, acetic acid and malic acid inhibited DTF transport, ascribed to the enhanced electrostatic attraction between DTF and porous media and the additional binding sites provided by the deposited LMWOAs. However, citric acid slightly enhanced DTF mobility due to the fact that the inhibitory effect was weakened by the steric hindrance effect induced by the deposited citric acid with a large molecular size. In comparison, all three LMWOAs promoted NTP transport at pH 5.0. Because the interaction between NTP with soil organic matter (e.g., via π-π stacking interaction) was masked by the LMWOAs coating on soil surfaces. Nevertheless, LMWOAs could promote the mobility of both neonicotinoid pesticides at pH 7.0 due to the steric hindrance effect caused by the deposited organic acids and the competitive retention between LMWOAs and pesticides for effective surface deposition sites of soil particles. Furthermore, the extent of the promotion effects of LMWOAs generally followed the order of citric acid > malic acid > acetic acid. This pattern was highly related to their molecular structures (e.g., number and type of functional groups and molecular size). Additionally, when the background solutions contained Ca2+, the bridging effect of cations also contributed to the transport-enhancement effects of LMWOAs. The findings provide valuable information about the mobility behaviors of neonicotinoid pesticides co-existing with LMWOAs in soil-water systems.
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Contaminantes del Suelo , Suelo , Estructura Molecular , Suelo/química , Porosidad , Compuestos Orgánicos/química , Ácido Cítrico/química , Peso Molecular , Ácido Acético/farmacología , Neonicotinoides , Contaminantes del Suelo/análisisRESUMEN
Accurate identification of driver mutations is crucial in genetic studies of human cancers. While numerous cancer driver missense mutations have been identified, research into potential cancer drivers for synonymous mutations has shown limited success to date. Here, we developed a novel machine learning framework, epSMic, for predicting cancer driver synonymous mutations. epSMic employs an iterative feature representation scheme that facilitates the learning of discriminative features from various sequential models in a supervised iterative mode. We constructed the benchmark datasets and encoded the embedding sequence, physicochemical property, and basic information such as conservation and splicing feature. The evaluation results on benchmark test datasets demonstrate that epSMic outperforms existing methods, making it a valuable tool for researchers in identifying functional synonymous mutations in cancer. We hope epSMic can enable researchers to concentrate on synonymous mutations that have a functional impact on cancer.
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Neoplasias , Mutación Silenciosa , Humanos , Neoplasias/genética , Aprendizaje AutomáticoRESUMEN
Objective@#To investigate the association between self-rated health status and mortality risk, and to evaluate the predictive value of self-rated health status for mortality risk among the elderly.@*Methods@#Based on the China Health and Retirement Longitudinal Study (CHARLS) database, data of sociodemographic information, self-rated health status and mortality of the elderly aged 60 years and older were collected from 2011 to 2018. The association between self-rated health status and mortality risk among the elderly was analyzed using a multivariable Cox proportional risk regression model.@*Results@#Totally 4 850 individuals were included, with an median age of 65 (interquartile range, 8) years. There were 2 485 males (51.24%) and 2 365 females (48.76%). There were 877 individuals (18.08%) rated their health as good, 2 078 individuals (42.85%) as general, 1 895 individuals (39.07%) as poor. A total of 28 955 person-years were followed up, with an average follow-up of 5.97 years per person. There were 855 deaths by the end of follow-up in 2018, and the median survival time was 7 (interquartile range, 3) years. Multivariable Cox proportional risk regression analysis showed that there were interactive effects of age, sex and self-rated health status on mortality, respectively (both P<0.05). The results of gender-stratified analysis showed that there was no significant association between self-rated health status and mortality risk in old women (P>0.05). The mortality risk was higher in old men with poor self-rated health than with good self-rated health (<70 years, HR=5.382, 95%CI: 3.263-8.876; 70 to 79 years, HR=3.536, 95%CI: 1.070-11.686; ≥80 years, HR=3.043, 95%CI: 1.827-5.066).@*Conclusion@#There is an association between self-rated health status and mortality risk among the elderly, the old men with poor self-rated health had a higher mortality risk.
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The potential applications of multilayer graphene in many fields, such as superconductivity and thermal conductivity, continue to emerge. However, there are still many problems in the growth mechanism of multilayer graphene. In this paper, a simple control strategy for the preparation of interlayer-coupled multilayer graphene on a liquid Cu substrate was developed. By adjusting the flow rate of a carrier gas in the CVD system, the effect for finely controlling the carbon source supply was achieved. Therefore, the carbon could diffuse from the edge of the single-layer graphene to underneath the layer of graphene and then interlayer-coupled multilayer graphene with different shapes were prepared. Through a variety of characterization methods, it was determined that the stacked mode of interlayer-coupled multilayer graphene conformed to AB-stacking structure. The small multilayer graphene domains stacked under single-layer graphene was first found, and the growth process and growth mechanism of interlayer-coupled multilayer graphene with winged and umbrella shapes were studied, respectively. This study reveals the growth mechanism of multilayer graphene grown by using a carbon source through edge diffusion, paving the way for the controllable preparation of multilayer graphene on a liquid Cu surface.
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BACKGROUND: Hydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by coupling the brain metabolomics and biological target network methods. METHODS AND RESULTS: HRW significantly improves the cognitive impairment in rats exposed to ionizing radiation. Based on metabolomics and biological network results, we identified 54 differential metabolites and 93 target genes. The KEGG pathway indicates that glutathione metabolism, ascorbic acid and aldehyde acid metabolism, pentose and glucuronic acid interconversion, and glycerophospholipid metabolism play important roles in ionizing radiation therapy. CONCLUSION: Our study has systematically elucidated the molecular mechanism of HRW against ionizing radiation, which can be mediated by modulating targets, pathways and metabolite levels. This provides a new perspective for identifying the underlying pharmacological mechanism of HRW.
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Encéfalo , Disfunción Cognitiva , Animales , Ratas , Disfunción Cognitiva/etiología , Tecnología , Hidrógeno/farmacología , AguaRESUMEN
Covalent organic frameworks (COFs), as a burgeoning class of crystalline porous materials, have made significant progress in their application to optoelectronic devices such as field-effect transistors, memristors, and photodetectors. However, the insoluble features of microcrystalline two-dimensional (2D) COF powders limit development of their thin film devices. Additionally, the exploration of spin transport properties in this category of π-conjugated skeleton materials remains vacant thus far. Herein, an imine-linked 2D Py-Np COF nanocrystalline powder was synthesized by Schiff base condensation of 4,4',4'',4'''-(pyrene-1,3,6,8-tetrayl)tetraaniline and naphthalene-2,6-dicarbaldehyde. Then, we prepared a large-scale free-standing Py-Np COF film via a top-down strategy of chemically assisted acid exfoliation. Moreover, high-quality COF films acted as active layers were transferred onto ferromagnetic La0.67 Sr0.33 MnO3 (LSMO) electrodes for the first attempt to fabricate organic spin valves (OSVs) based on 2D COF materials. This COF-based OSV device with a configuration of LSMO/Py-Np COF/Co/Au demonstrated a remarkable magnetoresistance (MR) value up to -26.5 % at 30â K. Meanwhile, the MR behavior of the COF-based OSVs exhibited a highly temperature dependence and operational stability. This work highlights the enormous application prospects of 2D COFs in organic spintronics and provides a promising approach for developing electronic and spintronic devices based on acid-exfoliated COF thin films.
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Count time series are widely available in fields such as epidemiology, finance, meteorology, and sports, and thus there is a growing demand for both methodological and application-oriented research on such data. This paper reviews recent developments in integer-valued generalized autoregressive conditional heteroscedasticity (INGARCH) models over the past five years, focusing on data types including unbounded non-negative counts, bounded non-negative counts, Z-valued time series and multivariate counts. For each type of data, our review follows the three main lines of model innovation, methodological development, and expansion of application areas. We attempt to summarize the recent methodological developments of INGARCH models for each data type for the integration of the whole INGARCH modeling field and suggest some potential research topics.