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SUMMARY: Mechanistic models are important tools to describe and understand biological processes. However, they typically rely on unknown parameters, the estimation of which can be challenging for large and complex systems. pyPESTO is a modular framework for systematic parameter estimation, with scalable algorithms for optimization and uncertainty quantification. While tailored to ordinary differential equation problems, pyPESTO is broadly applicable to black-box parameter estimation problems. Besides own implementations, it provides a unified interface to various popular simulation and inference methods. AVAILABILITY AND IMPLEMENTATION: pyPESTO is implemented in Python, open-source under a 3-Clause BSD license. Code and documentation are available on GitHub (https://github.com/icb-dcm/pypesto).
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Algoritmos , Programas Informáticos , Simulación por Computador , Incertidumbre , Documentación , Modelos BiológicosRESUMEN
Reproducibility and reusability of the results of data-based modeling studies are essential. Yet, there has been-so far-no broadly supported format for the specification of parameter estimation problems in systems biology. Here, we introduce PEtab, a format which facilitates the specification of parameter estimation problems using Systems Biology Markup Language (SBML) models and a set of tab-separated value files describing the observation model and experimental data as well as parameters to be estimated. We already implemented PEtab support into eight well-established model simulation and parameter estimation toolboxes with hundreds of users in total. We provide a Python library for validation and modification of a PEtab problem and currently 20 example parameter estimation problems based on recent studies.
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Lenguajes de Programación , Biología de Sistemas/métodos , Algoritmos , Bases de Datos Factuales , Modelos Biológicos , Modelos Estadísticos , Reproducibilidad de los ResultadosRESUMEN
Curcumin is an active ingredient with multiple functions, but its application is often restricted due to its poor water solubility, weak stability, and consequently low bioaccessibility. Based on this, the aim of this work is to develop a new vehicle to overcome these restrictions. Here we developed a curcumin-loaded nanoemulsion and then curcumin-loaded silica-lipid hybrid microparticles through emulsification and vacuum drying, respectively. The loading of curcumin in the nanoemulsion and microparticles was (0.30±0.02) and (0.67±0.02) %, respectively. FTIR and XRD analyses of microparticles revealed that curcumin was encapsulated in porous, amorphous silica. In vitro antioxidant activities showed that the encapsulation would not affect the antioxidant activity of curcumin. In vitro simulated digestion indicated that nanoemulsion and microparticles had higher curcumin bioaccessibility than the control group. The storage stability of microparticles remained the same during 6 weeks in the dark at 4, 25 and 40 °C. Moreover, the microparticles had a better chemical stability than nanoemulsion under the light. The cell viability was over 80% when the concentration of nanocarriers was less than 45 µg/mL. Hence, the microparticles could be a promising means to load curcumin and improve its solubility, light stability and bioaccessibility.
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The fields of medicine science and health informatics have made great progress recently and have led to in-depth analytics that is demanded by generation, collection and accumulation of massive data. Meanwhile, we are entering a new period where novel technologies are starting to analyze and explore knowledge from tremendous amount of data, bringing limitless potential for information growth. One fact that cannot be ignored is that the techniques of machine learning and deep learning applications play a more significant role in the success of bioinformatics exploration from biological data point of view, and a linkage is emphasized and established to bridge these two data analytics techniques and bioinformatics in both industry and academia. This survey concentrates on the review of recent researches using data mining and deep learning approaches for analyzing the specific domain knowledge of bioinformatics. The authors give a brief but pithy summarization of numerous data mining algorithms used for preprocessing, classification and clustering as well as various optimized neural network architectures in deep learning methods, and their advantages and disadvantages in the practical applications are also discussed and compared in terms of their industrial usage. It is believed that in this review paper, valuable insights are provided for those who are dedicated to start using data analytics methods in bioinformatics.
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Biología Computacional , Minería de Datos , Algoritmos , Teorema de Bayes , Aprendizaje Automático , Encuestas y CuestionariosRESUMEN
BACKGROUND: Few studies, to our knowledge, have examined the longitudinal association of snacking with child body mass index (BMI), especially in China, where the incidence of overweight and obesity has increased rapidly. OBJECTIVES: Our objective was to examine the longitudinal association between snacking and BMI z score and to test whether this association differs by baseline weight status. METHODS: Using data from the China Health and Nutrition Survey (2006, 2009, and 2011), we characterized snack intake for 9 provinces and 3 megacities. We used linear mixed-effects models to examine longitudinally the association between snacking (none, low, medium, and high tertiles according to energy) and BMI z score in children aged 2-13 y at baseline, controlling for sex, urbanicity, parental education, physical activity, and foods consumed at meals (n = 2277 observations). We tested whether this association differed by baseline underweight, normal weight, or overweight/obese. RESULTS: Snacking is prevalent in Chinese children, with fruit being the most common snack. Snacking was not associated with meaningful BMI z score changes in normal-weight children. However, in children who were underweight at baseline, snacking in the top tertiles was associated with increases in BMI z scores from 2006 to 2011 (+1.2 and +1.1 BMI z score units for ages 2-6 and 7-13 y, respectively) (P < 0.05). In overweight/obese 2- to 6-y-old children at baseline, being in the lowest snacking tertile was associated with declines in BMI z score (-3.3), whereas in overweight 7- to 13-y-old children, being in the top tertile of snacking was associated with the greatest decline in BMI z score (-2.1) (P < 0.05). The direction and magnitude of associations did not vary regardless of adjustment for total energy intake. CONCLUSIONS: Snacking in China, dominated by fruit consumption, is associated with decreased BMI in overweight/obese children and increased BMI in underweight children. More work will be needed to monitor this relation as Chinese diets continue to westernize.
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Índice de Masa Corporal , Conducta Alimentaria , Obesidad/epidemiología , Sobrepeso/epidemiología , Bocadillos , Delgadez/epidemiología , Adolescente , Niño , Preescolar , China/epidemiología , Estudios Transversales , Ingestión de Energía , Ejercicio Físico , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Encuestas Nutricionales , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To evaluate the pattern and level of physical activity (PA) and sedentary behaviors in Chinese children and adolescents. METHODS: The data of present study were derived from China Health and Nutrition Survey in 2011. Subjects aged 7-18 years with completed demographic, PA and sedentary behavior data were included to analyze the proportions of participations in PA outside school, PA in school, domestic PA, PA in travel and sedentary behaviors. In subjects with PA and sedentary behaviors, PA and sedentary behavior levels were estimated by age, gender, residence areus and household income. RESULTS: Amony the five types of activities studies, the proportion of children and adolescents with sedentary behaviors was highest (97.9%), while that of PA outside school was lowest (33.6%), the distribution of participations of various PA and sedentary behaviors were similor regardless of age and gender. The median levels of PA outside school and sedentary behaviors in children and adolescents having corresponding activities were the highest, 39.9 and 36.1 MET-h/week, respectively, which suggested that the time on sedentary behaviors was long. The differences in levels of various PA and sedentary behaviors by age, gender and residence were observed (all P < 0.05). CONCLUSION: In general, PA is deficient in Chinese children and adolescents. The promotion programmes to increas PA level need to be strengthened.
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Ejercicio Físico , Conducta Sedentaria , Adolescente , Pueblo Asiatico , Niño , China , Ciudades , Humanos , Encuestas Nutricionales , Instituciones AcadémicasRESUMEN
OBJECTIVE: To examine and characterize the snacking patterns of Chinese children and adolescents. METHODS: A total of 1195 subjects from the China Health and Nutrition Survey 2011 were included in the study. A multistage, stratified, sampling design was used. 24-h dietary recall method was used to collect food intake information in3 consecutive days. Snacking patterns were analyzed using cluster analysis. RESULTS: The highest consumption rates of snacks were fruits and products in 4-10 years old and 11-17 years old groups of urban and rural areas( 77%-84%). The major snacking food pattern of more than 90% children aged 4-10 years old in ubran and rual areas were fruits and dairy products. The major snacking food pattern of 82. 6% adolescents aged11-17 years old in ubran area were fruits products. And 47. 4% adolescents in rural area were beverage and fruits products. CONCLUSION: Four types of snacking food patterns are identified in 4-10 years old and 11-17 years old groups of urban and rural areas intwelve provinces of China.
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Conducta Alimentaria , Encuestas Nutricionales , Bocadillos , Adolescente , Niño , Preescolar , China , Dieta , HumanosRESUMEN
OBJECTIVE: To study meal and snack consumption and their contribution to daily dietary energy and macronutrients intakes among Chinese children and adolescents. METHODS: Children and adolescents aged 4-17 years old( n = 1905) from the 2011 China Health and Nutrition Survey were included by the cluster random sampling method. Three consecutive 24 h recalls and household condiment weighing were used to estimate dietary intakes. Energy and nutrients were calculated based on the most recent China Food Composition Table. Eating occasions were divided into meals( breakfast, lunch and dinner) and snacks( morning snack, afternoon snack and evening snack). Descriptive analysis for four age categories( 4-6 y, 7-10 y, 11-13 y and 14-17 y) was conducted to study the frequency, energy and macronutrient contribution, and sources of foods during each eating occasion. RESULTS: Most children and adolescents consumed regular meals, while the snacks consumption rate was 65%-76%. Meals( excluding cooking oil) provided 71%-76% of total energy, 88%-92% of protein, 50%-53%of total fat, and 83%-89% of carbohydrate daily intake. Homemade foods( including raw foods) provided the majority of foods in meals, while restaurant made foods and processed foods provided 14. 0% to 20. 5% and 14. 5% to 19. 2% of total energy from meals, respectively. Snacks typically provided disproportionally more carbohydrate and less protein for children and adolescents, and had more impact on the diets of younger children than the older ones. In contrast to meals, processed foods were highly consumed as snacks in children and adolescents, providing 40. 6% to 47. 7% of total daily energy. CONCLUSION: Nutrition education campaigns should encourage children and adolescents to have regular meals and choose fresh, low-energy, low-salt, and low-fat snacks.
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Pueblo Asiatico , Ingestión de Energía , Conducta Alimentaria , Bocadillos , Adolescente , Niño , Preescolar , China , Estudios Transversales , Dieta , HumanosRESUMEN
OBJECTIVE: To evaluate breakfast behaviors among children and adolescents in 12 provinces of China. METHODS: A multistage, stratified, sampling design was used and the participants who were 4-17 years old and had completed personal information data during the 2011 China Health and Nutrition Survey( CHNS) were included. Breakfast prevalence, eating location, food preparation location, preparationmethod, food variety, and dietary structure were analyzed. RESULTS: Nearly all children and adolescents reported having breakfast( 96. 9%). The proportions of children and adolescents who had home-made breakfast and ate breakfast at home were 73. 0% and82. 8%, respectively. Boiling was the most frequently used cooking method( 81. 7%)and grain was the most popular food choice( 84. 1%). Three breakfast patterns were identified: cereal, vegetables and fruits( mostly plant origin), dairy, meat and eggs( mostly animal origin) and convenient foods( mostly snack foods). The proportions of children and adolescents who ate breakfast and chose milk, bean, meat and egg as breakfast were higher in high-level urbanization community( 22. 7% ã40. 7% and 47. 4%)and high-income family( 19. 1% ã38. 9% and 42. 0%). However, the proportions of children and adolescents who ate breakfast at home and chose cereal, vegetable, and fruits as breakfast were higher in low-level urbanization community( 86. 4% ã94. 5% and32. 0%) and low-income family( 91. 2% ã97. 8% and 41. 5%). CONCLUSION: Unhealthy breakfast habits exist among 4-17 years old in 12 provinces of China. The level of community urbanization and household income have influence on breakfast behaviors. Targeted nutritional interventions are needed to improve the nutritional quality of breakfast for better health of Chinese children and adolescents.
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Desayuno , Conducta Alimentaria , Urbanización , Adolescente , Animales , Pueblo Asiatico , Niño , Preescolar , China , Estudios Transversales , Dieta , Ingestión de Alimentos , Humanos , MasculinoRESUMEN
Epimedium koreanum is a traditional Chinese tonic herb. Its main medicinal components are secondary metabolites such as flavonoids and flavonol glycosides, but the biosynthetic mechanism is still unclear. Moisture conditions are a key environmental factor affecting E. koreanum medicinal components during harvesting. Different stages of E. koreanum under natural conditions after rainfall were selected to study changes in physiological properties, herb quality, and transcriptome. Malondialdehyde (MDA) content increased significantly in the D3 stage after rainfall, and protective enzyme levels also rose. Additionally, the flavonol glycoside content was relatively high. We sequenced the transcriptomes of D1, D3, and D9 (R) and identified differentially expressed genes (DEGs) related to flavonoid synthesis. This analysis allowed us to predict the roadmap and key genes involved in flavonoid biosynthesis for E. koreanum. These results suggest that the E. koreanum quality can be enhanced by natural drought conditions in the soil after precipitation during harvest. The harvesting period of E. koreanum is optimal when soil moisture naturally dries to a relative water content of 26% after precipitation. These conditions help E. koreanum tolerate a certain level of water scarcity, resulting in increased expression of flavonoid-related genes and ultimately enhancing the quality of the herb.
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Epimedium , Flavonoides , Regulación de la Expresión Génica de las Plantas , Suelo , Transcriptoma , Epimedium/genética , Epimedium/metabolismo , Flavonoides/biosíntesis , Flavonoides/metabolismo , Suelo/química , Perfilación de la Expresión Génica/métodos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Malondialdehído/metabolismo , Agua/metabolismoRESUMEN
CO2 absorption-microalgae conversion (CAMC) system is a promising carbon capture and utilization technology. However, the use of HCO3- as a carbon source often led to a slower growth rate of microalgae, which also limited the application of CAMC system. In this study, the assimilation efficiency of HCO3- in CAMC system was improved through mixotrophic, and the potential mechanism was investigated. The HCO3- assimilation efficiency and biomass under mixotrophic were 34.79% and 31.76% higher than that of control. Mixotrophic increased chlorophyll and phycocyanin content, which were beneficial to capture more light energy. The content of ATP and NADPH reached 566.86 µmol/gprot and 672.86 nmol/mgprot, which increased by 31.83% and 27.67% compared to autotrophic. The activity of carbonic anhydrase and Rubisco increased by 18.52% and 22.08%, respectively. Transcriptome showed that genes related to photosynthetic and respiratory electron transport were up-regulated. The synergy of photophosphorylation and oxidative phosphorylation greatly improved energy metabolism efficiency, thus accelerating the assimilation of HCO3-. These results revealed a potential mechanism of promoting the HCO3- assimilation under mixotrophic, it also provided a guidance for using CAMC system to serve carbon neutrality.
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Bicarbonatos , Microalgas , Microalgas/metabolismo , Dióxido de Carbono/metabolismo , Fotosíntesis , Carbono/metabolismo , BiomasaRESUMEN
PURPOSE: The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate trajectories for microbiome maturation and bone development and to identify the influence of dietary factors in the process. PARTICIPANTS: The recruitment started in September 2021 and was completed in February 2023. A total of 1380 subjects were recruited, 690 at birth (group 1) and 690 at 6 months of age (group 2). Groups 1 and 2 will be followed up for 12 months and 36 months, respectively. FINDINGS TO DATE: The age of the mothers was 31.1±3.7 (mean±SD), and the birth weight of infants was 3.3±0.5 kg with an incidence of caesarean section 50.4%. Food diary information of the first 100 subjects showed that 64 food items were introduced by 6 months. A pilot microbiome analysis revealed that at the species level, bacterial communities were composed of mostly Bacteroides dorei, Bacteroides vulgatus and Escherichia coli, which were consistent with that of previous reports. Feasibility assessments of breast milk vitamin D and human milk oligosaccharides were validated through certified reference measurements. The early data assessment showed a high reliability of the data generated from this study. FUTURE PLANS: Data collection will be completed in August 2025. Four stage-statistical analyses will be performed as the cohort reaches certain age thresholds before the final report. Analysis of BAMBOO data will be used to develop age-appropriate trajectories for microbiome maturation and bone development for children aged 0-3 years and investigate the contribution of dietary factors in the process. TRIAL REGISTRATION NUMBER: ChiCTR2100049972.
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Desarrollo Óseo , Humanos , China , Lactante , Femenino , Estudios Prospectivos , Recién Nacido , Masculino , Desarrollo Óseo/fisiología , Leche Humana/microbiología , Microbioma Gastrointestinal/fisiología , Adulto , Preescolar , Vitamina D , Dieta , Estudios de CohortesRESUMEN
[This corrects the article DOI: 10.3389/fnut.2023.1169904.].
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Background: Indonesian children under-five have a high prevalence of micronutrient deficiencies. Improving young child feeding practices may be the solution. Increasing the consumption of appropriate milk products could help to reduce nutrient inadequacy. Methods: The objective of this study was to assess nutrient inadequacy in Indonesian children to evaluate the potential improvement using dietary modeling analysis. Data from children aged 1-5 years from the Indonesian Individual Dietary Consumption Survey in 2014 were used in this analysis (n = 11,020). Diet modeling was conducted in two scenarios, substitution volume to volume and calories to calories. Results: The proportion of children consuming young child milk (YCM) was the highest compared to other milk types across all age groups, followed by condensed milk and cow's milk. YCM, also called "Growing-Up Milk" (GUM), are marketed as a product specifically formulated for the nutritional needs of young children. YCM consumers had lower prevalence of inadequate intakes in iron, zinc, vitamins A, C and D across age groups when compared to condensed milk consumers. The prevalence of inadequate intakes of nutrients in condensed milk consumers was Vitamin A (67, 64%), folate (92, 91%), Vitamin D (87, 84%), iron (84, 76%), and zinc (76, 76%) in 1-2y and 3-4y, respectively. The substitution of condensed milk with a YCM reduced the prevalence of inadequate intakes of micronutrients, such as Vitamin A, vitamin D, folate, iron and zinc, which are important for immune function. YCM reduced the prevalence of inadequate intakes of micronutrients by 20-40% (Vit A and folate) and 40-50% (Vit D and zinc). The reduction of prevalence of inadequate iron intake was 31% in 1-2y and 63% in 3-4y. Conclusion: The prevalence of inadequate micronutrient intakes was high among children aged 1-5 years old in Indonesia. YCM consumers had better nutrient intake. The substitution of condensed milk with a YCM reduced the prevalence of inadequate of micronutrient intake. Thus, nutrient intakes could be improved by YCM consumption in 1-5 years old children in Indonesia, along with nutrition education on feeding practices.
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Monitoring disease response after intensive chemotherapy for acute myeloid leukemia (AML) currently requires invasive bone marrow biopsies, imposing a significant burden on patients. In contrast, cell-free tumor DNA (ctDNA) in peripheral blood, carrying tumor-specific mutations, offers a less-invasive assessment of residual disease. However, the relationship between ctDNA levels and bone marrow blast kinetics remains unclear. We explored this in 10 AML patients with NPM1 and IDH2 mutations undergoing initial chemotherapy. Comparison of mathematical mixed-effect models showed that (1) inclusion of blast cell death in the bone marrow, (2) transition of ctDNA to peripheral blood, and (3) ctDNA decay in peripheral blood describes kinetics of blast cells and ctDNA best. The fitted model allows prediction of residual bone marrow blast content from ctDNA, and its scaling factor, representing clonal heterogeneity, correlates with relapse risk. Our study provides precise insights into blast and ctDNA kinetics, offering novel avenues for AML disease monitoring.
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Clonal hematopoiesis of indeterminate potential (CHIP) describes the age-related acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC) leading to clonal blood cell expansion. Although CHIP mutations drive myeloid malignancies like myelodysplastic syndromes (MDS) it is unknown if clonal expansion is attributable to changes in cell type kinetics, or involves reorganization of the hematopoietic hierarchy. Using computational modeling we analyzed differentiation and proliferation kinetics of cultured hematopoietic stem cells (HSC) from 8 healthy individuals, 7 CHIP, and 10 MDS patients. While the standard hematopoietic hierarchy explained HSPC kinetics in healthy samples, 57% of CHIP and 70% of MDS samples were best described with alternative hierarchies. Deregulated kinetics were found at various HSPC compartments with high inter-individual heterogeneity in CHIP and MDS, while altered HSC rates were most relevant in MDS. Quantifying kinetic heterogeneity in detail, we show that reorganization of the HSPC compartment is already detectable in the premalignant CHIP state.
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Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1alpha, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1(+/-) mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1(+/-) mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1alpha in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-alpha. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1alpha and secretion of TNF-alpha. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1alpha, which, in turn, is necessary for increased TNF-alpha secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1alpha activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1alpha expression can positively impact animal longevity.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Inmunidad , Proteínas de la Membrana/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular , Citocinas/biosíntesis , Metabolismo Energético , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Hígado/metabolismo , Longevidad , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/inmunología , Oxigenasas de Función Mixta , Mutación , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The rapid development of nutrition science is embracing digital transformation to generate large amounts of data. Precision nutrition and "Big Data" place increasing demand for data repositories and visualization, which enhances the digital transformation. We defined the need for an integrated nutrition data platform as a web-based platform that can collect, store, track, analyze, monitor, and visually display key metrics in nutrition and health while allowing users to interact with visuals and download data provided in the platform. Interactive dashboards create new opportunities for scholars and practitioners to generate and test hypotheses. We present the development and implementation of the Global Nutrition and Health Atlas (GNHA; https://sites.tufts.edu/gnha/), an open-access online platform covering nutrition and health data with 26 themes and 500+ indicators from 190+ countries up to 30 y. We view GNHA as an interactive tool aiming to share information and perspectives and foster collaborations and innovations.
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The rapid expansion of food and nutrition information requires new ways of data sharing and dissemination. Interactive platforms integrating data portals and visualization dashboards have been effectively utilized to describe, monitor, and track information related to food and nutrition; however, a comprehensive evaluation of emerging interactive systems is lacking. We conducted a systematic review on publicly available dashboards using a set of 48 evaluation metrics for data integrity, completeness, granularity, visualization quality, and interactivity based on 4 major principles: evidence, efficiency, emphasis, and ethics. We evaluated 13 dashboards, summarized their characteristics, strengths, and limitations, and provided guidelines for developing nutrition dashboards. We applied mixed effects models to summarize evaluation results adjusted for interrater variability. The proposed metrics and evaluation principles help to improve data standardization and harmonization, dashboard performance and usability, broaden information and knowledge sharing among researchers, practitioners, and decision makers in the field of food and nutrition, and accelerate data literacy and communication.
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Enterprises acquire heterogeneous knowledge through external knowledge search and adapt to the change of external environment, which is of great significance to enterprise breakthrough innovation. This paper takes the innovation ecosystem as the boundary of the research paradigm. Based on innovation ecosystem theory, knowledge management theory and enterprise innovation theory, this paper constructs a moderated mediation model of the enterprise knowledge search, knowledge integration and breakthrough innovation under the characteristics of innovation ecosystem network. This model is tested on the survey data of 344 technology enterprise and manufacturing industries including R&D departments in the Beijing-Tianjin-Hebei region. The research results show that: knowledge integration plays part of the intermediary role between knowledge search and enterprise breakthrough innovation; the larger the network scale, the stronger the network connection, the stronger the intermediary role of knowledge integration on the relationship between knowledge search and enterprise breakthrough innovation. The research results reveal the important role of the innovation ecosystem in enterprise breakthrough innovation. At the same time, the research on knowledge search and enterprise breakthrough innovation should consider the network characteristics of innovation ecosystem and the ability of enterprise knowledge integration.