TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer

Influence of pH and ionic strength on the color parameters and antioxidant properties of an ethanolic red grape marc extract

The aim of present study was to investigate the influences of pH and several salts on the antioxidant activity and color of an ethanolic grape marc extract. Furthermore, the phenolic content of the extract was analyzed using HPLC and spectrophotometric methods while the total antioxidant activity was assessed by the reaction with ABTS radical. Gallic acid, procyanidins B1, B2, polydatin, catechin, epicatechin, hyperoside, ferulic, chlorogenic, and salicylic acids were among the main identified polyphenols. Different pH values had slight influence on the antioxidant activity, the highest value being determined for pH 3.7. The redness, chroma, and hue were significantly enhanced at pH 3.7 and 2.6. The chromaticity decreased at pH = 5.5 and pH = 7.4, so the extract should be used with care in products with such media. The presence of salts did not noticeably affect the antioxidant activity, except the higher concentrations of CaCl2, which decreased the antioxidant activity but enhanced the color intensity

Physical and psychological paths toward less severe fibromyalgia: A structural equation model

The authors gratefully acknowledge all the participants for their collaboration and enthusiasm. We thank the assistant researchers involved in this study and all the members of the Physical Activity for HEaLth Promotion (PA-HELP; CTS-1018) research group.Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.rehab.2019.06.017.Objectives: Previous research suggested isolated associations of physical and psychological factors with fibromyalgia severity. Integration of physical and psychological, experienced and observed, modifiable factors associated with fibromyalgia severity in a single model will reveal therapeutic paths toward less severity of disease. We aimed to examine an encompassing model of determinants of fibromyalgia severity. Methods: This observational, population-based cross-sectional study included 569 people with fibromyalgia. An integrative model of fibromyalgia severity was tested by using structural equation modelling. This model included 8 factors: resilience, catastrophizing, active lifestyle, declarative memory, subjective fitness, objective fitness, psychological distress, and physical fatigue. Results: Two core paths were associated with reduced fibromyalgia severity: 1) a psychological path connecting high resilience and low catastrophizing with low distress and 2) a physical path, connecting a more active lifestyle (directly and via high objective and subjective physical fitness) with low fatigue. Additional interconnecting paths especially suggested a connection from the psychological to physical path. Our model explained 83% of the fibromyalgia severity. Conclusions: The present model integrated the complexity of mutually influencing factors of fibromyalgia severity, which may help to better understand the disease. It emphasised the importance of: 1) physical factors and psychological factors and their interconnections, 2) patients’ experiences and clinical measurements, and 3) positive and negative signs such as physical fitness and distress. Future longitudinal and experimental research should aim at testing the causal direction of the associations in the model as well as the clinical implications suggested by the model. For instance, to reduce fatigue, exercise should enhance not only objective fitness but also fitness-related perceptions. Reducing distress and fatigue seems crucial for lowering fibromyalgia severity.This work was supported by the Spanish Ministry of Economy and Competitiveness [I+D+i DEP2010-15639, I+D+I DEP2013-40908, I+D+I PSI2015-65241-R, and BES-2014-067612] and the Spanish Ministry of Education [FPU15/00002]. This study was funded in part by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ref. SOMM17/6107/UGR) and University of Jaén, Plan de Apoyo a la Investigación 2017-2019 [EI_SEJ07_2017]. The funders did not have any role in the study design, data collection and analyses, decision to publish, or preparation of the manuscript

Batch Signatures, Revisited

We revisit batch signatures (previously considered in a draft RFC, and used in multiple recent works), where a single, potentially expensive, inner digital signature authenticates a Merkle tree constructed from many messages. We formalise a construction and prove its unforgeability and privacy properties. We also show that batch signing allows us to scale slow signing algorithms, such as those recently selected for standardisation as part of NIST\u27s post-quantum project, to high throughput, with a mild increase in latency. For the example of Falcon-512 in TLS, we can increase the amount of connections per second by a factor 3.2x, at the cost of an increase in the signature size by ~14% and the median latency by ~25%, where both are ran on the same 30 core server. We also discuss applications where batch signatures allow us to increase throughput and to save bandwidth. For example, again for Falcon-512, once one batch signature is available, the additional bandwidth for each of the remaining N-1 is only 82 bytes

学会抄録

Project workplan. (DOCX 22 kb

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer

One-Year-Olds Think Creatively, Just Like Their Parents

Creativity is an essential human ability, allowing adaptation and survival. Twenty-three 1-year-olds and their parents were tested on divergent thinking (DT), a measure of creative potential counting how many ideas one can generate. Toddlers’ and parents’ DT was moderately to highly correlated. Toddlers showed a wide range of DT scores, which were reliable on re-testing. This is the first study to show children think divergently as early as 1 year. This research also suggests 1-year-olds’ DT is related to parents’, opening up future research into whether this relationship is due to genetics, and/or social learning at its emergence. Understanding DT at its emergence could allow for interventions while neurological development is most plastic, which could improve DT across the lifespan

Study protocol: realist evaluation of effectiveness and sustainability of a community health workers programme in improving maternal and child health in Nigeria.

BACKGROUND: Achievement of improved maternal and child health (MCH) outcomes continues to be an issue of international priority, particularly for sub-Saharan African countries such as Nigeria. Evidence suggests that the use of Community Health Workers (CHWs) can be effective in broadening access to, and coverage of, health services and improving MCH outcomes in such countries. METHODS/DESIGN: In this paper, we report the methodology for a 5-year study which aims to evaluate the context, processes, outcomes and longer-term sustainability of a Nigerian CHW scheme. Evaluation of complex interventions requires a comprehensive understanding of intervention context, mechanisms and outcomes. The multidisciplinary and mixed-method realist approach will facilitate such evaluation. A favourable policy environment within which the study is conducted will ensure the successful uptake of results into policy and practice. A realist evaluation provides an overall methodological framework for this multidisciplinary and mixed methods research, which will be undertaken in Anambra state. The study will draw upon health economics, social sciences and statistics. The study comprises three steps: (1) initial theory development; (2) theory validation and (3) theory refinement and development of lessons learned. Specific methods for data collection will include in-depth interviews and focus group discussions with purposefully identified key stakeholders (managers, service providers and service users), document reviews, analyses of quantitative data from the CHW programme and health information system, and a small-scale survey. The impact of the programme on key output and outcome indicators will be assessed through an interrupted time-series analysis (ITS) of monthly quantitative data from health information system and programme reports. Ethics approvals for this study were obtained from the University of Leeds and the University of Nigeria. DISCUSSION: This study will provide a timely and important contribution to health systems strengthening specifically within Anambra state in southeast Nigeria but also more widely across Nigeria. This paper should be of interest to researchers who are interested in adapting and applying robust methodologies for assessing complex health system interventions. The paper will also be useful to policymakers and practitioners who are interested in commissioning and engaging in such complex evaluations to inform policies and practices