The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis

An Expanded Evaluation of Protein Function Prediction Methods Shows an Improvement In Accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent

An expanded evaluation of protein function prediction methods shows an improvement in accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent. Keywords: Protein function prediction, Disease gene prioritizationpublishedVersio

Prevalence of Frailty in European Emergency Departments (FEED): an international flash mob study

Introduction Current emergency care systems are not optimized to respond to multiple and complex problems associated with frailty. Services may require reconfiguration to effectively deliver comprehensive frailty care, yet its prevalence and variation are poorly understood. This study primarily determined the prevalence of frailty among older people attending emergency care. Methods This cross-sectional study used a flash mob approach to collect observational European emergency care data over a 24-h period (04 July 2023). Sites were identified through the European Task Force for Geriatric Emergency Medicine collaboration and social media. Data were collected for all individuals aged 65 + who attended emergency care, and for all adults aged 18 + at a subset of sites. Variables included demographics, Clinical Frailty Scale (CFS), vital signs, and disposition. European and national frailty prevalence was determined with proportions with each CFS level and with dichotomized CFS 5 + (mild or more severe frailty). Results Sixty-two sites in fourteen European countries recruited five thousand seven hundred eighty-five individuals. 40% of 3479 older people had at least mild frailty, with countries ranging from 26 to 51%. They had median age 77 (IQR, 13) years and 53% were female. Across 22 sites observing all adult attenders, older people living with frailty comprised 14%. Conclusion 40% of older people using European emergency care had CFS 5 + . Frailty prevalence varied widely among European care systems. These differences likely reflected entrance selection and provide windows of opportunity for system configuration and workforce planning

Evaluation of dimensional stability and details reproduction of alginate molds storage in different times and temperature [Avaliação da estabilidade dimensional e reprodução de detalhes de moldes de alginatos armazenados por diferentes tempos e temperatura]

Made available in DSpace on 2019-09-11T20:51:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2018Objective: The aim of this study was to evaluate dimensional stability and detail reproduction in alginate molds stored at different times and temperatures. Material and Methods: Three different commercially available alginates (Cavex Color Change, Jeltrate Plus and Hydrogum 5) were tested at four different times (0 - control, 1, 3 and 5 days) and two temperatures (25ºC and 37ºC) (n=5). The alginates were handled following the manufacturer’s instructions. The impression procedures occurred in an environment with controlled room temperature (25ºC) and relative humidity (50±5%). A metallic model (ISO 1563:1990) was used to perform the impressions. The tray containing alginate remained on the metallic model under constant pressure (2 kgf) until the alginate gelation process. The molds were stored (different times and temperatures) and analyzed in stereomicroscope at 30x magnification and 0.5 μm accuracy (Olympus Measuring Microscope STM). The molds and the metallic model measurements were compared, and the data were statistically analyzed by Kolmogorov-Smirnov and three-way ANOVA tests, and the means were compared by Tukey test (5%). Results: The results showed no double interactions (p>0.05) and the different alginates presented statistically similar values of dimensional stability (p=0.102). However, 25ºC (temperature) and control group (time) showed the highest values of dimensional stability (p<0.05). Jeltrate Plus was the only material that presented inaccuracy in details reproduction. Conclusion: It is recommended that, for tested alginates, the stone casts should be poured immediately, even though the molds are dimensionally stable up to 5 days when stored at 25ºC. © 2018, Universidade Estadual Paulista, Institute of Science and Technology of Sao Jose dos Campos. All rights reserved.Penfold, R.R.S., Department of Prosthodontics, School of Dentistry, São Leopoldo Mandic, Campinas, SP, BrazilBrandt, W.C., Department of Implantology, School of Dentistry, University of Santo Amaro, São Paulo, BrazilMiranda, M.E., Department of Prosthodontics, School of Dentistry, São Leopoldo Mandic, Campinas, SP, BrazilVitti, R.P., Department of Prosthodontics, School of Dentistry, University of Taubaté, Taubaté, SP, Brazi

Empoderamiento de las organizciones: la importancia de conocer su percepcion sobre el entorno economico

Functional Genomics of Systemic Disorder