An immediate-late gene expression module decodes ERK signal duration

The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function. We find that mRNA longevity enables these ILGs to respond late and thus translate ERK signal duration into response amplitude. Despite their late response, their GC-rich promoter structure suggested and metabolic labelling with 4SU confirmed that transcription of ILGs is induced immediately. A comparative analysis shows that the principle of duration decoding is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Altogether, our findings suggest that ILGs function as a gene expression module to decode ERK signal duration

Normalized indices derived from visceral adipose mass assessed by MRI and their correlation with markers for insulin resistance and prediabetes

Visceral adipose tissue (VAT) plays an important role in the pathogenesis of insulin resistance (IR), prediabetes and type 2 diabetes. However, VAT volume alone might not be the best marker for insulin resistance and prediabetes or diabetes, as a given VAT volume may differently impact on these metabolic traits based on body height, gender, age and ethnicity. In a cohort of 1295 subjects from the Tübingen Diabetes Family Study (TDFS) and in 9978 subjects from the UK Biobank (UKBB), undergoing magnetic resonance imaging for quantification of VAT volume, total adipose tissue (TAT, in the TDFS), total abdominal adipose tissue (TAAT) in the UKBB, and total lean tissue (TLT), VAT volume and several VAT-indices were investigated for their relationships with insulin resistance and glycemic traits. VAT-related indices were calculated by correcting for body height (VAT/m: VAT/body height; VAT/m²: VAT/(body height)², and VAT/m³: VAT/(body height)³), TAT (%VAT), TLT (VAT/TLT) and weight (VAT/WEI), with closest equivalents used within the UKBB dataset. Prognostic values of VAT and VAT-related indices for insulin sensitivity, HbA1c levels and prediabetes/diabetes were analyzed for males and females. Males had higher VAT volume and VAT-related indices than females in both cohorts (p < 0.0001) and VAT volume has shown to be a stronger determinant for insulin sensitivity than anthropometric variables. Among the parameters uncorrected VAT and derived indices, VAT/m³ most strongly correlated negatively with insulin sensitivity and positively with HbA1c levels and prediabetes/diabetes in the TDFS (R² = 0.375/0.305 for females/males for insulin sensitivity, 0.178/0.148 for HbA1c levels vs. – e.g. – 0.355/0.293 and 0.144/0.133 for VAT, respectively) and positively with HbA1c (R² = 0.046/0.042) in the UKBB for females and males. Furthermore, VAT/m³ was found to be a significantly better determinant of insulin resistance or prediabetes than uncorrected VAT volume (p < 0.001/0.019 for females/males regarding insulin sensitivity, p < 0.001/< 0.001 for females/males regarding HbA1c). Evaluation of several indices derived from VAT volume identified VAT/m³ to most strongly correlate with insulin sensitivity and glucose metabolism. Thus, VAT/m³ appears to provide better indications of metabolic characteristics (insulin sensitivity and pre-diabetes/diabetes) than VAT volume alone

Can agricultural cultivation methods influence the healthfulness of crops for foods

The aim of the current study was to investigate if there are any health effects of long-term consumption of organically grown crops using a rat model. Crops were retrieved over two years from along-term field trial at three different locations in Denmark, using three different cultivation systems(OA, organic based on livestock manure; OB, organic based on green manure; and C, conventional with mineral fertilizers and pesticides)with two field replicates. The cultivation system had an impact on the nutritional quality, affecting γ-tocopherol, some amino acids, and fatty acid composition. Additionally, the nutritional quality was affected by harvest year and location. However, harvest year and location rather than cultivation system affected the measured health biomarkers. In conclusion, the differences in dietary treatments composed of ingredients from different cultivation systems did not lead to significant differences in the measured health biomarkers, except for a significant difference in plasma IgGl evels

Parameterized optimized effective potential for atoms

The optimized effective potential equations for atoms have been solved by parameterizing the potential. The expansion is tailored to fulfill the known asymptotic behavior of the effective potential at both short and long distances. Both single configuration and multi configuration trial wave functions are implemented. Applications to several atomic systems are presented improving previous works. The results here obtained are very close to those calculated in either the Hartree-Fock and the multi configurational Hartree-Fock framework.Comment: 8 pages, 3 figure

Performance-based financing as a health system reform : mapping the key dimensions for monitoring and evaluation

Peer reviewedPublisher PD

Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available for only a small percentage of manufactured compounds. Test methods with a higher throughput than current regulatory guideline methods, and with improved human relevance are urgently needed. We therefore explored the feasibility of DNT hazard assessment based on new approach methods (NAMs). An in vitro battery (IVB) was assembled from ten individual NAMs that had been developed during the past years to probe effects of chemicals on various fundamental neurodevelopmental processes. All assays used human neural cells at different developmental stages. This allowed us to assess disturbances of: (i) proliferation of neural progenitor cells (NPC); (ii) migration of neural crest cells, radial glia cells, neurons and oligodendrocytes; (iii) differentiation of NPC into neurons and oligodendrocytes; and (iv) neurite outgrowth of peripheral and central neurons. In parallel, cytotoxicity measures were obtained. The feasibility of concentration-dependent screening and of a reliable biostatistical processing of the complex multi-dimensional data was explored with a set of 120 test compounds, containing subsets of pre-defined positive and negative DNT compounds. The battery provided alerts (hit or borderline) for 24 of 28 known toxicants (82% sensitivity), and for none of the 17 negative controls. Based on the results from this screen project, strategies were developed on how IVB data may be used in the context of risk assessment scenarios employing integrated approaches for testing and assessment (IATA).European Food Safety Authority (EFSA-Q-2018-00308), the Danish Environmental Protection Agency (EPA), Denmark, under the grant number MST-667-00205, the State Ministry of Baden-Wuerttemberg, Germany, for Economic Affairs, Labour and Tourism (NAM-Accept), the project CERST (Center for Alternatives to Animal Testing) of the Ministry for culture and science of the State of North-Rhine Westphalia, Germany (file number 233–1.08.03.03- 121972/131–1.08.03.03–121972), the European Chemical Industry Council Long-Range Research Initiative (Cefic LRI) under the project name AIMT11 and the BMBF (NeuroTool). It has also received funding from the European Union's Horizon 2020 research and innovation program under grant agreements No. 964537 (RISK-HUNT3R), No. 964518 (ToxFree), No. 101057014 (PARC) and No. 825759 (ENDpoiNTs)

Learning needs analysis to guide teaching evidence-based medicine: knowledge and beliefs amongst trainees from various specialities

<p>Abstract</p> <p>Background</p> <p>We undertook a needs assessment exercise using questionnaire survey of junior doctors' knowledge and beliefs concerning evidence-based medicine (EBM) and critical literature appraisal, as this is a core competence in postgraduate medical education.</p> <p>Methods</p> <p>We surveyed 317 junior doctors in various specialities in the UK West Midlands Deanery. Using validated questionnaires we compared the needs of different trainee groups. Results overall were internally consistent (Cronbach's alpha 0.929).</p> <p>Results</p> <p>Respondents' generally felt that they had poor training in EBM (Mean score 2.2, possible range 1 – 6) and that they needed more education (Mean score 5.3, possible range 1–6). Male trainees felt more confident at evaluating statistical tests than females (p = 0.002). Female trainees considered patient choice above the evidence more often than males (p = 0.038). Trainees from surgical speciality felt more confident at assessing research evidence (p = 0.009) whereas those from medical speciality felt more confident at evaluating statistical tests (p = 0.038) than other specialities. However, non-surgical specialities tended to believe that EBM had little impact on practice (p = 0.029). Respondents who had been qualified for 11 years or over felt overall more confident in their knowledge relating to EBM than those who had been qualified less than 10 years. In particular, they felt more confident at being able to assess study designs (p = < 0.001) and the general worth of research papers (p = < 0.001). Trainees with prior research experience were less likely to find original work confusing (p = 0.003) and felt more confident that they can assess research evidence (p = < 0.001) compared to those without previous research experience. Trainees without previous research experience felt that clinical judgement was more important than evidence (p = < 0.001).</p> <p>Conclusion</p> <p>There is a perceived deficit in postgraduate doctors' EBM knowledge and critical appraisal skills. Learning needs vary according to gender, place of basic medical qualification, time since graduation, prior research experience and speciality. EBM training curricular development should take into account the findings of our needs assessment study.</p

How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review

Background Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses. To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review. Methods We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers. Results Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool. Conclusion There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect