Epigenetic hereditary transcription profiles III, evidence for an epigenetic network resulting in gender, tissue and age-specific variation in overall transcription

<p>Abstract</p> <p>Background</p> <p>We have previously shown that deviations from the average transcription profile of a group of functionally related genes are not only heritable, but also demonstrate specific patterns associated with age, gender and differentiation, thereby implicating genome-wide nuclear programming as the cause. To determine whether these results could be reproduced, a different micro-array database (obtained from two types of muscle tissue, derived from 81 human donors aged between 16 to 89 years) was studied.</p> <p>Results</p> <p>This new database also revealed the existence of age, gender and tissue-specific features in a small group of functionally related genes. In order to further analyze this phenomenon, a method was developed for quantifying the contribution of different factors to the variability in gene expression, and for generating a database limited to residual values reflecting constitutional differences between individuals. These constitutional differences, presumably epigenetic in origin, contribute to about 50% of the observed residual variance which is connected with a network of interrelated changes in gene expression with some genes displaying a decrease or increase in residual variation with age.</p> <p>Conclusion</p> <p>Epigenetic variation in gene expression without a clear concomitant relation to gene function appears to be a widespread phenomenon. This variation is connected with interactions between genes, is gender and tissue specific and is related to cellular aging.</p> <p>This finding, together with the method developed for analysis, might contribute to the elucidation of the role of nuclear programming in differentiation, aging and carcinogenesis</p> <p>Reviewers</p> <p>This article was reviewed by Thiago M. Venancio (nominated by Aravind Iyer), Hua Li (nominated by Arcady Mushegian) and Arcady Mushegian and J.P.de Magelhaes (nominated by G. Church).</p

Hereditary profiles of disorderly transcription?

BACKGROUND: Microscopic examination of living cells often reveals that cells from some cell strains appear to be in a permanent state of disarray without obvious reason. In all probability such a disorderly state affects cell functioning. The aim of this study was to establish whether a disorderly state could occur that adversely affects gene expression profiles and whether such a state might have biomedical consequences. To this end, the expression profiles of the 14 genes of the proteasome derived from the GEO SAGE database were utilized as a model system. RESULTS: By adopting the overall expression profile as the standard for normal expression, deviation in transcription was frequently observed. Each deviating tissue exhibited its own characteristic profile of over-expressed and under-expressed genes. Moreover such a specific deviating profile appeared to be epigenetic in origin and could be stably transmitted to a clonal derivative e.g. from a precancerous normal tissue to its tumor. A significantly greater degree of deviation was observed in the expression profiles from the tumor tissues. The changes in the expression of different genes display a network of interdependencies. Therefore our hypothesis is that deviating profiles reflect disorder in the localization of genes within the nucleus The underlying cause(s) for these disorderly states remain obscure; it could be noise and/or deterministic chaos. Presence of mutational damage does not appear to be predominantly involved. CONCLUSION: As disturbances in expression profiles frequently occur and have biomedical consequences, its determination could prove of value in several fields of biomedical research. REVIEWERS: This article was reviewed by Trey Ideker, Itai Yanai and Stephan Bec

F-18-fluorodeoxyglucose positron emission tomography combined with CT in critically ill patients with suspected infection

Contains fulltext : 88623.pdf (publisher's version ) (Closed access)PURPOSE: To assess the value of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) combined with CT in critically ill patients suspected of having an infection. METHODS: FDG-PET CT scans requested for evaluation of a suspected infection or inflammatory process in critically ill, mechanically ventilated patients were analyzed (blinded for the final clinical diagnosis) and compared with clinical follow-up. RESULTS: Thirty-five FDG-PET/CT scans performed in 33 ICU patients (28 adults and 5 children), median age 58 years (range 1 month-72 years), were analyzed. Twenty-one FDG-PET/CT scans were true positive. Three FDG-PET/CT scans were considered false positive, in one case leading to additional diagnostic procedures (specificity 79%). Additionally, 11 true negatives were found (sensitivity 100%), leading to an overall accuracy of 91%. CONCLUSIONS: FDG-PET/CT scanning is of additional value in the evaluation of suspected infection in critically ill patients in whom conventional diagnostics did not lead to a diagnosis. Apart from the high accuracy, in this study it appeared that, in addition to conventional diagnostic techniques that were routinely performed, a normal FDG-PET/CT ruled out important infections requiring prolonged antibiotic therapy or drainage. Since sensitivity is lower in highly metabolic active tissues (e.g., endocarditis, meningitis), the FDG-PET/CT scan is not suited to detect infections in these tissues.01 maart 201

Mantle structure and tectonic history of SE Asia

Seismic travel-time tomography of the mantle under SE Asia reveals patterns of subduction-related seismic P-wave velocity anomalies that are of great value in helping to understand the region's tectonic development. We discuss tomography and tectonic interpretations of an area centred on Indonesia and including Malaysia, parts of the Philippines, New Guinea and northern Australia. We begin with an explanation of seismic tomography and causes of velocity anomalies in the mantle, and discuss assessment of model quality for tomographic models created from P-wave travel times. We then introduce the global P-wave velocity anomaly model UU-P07 and the tectonic model used in this paper and give an overview of previous interpretations of mantle structure. The slab-related velocity anomalies we identify in the upper and lower mantle based on the UU-P07 model are interpreted in terms of the tectonic model and illustrated with figures and movies. Finally, we discuss where tomographic and tectonic models for SE Asia converge or diverge, and identify the most important conclusions concerning the history of the region. The tomographic images of the mantle record subduction beneath the SE Asian region to depths of approximately 1600. km. In the upper mantle anomalies mainly record subduction during the last 10 to 25. Ma, depending on the region considered. We interpret a vertical slab tear crossing the entire upper mantle north of west Sumatra where there is a strong lateral kink in slab morphology, slab holes between c.200-400. km below East Java and Sumbawa, and offer a new three-slab explanation for subduction in the North Sulawesi region. There is a different structure in the lower mantle compared to the upper mantle and the deep structure changes from west to east. What was imaged in earlier models as a broad and deep anomaly below SE Asia has a clear internal structure and we argue that many features can be identified as older subduction zones. We identify remnants of slabs that detached in the Early Miocene such as the Sula slab, now found in the lower mantle north of Lombok, and the Proto-South China Sea slab now at depths below 700. km curving from northern Borneo to the Philippines. Based on our tectonic model we interpret virtually all features seen in upper mantle and lower mantle to depths of at least 1200. km to be the result of Cenozoic subduction

Associations between momentary mental states and concurrent social functioning after remission from first episode psychosis:A HAMLETT ecological momentary assessment study

Background: Symptom severity and social functioning are important outcomes after first episode psychosis (FEP), yet current evidence about associations between them is inconsistent and lacks (subclinical) momentary insights. Methods: The current Ecological Momentary Assessment (EMA) study was conducted in 58 people in remission from FEP, as part of the HAMLETT (Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment) trial. At baseline, participants were prompted to report momentary mental states and social context 10x/day for eight consecutive days, including psychotic experiences (PEs), motivation/drive and negative affect, that may indicate proxies of (subclinical) psychotic, negative and general affective symptoms, respectively. We employed multilevel mixed-effects regressions to investigate associations between self-reported mental states and concurrent activity or social company and subjective appraisal thereof. We also conducted retrospective clinical assessments of symptoms (PANSS) and social functioning (WHODAS 2.0) and investigated their cross-sectional associations using multivariable linear regression. Results: Analyses of 3101 EMA-questionnaires showed that lower motivation/drive was associated with more passive activity and less company (OR = 0.96 [95%CI: 0.96; 0.97], OR = 0.95 [95%CI: 0.93; 0.96], N.B. ORs per 1-point symptom-score change). PEs and negative affect were associated with more proactive activity (OR = 1.02 [95%CI: 1.00; 1.03], OR = 1.02 [95%CI: 1.01; 1.03]). All three mental state domains were associated with lower activity appraisal overall, though activity-specific associations differed. PEs and negative affect were associated with lower company appraisal (B = −0.25 [95%CI: −0.36; −0.14], B = −0.15 [95%CI: −0.23; −0.06]). When assessed retrospectively, only PANSS general psychopathology was associated with poorer social functioning (B = 2.52 [95%CI: 1.69; 3.34]). Conclusion: Self-reported PEs, momentary motivation/drive and general affective symptoms are associated with daily-life functioning after remission from FEP. Retrospective observer-rated and momentary self-report assessment methods do not measure the same aspects or intensity of psychopathology.</p

Psychological side effects of antipsychotic medication after remission from first-episode psychosis:a HAMLETT ecological momentary assessment study

BACKGROUND: Evidence on psychological side effects (PSEs) of antipsychotic medication after remission from first-episode psychosis (FEP), and their momentary impact on daily life, is limited. This study examined how Dopamine-2 (D2) affinity and antipsychotic dosage relate to momentary PSEs.METHODS: This ecological momentary assessment (EMA) study included baseline data from 56 participants in the ongoing Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment (HAMLETT) trial. Momentary mental states indicative of reduced affect intensity, stability, and variability, as well as avolition and mental fatigue, were assessed 10×/day for eight days (N = 3,005 data points). Since these PSEs may result from D2-receptor actions, antipsychotics were classified by receptor affinity and mechanism of action. Multilevel mixed-effects regression models examined serial cross-sectional associations between D2 affinity or dosage and concurrent PSEs, both overall and separately for mornings, daytimes, and evenings.RESULTS: Higher antipsychotic dosages were associated with reduced affect variability (Beta [B] = -1.40 [95% confidence interval [CI]: -2.52; -0.29]) and decreased positive affect stability (B = 0.23 [95% CI: 0.04; 0.42]) and intensity (B = -1.11 [95% CI: -1.97; -0.24]). The latter was also associated with the use of high-affinity D2 antagonists versus partial D2 agonists (B = 12.98 [95% CI: 2.43; 23.53]) and versus low-affinity D2 antagonists (B = 10.04 [95% CI: 0.59; 19.49]). Other PSEs were not associated with D2 affinity/dosage. Results were relatively consistent across daytimes.CONCLUSIONS: Higher antipsychotic dosage and high-affinity D2 antagonists were associated with decreased positive affect after remission from FEP, which may partly drive the frequently reported blunting of emotional experience.</p

A Simplified Water Accounting Procedure to Assess Climate Change Impact on Water Resources for Agriculture across Different European River Basins

[EN] European agriculture and water policies require accurate information on climate change impacts on available water resources. Water accounting, that is a standardized documentation of data on water resources, is a useful tool to provide this information. Pan-European data on climate impacts do not recognize local anthropogenic interventions in the water cycle. Most European river basins have a specific toolset that is understood and used by local experts and stakeholders. However, these local tools are not versatile. Thus, there is a need for a common approach that can be understood by multi-fold users to quantify impact indicators based on local data and that can be used to synthesize information at the European level. Then, policies can be designed with the confidence that underlying data are backed-up by local context and expert knowledge. This work presents a simplified water accounting framework that allows for a standardized examination of climate impacts on water resource availability and use across multiple basins. The framework is applied to five different river basins across Europe. Several indicators are extracted that explicitly describe green water fluxes versus blue water fluxes and impacts on agriculture. The examples show that a simplified water accounting framework can be used to synthesize basin-level information on climate change impacts which can support policymaking on climate adaptation, water resources and agriculture.This research was funded by Horizon 2020 IMPREX project, grant number 641811Hunink, J.; Simons, G.; Suárez-Almiñana, S.; Solera Solera, A.; Andreu Álvarez, J.; Giuliani, M.; Zamberletti, P.... (2019). A Simplified Water Accounting Procedure to Assess Climate Change Impact on Water Resources for Agriculture across Different European River Basins. 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