93 research outputs found
Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation
SummaryPeriod (PER) proteins are essential components of the mammalian circadian clock. They form complexes with cryptochromes (CRY), which negatively regulate CLOCK/BMAL1-dependent transactivation of clock and clock-controlled genes. To define the roles of mammalian CRY/PER complexes in the circadian clock, we have determined the crystal structure of a complex comprising the photolyase homology region of mouse CRY1 (mCRY1) and a C-terminal mouse PER2 (mPER2) fragment. mPER2 winds around the helical mCRY1 domain covering the binding sites of FBXL3 and CLOCK/BMAL1, but not the FAD binding pocket. Our structure revealed an unexpected zinc ion in one interface, which stabilizes mCRY1-mPER2 interactions in vivo. We provide evidence that mCRY1/mPER2 complex formation is modulated by an interplay of zinc binding and mCRY1 disulfide bond formation, which may be influenced by the redox state of the cell. Our studies may allow for the development of circadian and metabolic modulators
Long-Chain Polyunsaturated Fatty Acids, Homocysteine at Birth and Fatty Acid Desaturase Gene Cluster Polymorphisms Are Associated with Children’s Processing Speed up to Age 9 Years
Both pre- and early postnatal supplementation with docosahexaenoic acid (DHA), arachidonic
acid (AA) and folate have been related to neural development, but their long-term effects
on later neural function remain unclear. We evaluated the long-term effects of maternal prenatal
supplementation with fish-oil (FO), 5-methyltetrahydrofolate (5-MTHF), placebo or FO + 5-MTHF,
as well as the role of fatty acid desaturase (FADS) gene cluster polymorphisms, on their offspring’s
processing speed at later school age. This study was conducted in NUHEAL children at 7.5 (n = 143)
and 9 years of age (n = 127). Processing speed tasks were assessed using Symbol Digit Modalities
Test (SDMT), Children Color Trails Test (CCTT) and Stroop Color andWord Test (SCWT). Long-chain
polyunsaturated fatty acids, folate and total homocysteine (tHcy) levels were determined at delivery
from maternal and cord blood samples. FADS and methylenetetrahydrofolate reductase (MTHFR)
677 C > T genetic polymorphisms were analyzed. Mixed models (linear and logistic) were performed.
There were significant differences in processing speed performance among children at different ages
(p < 0.001). The type of prenatal supplementation had no effect on processing speed in children
up to 9 years. Secondary exploratory analyses indicated that children born to mothers with higher
AA/DHA ratio at delivery (p < 0.001) and heterozygotes for FADS1 rs174556 (p < 0.05) showed better
performance in processing speed at 9 years. Negative associations between processing speed scores and maternal tHcy levels at delivery were found. Our findings suggest speed processing development
in children up to 9 years could be related to maternal factors, including AA/DHA and tHcy
levels, and their genetic background, mainly FADS polymorphism. These considerations support
that maternal prenatal supplementation should be quantitatively adequate and individualized to
obtain better brain development and mental performance in the offspring.European Commission
212652
007036
QLK1-CT-1999-00888European Commission
European Commission Joint Research Centre
DYNAHEALTH-633595
Lifecycle-733206European Research Council Advanced Grant META-GROWTH ERC-2012AdG
322605Erasmus Plus Programme Early Nutrition eAcademy Southeast Asia
573651EPP-1-2016-1-DE-EPPKA2-CBHE-JPErasmus Plus Programme Capacity Building to Improve Early Nutrition and Health in South Africa
598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JPEU Interreg Programme Focus in CD-CE111European Joint Programming Initiative Project NutriPROGRAM and EndObesityGerman Ministry of Education and Research, Berlin
01 GI 0825German Research Foundation (DFG)
Ko912/12-1
INST 409/224-1 FUGGElse Kroner-Fresenius-FoundationLMU University Hospital
Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study
Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.This work was supported by the Commission of the European Communities, the Sixth Framework Programme NUTRIMENTHE (Grant Agreement No. 212652). Additional support was provided by Nutricia (Liverpool, UK)
Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation
Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors
Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.Peer reviewe
Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper
Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addresse
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