Cardio-metabolic risk in 5-year-old children prenatally exposed to maternal psychosocial stress: the ABCD study

<p>Abstract</p> <p>Background</p> <p>Recent evidence, both animal and human, suggests that modifiable factors during fetal and infant development predispose for cardiovascular disease in adult life and that they may become possible future targets for prevention. One of these factors is maternal psychosocial stress, but so far, few prospective studies have been able to investigate the longer-term effects of stress in detail, i.e. effects in childhood. Therefore, our general aim is to study whether prenatal maternal psychosocial stress is associated with an adverse cardio-metabolic risk profile in the child at age five.</p> <p>Methods/design</p> <p>Data are available from the Amsterdam Born Children and their Development (ABCD) study, a prospective birth cohort in the Netherlands. Between 2003-2004, 8,266 pregnant women filled out a questionnaire including instruments to determine anxiety (STAI), pregnancy related anxiety (PRAQ), depressive symptoms (CES-D), parenting stress (PDH scale) and work stress (Job Content Questionnaire).</p> <p>Outcome measures in the offspring (age 5-7) are currently collected. These include lipid profile, blood glucose, insulin sensitivity, body composition (body mass index, waist circumference and bioelectrical impedance analysis), autonomic nervous system activity (parasympathetic and sympathetic measures) and blood pressure.</p> <p>Potential mediators are maternal serum cortisol, gestational age and birth weight for gestational age (intrauterine growth restriction). Possible gender differences in programming are also studied.</p> <p>Discussion</p> <p>Main strengths of the proposed study are the longitudinal measurements during three important periods (pregnancy, infancy and childhood), the extensive measurement of maternal psychosocial stress with validated questionnaires and the thorough measurement of the children's cardio-metabolic profile. The availability of several confounding factors will give us the opportunity to quantify the independent contribution of maternal stress during pregnancy to the cardio-metabolic risk profile of her offspring. Moreover, the mediating role of maternal cortisol, intrauterine growth, gestational age and potential gender differences can be explored extensively. If prenatal psychosocial stress is indeed found to be associated with the offspring's cardio-metabolic risk, these results support the statement that primary prevention of cardiovascular disease may start even before birth by reducing maternal stress during pregnancy.</p

Cellular Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the first crystal structure of inhibitor-bound hFEN1 and show a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein– substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the unpairing of substrate DNA necessary for reaction. Other compounds were more competitive with substrate. Cellular thermal shift data showed engagement of both inhibitor types with hFEN1 in cells with activation of the DNA damage response evident upon treatment. However, cellular EC50s were significantly higher than in vitro inhibition constants and the implications of this for exploitation of hFEN1 as a drug target are discussed

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human

Nck adapter proteins: functional versatility in T cells

Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3 domain interactions lead to the formation of larger protein complexes. In T lymphocytes, Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. However, in this context, two different mechanisms and adapter complexes are discussed. In the first scenario, dependent on an activation-induced conformational change in the CD3ε subunits, a direct binding of Nck to components of the TCR/CD3 complex was shown. In the second scenario, Nck is recruited to the TCR complex via phosphorylated Slp76, another central constituent of the membrane proximal activation complex. Over the past years, a large number of putative Nck interactors have been identified in different cellular systems that point to diverse additional functions of the adapter protein, e.g. in the control of gene expression and proliferation

Lifestyle, stress and cortisol response: Review I: Mental stress

The incidences of diseases related to mental stress are increasing in Japan. Mental stress, unacknowledged for long periods, has been shown to lead to the development of a number of diseases. Thus, an index for mental stress is important to induce awareness of its presence. We focused on the relationship between cortisol and mental stress in this review. We will discuss both the usefulness and problems of cortisol as a mental stress index by summarizing the relationship between cortisol and mental stress. The present findings suggested that cortisol appears to be an adequate index for mental stress. However, there are several problems; the present group clarifies these problems and builds the comprehensive mental stress assessment systems by using saliva samples