Predicting the Effects of Supplemental EPA and DHA on the Omega-3 Index

Background: Supplemental long-chain omega-3 (n–3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. Objective: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. Methods: Deidentified data from 1422 individuals from 14 published n–3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. Results: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P \u3c 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P \u3c 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. Conclusions: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form

A pre-registered, multi-lab non-replication of the Action-sentence Compatibility Effect (ACE)

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero.Fil: Morey, Richard. Cardiff University; Reino UnidoFil: Kaschak, Michael. Florida State University; Estados UnidosFil: Díez Álamo, Antonio. Universidad de Salamanca; España. Arizona State University; Estados UnidosFil: Glenberg, Arthur. Arizona State University; Estados Unidos. Universidad de Salamanca; EspañaFil: Zwaan, Rolf A.. Erasmus University Rotterdam; Países BajosFil: Lakens, Daniël. Eindhoven University of Technology; Países BajosFil: Ibáñez, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Adolfo Ibañez; Chile. Trinity College Dublin; IrlandaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; Argentina. Universidad de Santiago de Chile; ChileFil: Gianelli, Claudia. Universitat Potsdam; Alemania. Scuola Universitaria Superiore; ItaliaFil: Jones, John L.. Florida State University; Estados UnidosFil: Madden, Julie. University of Tennessee; Estados UnidosFil: Alifano Ferrero, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bergen, Benjamin. University of California at San Diego; Estados UnidosFil: Bloxsom, Nicholas G.. Ashland University; Estados UnidosFil: Bub, Daniel N.. University of Victoria; CanadáFil: Cai, Zhenguang G.. The Chinese University; Hong KongFil: Chartier, Christopher R.. Ashland University; Estados UnidosFil: Chatterjee, Anjan. University of Pennsylvania; Estados UnidosFil: Conwell, Erin. North Dakota State University; Estados UnidosFil: Wagner Cook, Susan. University of Iowa; Estados UnidosFil: Davis, Joshua D.. University of California at San Diego; Estados UnidosFil: Evers, Ellen R. K.. University of California at Berkeley; Estados UnidosFil: Girard, Sandrine. University of Carnegie Mellon; Estados UnidosFil: Harter, Derek. Texas A&m University Commerce; Estados UnidosFil: Hartung, Franziska. University of Pennsylvania; Estados UnidosFil: Herrera, Eduar. Universidad ICESI; ColombiaFil: Huettig, Falk. Max Planck Institute for Psycholinguistics; Países BajosFil: Humphries, Stacey. University of Pennsylvania; Estados UnidosFil: Juanchich, Marie. University of Essex; Reino UnidoFil: Kühne, Katharina. Universitat Potsdam; AlemaniaFil: Lu, Shulan. Texas A&m University Commerce; Estados UnidosFil: Lynes, Tom. University of East Anglia; Reino UnidoFil: Masson, Michael E. J.. University of Victoria; CanadáFil: Ostarek, Markus. Max Planck Institute for Psycholinguistics; Países BajosFil: Pessers, Sebastiaan. Katholikie Universiteit Leuven; BélgicaFil: Reglin, Rebecca. Universitat Potsdam; AlemaniaFil: Steegen, Sara. Katholikie Universiteit Leuven; BélgicaFil: Thiessen, Erik D.. University of Carnegie Mellon; Estados UnidosFil: Thomas, Laura E.. North Dakota State University; Estados UnidosFil: Trott, Sean. University of California at San Diego; Estados UnidosFil: Vandekerckhove, Joachim. University of California at Irvine; Estados UnidosFil: Vanpaeme, Wolf. Katholikie Universiteit Leuven; BélgicaFil: Vlachou, Maria. Katholikie Universiteit Leuven; BélgicaFil: Williams, Kristina. Texas A&m University Commerce; Estados UnidosFil: Ziv Crispel, Noam. BehavioralSight; Estados Unido

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Studies on the normal and oncogenic signaling networks from the hematopoietic growth factor receptors c-Kit and Flt3

The closely related receptor tyrosine kinases c-Kit and Flt3 are mainly expressed in hematopoietic cells and are involved in driving cell proliferation and promoting survival in response to growth factor stimulation. Several gain-of-function mutations of both c-Kit and Flt3 have been found in malignancies like acute myeloid leukemia, gastrointestinal stroma tumors and small cell lung carcinomas, and the constitutively activated receptors are very potent oncogenes. We have studied the detailed signal transduction pathways downstream of c-Kit and Flt3, in order to understand the exact mechanism by which processes such as cell growth and differentiation are regulated. We looked into the negative regulation of RTKs by focusing on the E3 ubiquitin ligase Cbl and its interaction with c-Kit, and found that this interaction was dependent on Src family kinases to target the receptor for lysosomal degradation. Src is found to be involved in the development of a variety of tumors and this mechanism is crucial for a balanced signaling. In Flt3, we identified several novel phosphorylation sites involved in Src binding and activation as well as the binding of the adaptor proteins Grb2/Gab2. Upon Y-to-F point mutations of these residues, we investigated the downstream signaling pathways affected and the biological outcomes of this. Moreover, we compared phosphorylation and signaling patterns between the wild-type and the mutated versions of Flt3. The most common mutation in Flt3, an internal tandem duplication (ITD) in the juxtamembrane region of the receptor, is found in about 30% of patients with AML and is correlated to a worse prognosis. The ITD receptor activates the downstream signaling protein Stat5, an important mediator of survival, whereas the wild-type Flt3 does not. We found that this activation of Stat5 to some extent is induced by the function of Gab2 and its recruitment to the Flt3 receptor, and that this as an important pathway for cell viability and proliferation. By using phospho-specific Flt3 antibodies produced in-house, we compared the site-specific phosphorylation and kinetics of wild-type Flt3 with the two most common mutants in AML; D853Y and the ITD. We found both quantitative and qualitative differences, indicating that the oncogenic receptors act through specific signaling pathways, which provides potential therapeutic targets

Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.

Signal transduction in response to growth factors is a strictly controlled process with networks of feedback systems, highly selective interactions and finely tuned on-and-off switches. In the context of cancer, detailed signaling studies have resulted in the development of some of the most frequently used means of therapy, with several well established examples such as the small molecule inhibitors imatinib and dasatinib in the treatment of chronic myeloid leukemia. Impaired function of receptor tyrosine kinases is implicated in various types of tumors, and much effort is put into mapping the many interactions and downstream pathways. Here we discuss the hematopoietic growth factor receptors c-Kit and Flt3 and their downstream signaling in normal as well as malignant cells. Both receptors are members of the same family of tyrosine kinases and crucial mediators of stem-and progenitor-cell proliferation and survival in response to ligand stimuli from the surrounding microenvironment. Gain-of-function mutations/alterations render the receptors constitutively and ligand-independently activated, resulting in aberrant signaling which is a crucial driving force in tumorigenesis. Frequently found mutations in c-Kit and Flt3 are point mutations of aspartic acid 816 and 835 respectively, in the activation loop of the kinase domains. Several other point mutations have been identified, but in the case of Flt3, the most common alterations are internal tandem duplications (ITDs) in the juxtamembrane region, reported in approximately 30% of patients with acute myeloid leukemia (AML). During the last couple of years, the increasing understanding of c-Kit and Flt3 signaling has also revealed the complexity of these receptor systems. The impact of gain-of-function mutations of c-Kit and Flt3 in different malignancies is well established and shown to be of clinical relevance in both prognosis and therapy. Many inhibitors of both c-Kit or Flt3 or of their downstream substrates are in clinical trials with encouraging results, and targeted therapy using a combination of such inhibitors is considered a promising approach for future treatments

Direct binding of Cbl to Tyr(568) and Tyr(936) of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation

The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr(568) and Tyr(936) in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by SFK members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates mono-ubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit-mediated signalling

Oncogenic flt3 receptors display different specificity and kinetics of autophosphorylation.

OBJECTIVE: Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants. METHODS: We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the use of a panel of phospho-specific antibodies directed against potential tyrosine phosphorylation sites in FLT3, we identified several novel phosphorylation sites in FLT3 and studied the kinetics and specificity of ligand-induced phosphorylation in living cells. RESULTS: Eight phosphorylated tyrosines (pY589, pY591, pY599, pY726, pY768, pY793, pY842 and pY955) were investigated and shown to be differentially phosphorylated in the wild-type versus the mutated receptors. Furthermore, we show that tyrosines 726, 793 and 842 are novel phosphorylation sites of FLT3 in intact cells. CONCLUSION: In this study, we have looked at the site-specific phosphorylation in the wild-type FLT3 in comparison to the mutants found in AML. We observed not only quantitative changes but more importantly, qualitative differences in the phosphorylation patterns of the wild-type and the mutated FLT3 receptors, which might enhance the understanding of the mechanisms by which FLT3 contributes to AML in patients with mutations in FLT3

A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.

Summary The haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites, and characterised in terms of proliferation and viability. Interestingly, the Flt3 ITD promoted increased survival but after introducing the triple mutation, this phenotype was lost. When looking into different downstream pathways, this effect was mainly caused by decreased phosphoinositide 3-kinase and Stat5 signalling, and the Flt3 ITD carrying the Grb2 binding mutations showed less Akt and Stat5 activation compared to the regular Flt3 ITD receptor. These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions