118 research outputs found
Clinical diagnoses in young offspring from eastern Québec multigenerational families densely affected by schizophrenia or bipolar disorder
Maziade M, Gingras N, Rouleau N, Poulin S, Jomphe V, Paradis M-E, Mérette C, Roy M-A. Clinical diagnoses in young offspring from eastern Québec multigenerational families densely affected by schizophrenia or bipolar disorder
Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways
OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels.
RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.
RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 Ă 10â26), HFE (rs1800562/P = 2.6 Ă 10â20), TMPRSS6 (rs855791/P = 2.7 Ă 10â14), ANK1 (rs4737009/P = 6.1 Ă 10â12), SPTA1 (rs2779116/P = 2.8 Ă 10â9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 Ă 10â9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 Ă 10â54), MTNR1B (rs1387153/P = 4.0 Ă 10â11), GCK (rs1799884/P = 1.5 Ă 10â20) and G6PC2/ABCB11 (rs552976/P = 8.2 Ă 10â18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify âŒ2% of a general white population screened for diabetes with HbA1c.
CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c
Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways
Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNÎČ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.National Institutes of Health (U.S.) (R01-AI080621)New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (Developmental Grant AIO57159)Pew Charitable Trusts (Biomedical Scholars Program)Robert A. Swanson Career Development awardThe Knights Templar Eye Foundation, Inc.Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33)Cleo and Paul Schimmel Foundatio
Intergenerational Transmission of Multiple Problem Behaviors: Prospective Relationships between Mothers and Daughters
Much of the research examining intergenerational continuity of problems from mother to offspring has focused on homotypic continuity (e.g., depression), despite the fact that different types of mental health problems tend to cluster in both adults and children. It remains unclear whether mothers with multiple mental health problems compared to mothers with fewer or no problems are more likely to have daughters with multiple mental health problems during middle childhood (ages 7 to 11). Six waves of maternal and child data from the Pittsburgh Girls Study (nâ=â2,451) were used to examine the specificity of effects of maternal psychopathology on child adjustment. Child multiple mental health problems comprised disruptive behavior, ADHD symptoms, depressed mood, anxiety symptoms and somatic complaints, while maternal multiple mental health problems consisted of depression, prior conduct problems and somatic complaints. Generalized Estimating Equations (GEE) was used to examine the prospective relationships between motherâs single and multiple mental health problems and their daughterâs single and multiple mental health problems across the elementary school-aged period (ages 7â11Â years). The results show that multiple mental health problems in the mothers predicted multiple mental health problems in the daughters even when earlier mental health problem of the daughters, demographic factors, and childrearing practices were controlled. Maternal low parental warmth and harsh punishment independently contributed to the prediction of multiple mental health problems in their daughter, but mediation analyses showed that the contribution of parenting behaviors to the explanation of girlsâ mental health problems was small
Taking two to tango:fMRI analysis of improvised joint action with physical contact
<div><p>Many forms of joint action involve physical coupling between the participants, such as when moving a sofa together or dancing a tango. We report the results of a novel two-person functional MRI study in which trained couple dancers engaged in bimanual contact with an experimenter standing next to the bore of the magnet, and in which the two alternated between being the leader and the follower of joint improvised movements. Leading showed a general pattern of self-orientation, being associated with brain areas involved in motor planning, navigation, sequencing, action monitoring, and error correction. In contrast, following showed a far more sensory, externally-oriented pattern, revealing areas involved in somatosensation, proprioception, motion tracking, social cognition, and outcome monitoring. We also had participants perform a âmutualâ condition in which the movement patterns were pre-learned and the roles were symmetric, thereby minimizing any tendency toward either leading or following. The mutual condition showed greater activity in brain areas involved in mentalizing and social reward than did leading or following. Finally, the analysis of improvisation revealed the dual importance of motor-planning and working-memory areas. We discuss these results in terms of theories of both joint action and improvisation.</p></div
Organotin compounds in surface sediments of the Southern Baltic coastal zone: a study on the main factors for their accumulation and degradation
Abstract Sediment samples were collected in the Gulf of
GdaĆsk, and the Vistula and Szczecin Lagoonsâall located
in the coastal zone of the Southern Baltic Seaâjust after the
total ban on using harmful organotins in antifouling paints on
ships came into force, to assess their butyltin and phenyltin
contamination extent. Altogether, 26 sampling stations were
chosen to account for different potential exposure to organotin
pollution and environmental conditions: from shallow and
well-oxygenated waters, shipping routes and river mouths,
to deep and anoxic sites. Additionally, the organic carbon
content, pigment content, and grain size of all the sediment
samples were determined, and some parameters of the nearbottom
water (oxygen content, salinity, temperature) were
measured as well. Total concentrations of butyltin compounds
ranged between 2 and 182 ng Sn gâ1 d.w., whereas phenyltins
were below the detection limit. Sediments from the Gulf of
GdaĆsk and Vistula Lagoon were found moderately contaminated
with tributyltin, whereas those from the Szczecin
Lagoon were ranked as highly contaminated. Butyltin degradation
indices prove a recent tributyltin input into the sediments
adjacent to sites used for dumping for dredged harbor
materials and for anchorage in the Gulf of GdaĆsk (where two
big international ports are located), and into those collected in
the Szczecin Lagoon. Essential factors affecting the degradation
and distribution of organotins, based on significant correlations
between butyltins and environmental variables, were
found in the study area
Measurement of b hadron lifetimes in exclusive decays containing a J/psi in p-pbar collisions at sqrt(s)=1.96TeV
We report on a measurement of -hadron lifetimes in the fully reconstructed
decay modes B^+ -->J/Psi K+, B^0 --> J/Psi K*, B^0 --> J/Psi Ks, and Lambda_b
--> J/Psi Lambda using data corresponding to an integrated luminosity of 4.3
, collected by the CDF II detector at the Fermilab Tevatron. The
measured lifetimes are B^+ = , B^0 = and Lambda_b = . The lifetime ratios are B^+/B^0 = and Lambda_b/B^0 = . These are the most precise determinations
of these quantities from a single experiment.Comment: revised version. accepted for PRL publicatio
CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis
Studies on inflammatory disorders elucidated the pivotal role of the
CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases
progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with
severe cardiac inflammation, which may progress to heart failure. We therefore
investigated the influence of CX3CR1 ablation in the model of acute
myocarditis, which was induced by inoculation with 5x105 plaque forming units
of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days
after infection, myocardial inflammation, remodeling, and titin expression and
phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q
diamond stain. Cardiac function was assessed by tip catheter. Compared to WT
CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression
of inflammatory cytokines and chemokines, which was associated with an
increase of immune cell infiltration/presence. This shift towards a pro-
inflammatory immune response further resulted in increased cardiac fibrosis
and cardiomyocyte apoptosis, which was reflected by an impaired cardiac
function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings
demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and
indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced
myocarditis
Asexual expansion of Toxoplasma gondii merozoites is distinct from tachyzoites and entails expression of non-overlapping gene families to attach, invade, and replicate within feline enterocytes
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