957 research outputs found
Recommended from our members
Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice
Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster. DOI: http://dx.doi.org/10.7554/eLife.02676.00
Deficiency of Capicua disrupts bile acid homeostasis
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L-/-) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L-/- liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L-/- mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L-/- liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1 alpha), CCAAT/enhancer-binding protein beta (C/EBP beta), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXR alpha), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnf alpha) expression and decrease in the levels of FOXA2, C/EBP beta, and RXRa were found in Cic-L-/- liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L-/- mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.open11810Ysciescopu
Maternal Gestational Diabetes Associated with Higher Child BMI Z-Score at Preschool and Lower Likelihood of Breastfeeding Initiation
Objectives: To examine the association of maternal GDM with 1) child BMI z-score at preschool; 2) breastfeeding initiation and duration, while adjusting for child birthweight in addition to potential confounders.
Method: Sample included 53 children (3 - 5 years old) recruited from two preschools in Jeddah, Saudi Arabia. Mothers completed a self-administered questionnaire. Child anthropometry was completed using standardized procedures. BMI z-scores were calculated using the WHO standards/reference data. Linear regression models were tested to examine the association between maternal GDM and child BMI z-score, as well as breastfeeding duration. Logistic regression models were tested to examine the association between maternal GDM and breastfeeding initiation. Models were adjusted for child birthweight, maternal BMI, and maternal age at pregnancy.
Results: Mean child BMI z-score was 1.10 (SD= 1.22). About one quarter (24.5%) of mothers reported being diagnosed with GDM. Mean birthweight of children whose mothers were diagnosed with GDM was 3.10 kg (SD= 0.74). Adjusting for covariates, we found that maternal GDM was associated with increased child BMI z-score (B= 1.04, 95% CI= 0.14 - 1.94, P-value= 0.02), and lower odds of breastfeeding initiation (OR= 0.10, 95% CI= 0.02 – 0.49, P-value= 0.005). Maternal GDM was not associated with breastfeeding duration (B= -4.75, 95% CI: -11.79 – 2.29, P-value= 0.18).
Conclusion: Findings suggest that maternal GDM is associated with higher child BMI z-score at preschool and lower likelihood of breastfeeding initiation. Studies are needed in order to identify the underlying mechanisms of associations. Obesity prevention programs may target children whose mothers were diagnosed with GDM; prenatal breastfeeding counseling may be offered
Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy
AbstractOBJECTIVESThis study was designed to compare the hemodynamic efficacy of nonsurgical septal reduction therapy (NSRT) by intracoronary ethanol with standard therapy (surgical myectomy) for the treatment of hypertrophic obstructive cardiomyopathy (HOCM).BACKGROUNDNonsurgical septal reduction therapy has gained interest as a new treatment modality for patients with drug-refractory symptoms of HOCM; however, its benefits in comparison to surgery are unknown.METHODSForty-one consecutive NSRT patients at Baylor College of Medicine with one-year follow-up were compared with age- and gradient-matched septal myectomy patients at the Mayo Clinic. All patients had left ventricular outflow obstruction with a resting gradient ≥40 mm Hg and none had concomitant procedures.RESULTSThere were no baseline differences in New York Heart Association class, severity of mitral regurgitation, use of cardiac medications or exercise capacity. One death occurred during NSRT because of dissection of the left anterior descending artery. At one year, all improvements in both groups were similar. After surgical myectomy, more patients were on medications (p < 0.05) and there was a higher incidence of mild aortic regurgitation (p < 0.05). After NSRT, the incidence of pacemaker implantation for complete heart block was higher (22% vs. 2% in surgery; p = 0.02). However, seven of the nine pacemakers in the NSRT group were implanted before a modified ethanol injection technique and the use of contrast echocardiography.CONCLUSIONSNonsurgical septal reduction therapy resulted in a significantly higher incidence of complete heart block, but the risk was reduced with contrast echocardiography and slow ethanol injection. Surgical myectomy resulted in a significantly higher incidence of mild aortic regurgitation. Nonsurgical septal reduction therapy, guided by contrast echocardiography, is an effective procedure for treating patients with HOCM. The hemodynamic and functional improvements at one year are similar to those of surgical myectomy
Ionization structure and Fe K energy for irradiated accretion disks
We study the radial ionization structure at the surface of an X-ray
illuminated accretion disk. We plot the expected iron K line energy as
a function of the Eddington ratio and of the distance of the emitting matter
from the central source, for a non-rotating and a maximally-rotating black
hole. We compare the predicted disk line energies with those measured in an
archival sample of active galactic nuclei observed with {\it Chandra}, {\it
XMM-Newton} and {\it Suzaku}, and discuss whether the line energies are
consistent with the radial distances inferred from reverberation studies. We
also suggest using rapidly-variable iron K lines to estimate the
viscosity parameter of an accretion disk. There is a forbidden region in the
line energy versus Eddington ratio plane, at low Eddington ratios, where an
accretion disk cannot produce highly-ionized iron K lines. If such
emission is observed in low-Eddington-ratio sources, it is either coming from a
highly-ionized outflow, or is a blue-shifted component from fast-moving neutral
matter.Comment: 5 pages, 2 figures, accepted by MNRA
- …