Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P 5 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P 5 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P 5 0.0004). Conclusion: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-offunction telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis.
Background Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. Results GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. Conclusions As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders.
Introduction Congenital hypomyelinating neuropathy is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in a number of genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the CNTNAP1 gene with this condition. We report a neonate with congenital hypomyelinating neuropathy who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy. Methods/Results On whole exome sequencing we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function. Discussion This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations.
The non-competitive N-methyl-D-aspartate receptor antagonist dextromethorphan is protective against some types of brain injury. Unilateral carotid ligation in postnatal day 12 CD1 mice produces ischemic brain injury. To evaluate the neuroprotective potential of dextromethorphan against ischemic injury in the immature brain, seven litters of postnatal day 12 CD1 mice received either dextromethorphan or vehicle after a unilateral carotid ligation. Only the male pups were protected, and brain injury was unchanged in the female pups treated with dextromethorphan. These results suggest that dextromethorphan neuroprotection against ischemic injury in the immature brain is sex-dependent.
Middle school students with ADHD often experience negative academic outcomes. To intervene, schools frequently provide services through special education or section 504. These services include strategies, such as breaks, prompting, and sensory proprioception to remove the impact of construct-irrelevant variance. Student plans rarely include strategies, such as selfmanagement, designed to teach students skills to increase independent functioning. The purpose of this study was to compare the effectiveness of four strategies on engagement, disruptive behavior, and time to initiate tasks. Fifteen sixth and seventh grade students were randomized daily to one of four conditions. Results indicated large statistically significant differences. Social validity data indicated that students found prompting and self-management helpful, but preferred breaks and sensory proprioception. This study builds on a growing empirical base that supports the prioritization of strategies to teach skills over strategies to remove the impact of ADHD on performance.
No abstract
No abstract
We consider the impact of Fund-supported programs in fragile and conflict-affected states (FCS) on aid flows and what factors determine program success. Using several indicators of fragility in a multivariate setting, we find that the catalytic role of IMF engagement on aid is significant in general and particularly so in fragile states. There is clear evidence that risks are more elevated in FCS due to conflict and political instability. Probit analysis for metrics of program success indicates that programs in FCS have a significantly higher probability of non-completion than non-FCS. We find a strong negative effect of high public debt on program completion. Usage of prior actions is associated with weaker program performance, suggesting that their use occurs in situations that are perceived as more risky. We recommend a greater focus on the drivers of conflict and instability in FCS and consideration of program measures that contribute to better economic outcomes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.