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Articles by Y Liao
Total Records ( 4 ) for Y Liao
  Y Liao , L Deprez , S Maljevic , J Pitsch , L Claes , D Hristova , A Jordanova , S Ala Mello , A Bellan Koch , D Blazevic , S Schubert , E. A Thomas , S Petrou , A. J Becker , P De Jonghe and H. Lerche

Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na+ channel NaV1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na+ channel NaV1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na+ current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of NaV1.2 and of another voltage-gated Na+ channel, NaV1.6, using immunohistochemistry and real-time reverse transcription–polymerase chain reaction in mouse brain slices. We found that NaV1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by NaV1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant NaV1.2 channels.

  Y Liao , J Tang , M Ma , Z Wu , M Yang , X Wang , T Liu , X Chen , P. C Fletcher and W. Hao

Ketamine abuse has been shown to have a deleterious impact on brain function. However, the precise mechanisms of ketamine dependence-induced pathological change remain poorly understood. Although there is evidence for white matter changes in drug abuse, the presence of white matter abnormalities in chronic ketamine users has not been studied. White matter volumes were measured using in vivo diffusion tensor magnetic resonance imaging data in 41 ketamine-dependent subjects and 44 drug-free healthy volunteers. White matter changes associated with chronic ketamine use were found in bilateral frontal and left temporoparietal cortices. There was also evidence that frontal white matter fractional anisotropy correlated with the severity of drug use (as measured by estimated total ketamine consumption). We provide direct evidence for dose-dependent abnormalities of white matter in bilateral frontal and left temporoparietal regions following chronic ketamine use. The findings suggest a microstructural basis for the changes in cognition and experience observed with prolonged ketamine use. Moreover, the similarities of these changes to those observed in chronic schizophrenia have implications for the glutamate model of this illness.

  M. M McDermott , L Ferrucci , J Guralnik , L Tian , K Liu , F Hoff , Y Liao and M. H. Criqui

Background— Associations of pathophysiological calf muscle characteristics with functional decline in people with lower extremity peripheral arterial disease are unknown.

Methods and Results— Three hundred seventy participants with peripheral arterial disease underwent baseline measurement of calf muscle area, density, and percent fat with the use of computed tomography. Participants were followed up annually for 2 years. The outcome of mobility loss was defined as becoming unable to walk 1/4 mile or walk up and down 1 flight of stairs without assistance among those without baseline mobility limitations. Additional outcomes were ≥20% decline in 6-minute walk distance and becoming unable to walk for 6 minutes continuously among participants who walked continuously for 6 minutes at baseline. With adjustment for age, sex, race, body mass index, the ankle-brachial index, smoking, physical activity, relevant medications, and comorbidities, lower calf muscle density (P for trend <0.001) and lower calf muscle area (P for trend=0.039) were each associated with increased mobility loss rates. Compared with participants in the highest baseline tertiles, participants in the lowest tertile of calf muscle percent fat had a hazard ratio of 0.18 for incident mobility loss (95% confidence interval, 0.06 to 0.55; P=0.003), and participants in the lowest tertile of muscle density had a 3.50 hazard ratio for incident mobility loss (95% confidence interval, 1.28 to 9.57; P=0.015). No significant associations of calf muscle characteristics with 6-minute walk outcomes were observed.

Conclusions— Our findings suggest that interventions to prevent mobility loss in peripheral arterial disease should focus on reversing pathophysiological findings in calf muscle.

  Y Yuan , W Zhang , R Yan , Y Liao , L Zhao , C Ruan , X Du and K. Dai

Rationale: The interaction between platelet glycoprotein (GP) Ib-IX and von Willebrand factor (VWF) is initiated by conformational changes in immobilized VWF and is also regulated by the intraplatelet proteins 14-3-3 and filamin A. Both 14-3-3 and filamin A associate with the cytoplasmic domain of GPIb, whereas little is known about their relationship in regulating the VWF binding function of GPIb-IX.

Objective: To explore the mechanism underlying the roles of 14-3-3 and filamin A in regulating the VWF binding function of GPIb-IX.

Methods and Results: A truncation mutant of GPIb (565) deleting the C-terminal 14-3-3 binding sites retained 14-3-3 binding function, in contrast, deletion of the C-terminal residues 551 to 610 of GPIb totally abolished 14-3-3 binding, indicating that the residues 551 to 564 of GPIb are important in the interaction between 14-3-3 and GPIb-IX. An antibody recognizing phosphorylated R557GpSLP561 sequence reacted with GPIb suggesting phosphorylation of a population of GPIb molecules at Ser559, and a membrane permeable phosphopeptide (MP-P), R557GpSLP561 corresponding to residues 557 to 561 of GPIb eliminated the association of 14-3-3 with 565. MP-P also promoted GPIb-IX association with the membrane skeleton, and inhibited ristocetin-induced platelet agglutination, VWF binding to platelets and platelet adhesion to immobilized VWF. Furthermore, a GPIb-IX mutant replacing Ser559 of GPIb with alanine showed an enhanced association with the membrane skeleton, reduced ristocetin-induced VWF binding, and diminished ability to mediate cell adhesion to VWF under flow conditions.

Conclusions: These data suggest a phosphorylation-dependent binding of 14-3-3 to central filamin A binding site of GPIb, and the dimeric 14-3-3 binding to both the C-terminal site and central RGpSLP site inhibits GPIb-IX association with the membrane skeleton and promotes the VWF binding function of GPIb-IX.

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