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Articles by K Chen
Total Records ( 4 ) for K Chen
  D. C Koboldt , K Chen , T Wylie , D. E Larson , M. D McLellan , E. R Mardis , G. M Weinstock , R. K Wilson and L. Ding
 

Summary: Massively parallel sequencing technologies hold incredible promise for the study of DNA sequence variation, particularly the identification of variants affecting human disease. The unprecedented throughput and relatively short read lengths of Roche/454, Illumina/Solexa, and other platforms have spurred development of a new generation of sequence alignment algorithms. Yet detection of sequence variants based on short read alignments remains challenging, and most currently available tools are limited to a single platform or aligner type. We present VarScan, an open source tool for variant detection that is compatible with several short read aligners. We demonstrate VarScan's ability to detect SNPs and indels with high sensitivity and specificity, in both Roche/454 sequencing of individuals and deep Illumina/Solexa sequencing of pooled samples.

  K Chen and X. Tong
 

A maximum likelihood method with spline smoothing is proposed for linear transformation models with varying coefficients. The estimation and inference procedures are computationally easy. Under some regularity conditions, the estimators are proved to be consistent and asymptotically normal. A simulation study using the Stanford transplant data is presented to show that the proposed method performs well with a finite sample and is easy to use in practice.

  N Kaludercic , E Takimoto , T Nagayama , N Feng , E. W Lai , D Bedja , K Chen , K. L Gabrielson , R. D Blakely , J. C Shih , K Pacak , D. A Kass , F Di Lisa and N. Paolocci
 

Rationale: Monoamine oxidases (MAOs) are mitochondrial enzymes that catabolize prohypertrophic neurotransmitters, such as norepinephrine and serotonin, generating hydrogen peroxide. Because excess reactive oxygen species and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAOs could play an important role in this process.

Objective: Here, we investigated the role of MAO-A in maladaptive hypertrophy and heart failure.

Methods and Results: We report that MAO-A activity is triggered in isolated neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. All of these in vitro changes occur, in part, independently from - and β-adrenergic receptor–operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene reprogramming, metalloproteinase and caspase-3 activation, as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-Aneo), which were more protected against pressure overload than their wild-type littermates.

Conclusions: In addition to adrenergic receptor–dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in augmented reactive oxygen species generation, contributing to maladaptive remodeling and left ventricular dysfunction in hearts subjected to chronic stress.

  Y Alvarez , K Chen , A. L Reynolds , N Waghorne , J. J O'Connor and B. N. Kennedy
  Yolanda Alvarez, Kenneth Chen, Alison L. Reynolds, Nora Waghorne, John J. O'Connor, and Breandan N. Kennedy

Approximately 2.5 million people worldwide are clinically blind because of diabetic retinopathy. In the non-proliferative stage, the pathophysiology of this ocular manifestation of diabetes presents as morphological and functional disruption of the retinal vasculature, and dysfunction of retinal neurons. However, it is uncertain whether the vascular and neuronal changes are interdependent or independent events. In addition, the identity of the retinal neurons that are most susceptible to the hyperglycaemia associated with diabetes is unclear. Here, we characterise a novel model of non-proliferative diabetic retinopathy in adult zebrafish, in which the zebrafish were subjected to oscillating hyperglycaemia for 30 days. Visual function is diminished in hyperglycaemic fish. Significantly, hyperglycaemia disrupts cone photoreceptor neurons the most, as evidenced by prominent morphological degeneration and dysfunctional cone-mediated electroretinograms. Disturbances in the morphological integrity of the blood-retinal barrier were also evident. However, we demonstrate that these early vascular changes are not sufficient to induce cone photoreceptor dysfunction, suggesting that the vascular and neuronal complications in diabetic retinopathy can arise independently. Current treatments for diabetic retinopathy target the vascular complications. Our data suggest that cone photoreceptor dysfunction is a clinical hallmark of diabetic retinopathy and that the debilitating blindness associated with diabetic retinopathy may be halted by neuroprotection of cones.

 
 
 
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