The features of synonymous codon bias and GC-content relationship in human genes

728 human genes were divided to four groups according to the GC contents of their coding sequences (from GC<0.43 to GC>0.58). Examination of synonymous-codon bias in the 4 groups show that NTG (N represents any base of T, A, C, G) is most favored and NCG

Evaluation of Altered Kras Codon Bias and NOS Inhibition During Lung Tumorigenesis

The small GTPases HRAS, NRAS and KRAS are mutated in approximately one-third of all human cancers, rendering the proteins constitutively active and oncogenic. Lung cancer is the leading cause of cancer deaths worldwide, and more than 20% of human lung cancers harbor mutations in RAS, with 98% of those occurring in the KRAS isoform. While there have been many advances in the understanding of KRAS–driven lung tumorigenesis, it remains a therapeutic challenge. To further this understanding and assess novel approaches for treatment, I have investigated two aspects of Kras–driven tumorigenesis in the lung:

(I) Despite nearly identical protein sequences, the three RAS proto-oncogenes exhibit divergent codon usage. Of the three isoforms, KRAS contains the most rare codons resulting in lower levels of KRAS protein expression relative to HRAS and NRAS. To determine the consequences of rare codon bias during de novo tumorigenesis, we created a knock-in Krasex3op mouse in which synonymous mutations in exon 3 converted codons from rare to common. These mice had reduced tumor burden and fewer oncogenic mutations in the Krasex3op allele following carcinogen exposure. The reduction in tumorigenesis appeared to be a product of rare codons affecting both the oncogenic and non–oncogenic alleles. Converting rare codons to common codons yielded a more potent oncogenic allele that promoted growth arrest and enhanced tumor suppression by the non-oncogenic allele. Thus, rare codons play an integral role in Kras tumorigenesis.

(II) Lung cancer patients exhale higher levels of NO and iNOS-/- mice are resistant to chemically induced lung tumorigenesis. I hypothesize that NO promotes Kras–driven lung adenocarcinoma, and NOS inhibition may decrease Kras–driven lung tumorigenesis. To test this hypothesis, I assessed efficacy of the NOS inhibitor L–NAME in a genetically engineered mouse model of Kras-driven lung adenocarcinoma. Adenoviral Cre recombinase was delivered into the lungs intranasally, resulting in expression of oncogenic KrasG12D and dominant-negative Trp53R172H in lung epithelial cells. L–NAME treatment was provided in the water and continued until survival endpoints. In this model, L–NAME treatment decreased tumor growth and prolonged survival. These data establish a potential clinical role for NOS inhibition in lung cancer treatment.

The role of stimulus salience and attentional capture across the neural hierarchy in a stop-signal task.

Inhibitory motor control is a core function of cognitive control. Evidence from diverse experimental approaches has linked this function to a mostly right-lateralized network of cortical and subcortical areas, wherein a signal from the frontal cortex to the basal ganglia is believed to trigger motor-response cancellation. Recently, however, it has been recognized that in the context of typical motor-control paradigms those processes related to actual response inhibition and those related to the attentional processing of the relevant stimuli are highly interrelated and thus difficult to distinguish. Here, we used fMRI and a modified Stop-signal task to specifically examine the role of perceptual and attentional processes triggered by the different stimuli in such tasks, thus seeking to further distinguish other cognitive processes that may precede or otherwise accompany the implementation of response inhibition. In order to establish which brain areas respond to sensory stimulation differences by rare Stop-stimuli, as well as to the associated attentional capture that these may trigger irrespective of their task-relevance, we compared brain activity evoked by Stop-trials to that evoked by Go-trials in task blocks where Stop-stimuli were to be ignored. In addition, region-of-interest analyses comparing the responses to these task-irrelevant Stop-trials, with those to typical relevant Stop-trials, identified separable activity profiles as a function of the task-relevance of the Stop-signal. While occipital areas were mostly blind to the task-relevance of Stop-stimuli, activity in temporo-parietal areas dissociated between task-irrelevant and task-relevant ones. Activity profiles in frontal areas, in turn, were activated mainly by task-relevant Stop-trials, presumably reflecting a combination of triggered top-down attentional influences and inhibitory motor-control processes.

The Dietary Approaches to Stop Hypertension (DASH) eating pattern in special populations.

The Dietary Approaches to Stop Hypertension (DASH) trial showed that a diet rich in fruits, vegetables, low-fat dairy products with reduced total and saturated fat, cholesterol, and sugar-sweetened products effectively lowers blood pressure in individuals with prehypertension and stage I hypertension. Limited evidence is available on the safety and efficacy of the DASH eating pattern in special patient populations that were excluded from the trial. Caution should be exercised before initiating the DASH diet in patients with chronic kidney disease, chronic liver disease, and those who are prescribed renin-angiotensin-aldosterone system antagonist, but these conditions are not strict contraindications to DASH. Modifications to the DASH diet may be necessary to facilitate its use in patients with chronic heart failure, uncontrolled diabetes mellitus type II, lactose intolerance, and celiac disease. In general, the DASH diet can be adopted by most patient populations and initiated simultaneously with medication therapy and other lifestyle interventions.

Impact of Kidney Function on Effects of the Dietary Approaches to Stop Hypertension (Dash) Diet.

OBJECTIVES: Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure in adults with hypertension, how kidney function impacts this effect is not known. We evaluated whether Estimated Glomerular Filtration Rate (eGFR) modifies the effect of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function. METHODS: Secondary analysis of the DASH-Sodium trial, a multicenter, randomized, controlled human feeding study that evaluated the blood pressure lowering effect of the DASH diet at three levels of sodium intake. Data from 92 participants with pre-hypertension or stage 1 hypertension during the 3450 mg /day sodium diet assignment contributed to this analysis. Stored frozen plasma and urine specimens were used to measure kidney related laboratory outcomes. RESULTS: Effects of the DASH diet on blood pressure, phosphorus, intact parathyroid hormone, creatinine, and albuminuria were not modified by baseline eGFR (mean 84.5 ± 18.0 ml/min/1.73 m(2), range 44.1 to 138.6 ml/min/1.73 m(2)) or the presence of chronic kidney disease (N=13%). CONCLUSIONS: The impact of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function does not appear to be modified by eGFR in this small subset of DASH-Sodium trial participants with relatively preserved kidney function. Whether greater reduction in eGFR modifies the effects of DASH on kidney related measures is yet to be determined. A larger study in individuals with more advanced kidney disease is needed to establish the efficacy and safety of the DASH diet in this patient population.

Anterior thalmic lesions stop immediate early gene activation in selective laminae of the retrosplenial cortex: evidence of covert pathology in rats

Lesions involving the anterior thalamic nuclei stopped immediate early gene (IEG) activity in specific regions of the rat retrosplenial cortex, even though there were no apparent cytoarchitectonic changes. Discrete anterior thalamic lesions were made either by excitotoxin (Experiment 1) or radiofrequency (Experiment 2) and, following recovery, the rats foraged in a radial-arm maze in a novel room. Measurements made 6-12 weeks postsurgery showed that, in comparison with surgical controls, the thalamic lesions produced the same, selective patterns of Fos changes irrespective of method. Granular (caudal granular cortex and rostral granular cortex), but not dysgranular (dysgranular cortex), retrosplenial cortex showed a striking loss of Fos-positive cells. While a loss of between 79 and 89% of Fos-positive cells was found in the superficial laminae, the deeper layers appeared normal. In Experiments 3 and 4, rats 9-10 months postsurgery were placed in an activity box for 30 min. Anterior thalamic lesions (Experiment 3) led to a pronounced IEG decrease of both Fos and zif268 throughout the retrosplenial cortex that now included the dysgranular area. These IEG losses were found even though the same regions appeared normal using standard histological techniques. Lesions of the postrhinal cortex (Experiment 4) did not bring about a loss of retrosplenial IEG activity even though this region is also reciprocally connected with the retrosplenial cortex. This selective effect of anterior thalamic damage upon retrosplenial activity may both amplify the disruptive effects of anterior thalamic lesions and help to explain the posterior cingulate hypoactivity found in Alzheimer's disease.