Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain

Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (DeltaRG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of DeltaRG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of DeltaRG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the DeltaRG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder.     

Auditory modulation of the inferior temporal cortex neurons in rhesus monkey

We performed a systematic study to check whether neurons in the area TE (the anterior part of inferotemporal cortex) in rhesus monkey, regarded as the last stage of the ventral visual pathway, could be modulated by auditory stimuli. Two fixating rhesus monkeys were presented with visual, auditory or combined audiovisual stimuli while neuronal responses were recorded. We have found that the visually sensitive neurons are also modulated by audiovisual stimuli. This modulation is manifested as the change of response rate. Our results have shown also that the visual neurons were responsive to the sole auditory stimuli. Therefore, the concept of inferotemporal cortex unimodality in information processing should be re-evaluated.     

Effects of citalopram and fluoxetine on the corticocerebral blood flow in conscious rabbits

Depression, which is associated with an increased incidence of vascular events, frequently occurs following stroke. Selective serotonin reuptake inhibitory drugs (SSRIs) as antidepressants, are well tolerated, and also seem to be effective in post-stroke depression. The aim of this study was to investigate the effects of the SSRIs citalopram and fluoxetine, on the corticocerebral blood flow (cCBF) in rabbits with unilateral carotid occlusion induced cerebral ischemia. The cCBF was measured by the hydrogen clearance technique. After determination of the mean baseline cCBF, the effects of individual doses (0.1, 0.3 and I mg/kg) of citalopram or fluoxetine on the cCBF were investigated. Following the induction of an impaired cCBF, the changes in cCBF after drug treatments in this condition were likewise measured. The mean arterial blood pressure (MABP) and the heart rate (HR) from the electrocardiogram (ECG) were also determined. Neither citalopram nor fluoxetine influenced the cCBF in the control group. Fluoxetine improved the cCBF only very slightly in the ischemic animals. In contrast, all the doses of citalopram exerted pronounced and dose-dependent cCBF-increasing effects in the animals with unilateral carotid occlusion (maximal mean ACBF: 10, 16 and 27 ml/min/100 g tissue). The HR was decreased in both groups. Only citalopram treatment led to a slight MABP-decreasing effect. Besides enhancement of the serotonergic transmission in the brain, the cCBF-increasing effect of citalopram under ischemic conditions may be of benefit in post-stroke and vascular depression.     

Bow ties, metabolism and disease

Highly organized, universal structures underlying biological and technological networks mediate effective trade-offs among efficiency, robustness and evolvability, with predictable fragilities that can be used to understand disease pathogenesis. The aims of this article are to describe the features of one common organizational architecture in biology, the bow tie. Large-scale organizational frameworks such as the bow tie are necessary starting points for higher-resolution modeling of complex biologic processes     

Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy

We describe a novel phenotype in mice lacking the major antioxidant enzyme, CuZn-superoxide dismutase (Sod1(-/-) mice), namely a dramatic acceleration of age-related loss of skeletal muscle mass. Sod1(-/-) mice are 17 to 20% smaller and have a significantly lower muscle mass than wild-type mice as early as 3 to 4 months of age. Muscle mass in the Sod1(-/-) mice is further reduced with age and by 20 months, the hind-limb muscle mass in Sod1(-/-) mice is nearly 50% lower than in age-matched wild-type mice. Skeletal muscle tissue from young Sod1(-/-) mice has elevated oxidative damage to proteins, lipids, and DNA compared to muscle from young wild-type mice. The reduction in muscle mass and elevated oxidative damage are accompanied by a 40% decrease in voluntary wheel running by 6 months of age and decreased performance on the Rota-rod test at 13 months of age, but are not associated with a decline in overall spontaneous activity. In some of the old Sod1(-/-) mice, the loss in muscle mass is also associated with the presence of tremors and gait disturbances. Thus, the absence of CuZnSOD imposes elevated oxidative stress, loss of muscle mass, and physiological consequences that resemble an acceleration of normal age-related sarcopenia.