Citations

Tetrahydrobiopterin is an essential cofactor required for the synthesis of NO. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin production in endothelial cells, yet little is known about the subcellular localization of this enzyme. In this study, we demonstrated that GTPCH I is localized to caveolar membrane microdomains along with caveolin-1 and endothelial NO synthase. GTPCH I activity was detected in isolated caveolar membranes from cultured endothelial cells. Confocal and electron microscopy analyses confirmed GTPCH I colocalization with caveolin-1. Consistent with in vitro studies, GTPCH I activity was evident in isolated caveolar microdomains from lung homogenates of wild-type mice. Importantly, a 2-fold increase in GTPCH I activity was detected in the aortas of caveolin-1–deficient mice, suggesting that caveolin-1 may be involved in the control of GTPCH I enzymatic activity. Indeed, overexpression of caveolin-1 inhibits GTPCH I activity, and tetrahydrobiopterin biosynthesis is activated by the disruption of caveolae structure. These studies demonstrate that GTPCH I is targeted to caveolae microdomains in vascular endothelial cells, and tetrahydrobiopterin production occurs in close proximity to endothelial NO synthase. In addition, our findings provide new insights into the regulation of GTPCH I activity by the caveolar coat protein, caveolin-1.

The Wnt/β-catenin pathway exhibits distinct and developmental stage-specific roles during cardiogenesis. However, little is known about the molecular mechanisms of Wnt/β-catenin signaling in the establishment of cardiac left-right (LR) asymmetry. Using zebrafish as an animal model, we show here that Wnt/β-catenin signaling is differentially required in cardiac LR patterning. At an early stage, during asymmetric signal generation,Wnt/β-catenin signaling is necessary for Kupffer's vesicle development and for the regulation of both heart and visceral laterality. At a later stage, during asymmetric signal propagation, excessive Wnt/β-catenin signaling inhibits the transmission of asymmetric cues from the lateral plate mesoderm (LPM) to the cardiac field but not to the developing gut; as such, it only regulates heart laterality. Molecular analysis identifies Gata4 as the downstream target of Wnt/β-catenin signaling in the cardiac field that responds to the Wnt/β-catenin signaling and regulates the competence of the heart field to express left-sided genes. In summary, our results reveal a previously unexpected role of Wnt-Gata4 signaling in the control of asymmetric signal propagation from the LPM to the cardiac field.

This study compared the hemispheric dominance for language of three groups of 6- to 9-year-olds (10 language-disordered, 10 articulation-disordered, and 10 normal children). Two dichotic listening tests (digits and animal names) were administered. Statistical analysis revealed a left hemisphere dominance for the control and articulation-disordered groups but no significant hemisphere differences for the language-disordered group. The results support the hypothesis that the language-disordered child has an unlateralized cerebral dominance for language, while the articulation-disordered child has normal left cerebral hemisphere dominance for language. Furthermore, there is some evidence to suggest that the language-disordered child does not process auditory stimuli in the left hemisphere as efficiently as the articulation-disordered or normal child. These results also suggest the importance of developing strategies in the management of these disorders.

Based on the postulate that there is a continuum of reproductive casualty, it was hypothesized that potentially stressful perinatal experiences would subsequently produce measurable effects on certain psychologic tests in the children studied. Prospectively gathered data from 386 neurologically normal 7-year-old children were reviewed, and a perinatal stress score was derived for each by a simple count of deviant symptoms during pregnancy, delivery, and puerperium. Results marginally supported the concept of continuum of reproductive casualty but were neither clear nor systematic. The perinatal stress score may have been contaminated with items of little or no significance, which would have decreased its discriminating power.

Clonal disorders of large granular lymphocytes (LGL) result in leukemia due to the expansion of a discrete subset of either CD3 + T cells or natural killer (NK) cells. It has been hypothesized that a viral antigen acts as the initial stimulus causing the expansion of these cells. The possible involvement of human T cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) in this disease has been studied but no conclusive evidence has linked either virus with LGL leukemia. In this study, we examined whether HTLV-3 or HTLV-4, two newly identified HTLV groups discovered in Central Africa in primate hunters, is involved in LGL leukemia. We developed two specific real-time PCR quantitative assays that are highly sensitive, capable of detecting 10 copies of HTLV-3 or HTLV-4 pol sequences in a background of 1 μ g of DNA from human peripheral blood lymphocytes (PBL). We tested PBL DNA samples from 40 LGL leukemia patients in the United States and found that all samples were negative for HTLV-3 or HTLV-4 infection. These results suggest that HTLV-3 and HTLV-4 are not the causative agent of LGL leukemia.