Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation.

The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.

Sodium salicylate reduces the level of GABAB receptors in the rat's inferior colliculus.

Previous studies have indicated that sodium salicylate (SS) can cause hearing abnormalities through affecting the central auditory system. In order to understand central effects of the drug, we examined how a single intraperitoneal injection of the drug changed the level of subunits of the type-B γ-aminobutyric acid receptor (GABAB receptor) in the rat's inferior colliculus (IC). Immunohistochemical and western blotting experiments were conducted three hours following a drug injection, as previous studies indicated that a tinnitus-like behavior could be reliably induced in rats within this time period. Results revealed that both subunits of the receptor, GABABR1 and GABABR2, reduced their level over the entire area of the IC. Such a reduction was observed in both cell body and neuropil regions. In contrast, no changes were observed in other brain structures such as the cerebellum. Thus, a coincidence existed between a structure-specific reduction in the level of GABAB receptor subunits in the IC and the presence of a tinnitus-like behavior. This coincidence likely suggests that a reduction in the level of GABAB receptor subunits was involved in the generation of a tinnitus-like behavior and/or used by the nervous system to restore normal hearing following application of SS.

Organization of the Rudimentary Wing Locus in DROSOPHILA MELANOGASTER. I. the Isolation and Partial Characterization of Mutants Induced with Ethyl Methanesulfonate, Icr-170 and X Rays.

New rudimentary (r) mutants have been isolated following mutagenesis with ethyl methanesulfonate (r(LE)), ICR-170 (r(LI)) and X rays (r(LX)). From wing phenotype measurements on homoallelic females, it has been shown that the r(LE) mutant series includes several leaky alleles, as well as alleles that produce moderate and strong r phenotypes. All of the tested r(LI) alleles yielded strong r phenotypes in homoallelic females, whereas the r(LX) series was found to include both moderate and strong alleles. Based on allele complementation for the wing phenotype, it was found that all three mutant series include both complementing and noncomplementing alleles, but the relative frequencies of these two types of alleles differ considerably among the three series. Complementing alleles comprise most of the r(LE) mutant series (19 of 25) and almost one-half of the r(LX) series (five of 12), while only one of 16 r(LI) mutants is a complementing allele. Data from enzyme assays of mutants mostly support the direct correlation of genetic complementation units with the activities of the first three enzymes in the de novo pyrimidine biosynthetic pathway. All of these findings are discussed in light of evidence that these three enzymes are contained within a trienzyme complex in animals. We conclude that the available genetic evidence supports the contention that the trienzyme complex is encoded by a single mRNA.

Social support and long-term recovery from coronary artery surgery: effects on patients and spouses.

Using a longitudinal design, the effect of social support on recovery from coronary bypass surgery was examined in 155 patients and 103 of their spouses. Perception of the availability of 5 types of social support was relatively stable from preoperation to 1 year after surgery and was significantly related to emotional and functional outcomes. Of the 5 types of support measured, only esteem support was significantly and consistently related to outcomes for patients and spouses. This relationship was strongest within-time, and across-time relationships effects were weaker. Spouse's perception of support was related to patient outcomes, controlling for patient perceptions of support. Results suggest that perception of esteem support may be the most salient type of support related to feelings of well-being during and after an acute health-care event. In addition, perception of social support may be characterized by stable individual differences.

Procedural distress in critical care settings.

The diagnostic and treatment procedures experienced by critically ill patients are major sources of procedural distress. Procedural distress is defined broadly as unpleasant physical sensations and negative psychological states associated with specific diagnostic or treatment procedures. Although research in this area is limited by small sample sizes, findings suggest that mechanical ventilation is a particularly difficult procedure to experience, especially endotracheal suctioning and the weaning process. Interventions to reduce distress should focus on the preparation of patients for distress, the identification of procedural distress, and appropriate interventions for specific procedures.

The level and distribution of the GABA(B)R2 receptor subunit in the rat's central auditory system.

The GABA(B) receptor is important for the function of auditory neurons. We used Western blotting and immunohistochemical methods to examine the level and localization of GABA(B)R2, a required subunit of a functional GABA(B) receptor, in the rat's central auditory system. Results revealed that this subunit was expressed throughout the auditory system with the level being high in the layers I-V of the auditory cortex, medial geniculate nucleus, dorsomedial and lateral parts of the inferior colliculus, and the molecular and fusiform cell layers of the dorsal cochlear nucleus. Labeled cell bodies were found in all the areas showing immunoreactivity. Neuropil labeling was strong in areas with high overall levels of immunoreactivity. Regional distributions of the receptor subunit revealed clear boundaries of some auditory subnuclei including the dorsal and ventral cochlear nuclei and the lateral superior olivary nucleus. Differences in immunoreactivity were found between the central nucleus and the dorsal cortex of the inferior colliculus and between the dorsal and ventral parts of the ventral nucleus of the lateral lemniscus, although no clear boundaries were observed. No differences in immunoreactivity were found between the core and the belt areas of the auditory cortex and among the subdivisions of the medial geniculate nucleus. The regional distribution of the receptor subunit in auditory structures is consistent with inputs to these structures and the cellular localization of the receptor in auditory neurons supports the contribution of the GABA(B) receptor to synaptic responses in these neurons.

Drug profiles: maximizing therapeutic effectiveness.

Major cardiac events are inevitably followed with a pharmacologic plan of therapy for cardiac patients. Careful assessment of the patient's drug regimen is an important aspect of cardiovascular nursing practice. Such assessment will reveal implications for education, compliance counseling, and side effect evaluation. A thorough drug history should include information about both prescription and nonprescription drug use. Assessment for adherence is improved by using supportive, open-ended questions. Assessment for side effects that affect quality of life is important, particularly in the area of sexual dysfunction. Sexual function should be assessed before beginning cardiovascular drug therapy and monitored for changes during treatment. Using principles of chronopharmacology, or therapy based on the time-dependent effects of drugs, nurses can schedule cardiovascular medications and evaluate patient responses in relation to circadian variability in vulnerability and symptoms. Assessment for ease of self-management of the drug regimen should be a particular focus with non-English-speaking patients and those with complex or costly drug regimens.

alpha-, beta-, and gamma-Tubulin polymerization in response to DNA damage.

Microtubules provide structural support for a cell and play key roles in cell motility, mitosis, and meiosis. They are also the targets of several anticancer agents, indicating their importance in maintaining cell viability. We have investigated the possibility that alterations in microtubule structure and tubulin polymerization may be part of the cellular response to DNA damage. In this report, we find that gamma-radiation stimulates the production and polymerization of alpha-, beta-, and gamma- tubulin in hematopoeitic cell lines (Ramos, DP16), leading to visible changes in microtubule structures. We have found that this microtubule reorganization can be prevented by caffeine, a drug that concomitantly inhibits DNA damage-induced cell cycle arrest and apoptosis. Our results support the idea that microtubule polymerization is an important facet of the mammalian response to DNA damage.

The Dhod locus of Drosophila: mutations and interrelationships with other loci controlling de novo pyrimidine biosynthesis.

Mutations at the Dhod locus have been isolated following ethylmethanesulfonate mutagenesis. These mutants express those phenotypes common to other mutations of the de novo pyrimidine pathway: specific wing and leg defects and female sterility. Dihydroorotate dehydrogenase activity is severely reduced in all Dhod mutants, whereas levels of the other pathway enzymes are largely unaffected. The twelve Dhod mutations described here comprise a single complementation group. All of these mutations are nonlethal and the collection includes apparent amorphic as well as hypomorphic alleles. These results are discussed relative to the properties of the complex loci that encode the other steps of de novo pyrimidine biosynthesis.

Abundance of cyclin B1 regulates gamma-radiation-induced apoptosis.

gamma-Radiation is a potent inducer of apoptosis. There are multiple pathways regulating DNA damage-induced apoptosis, and we set out to identify novel mechanisms regulating gamma-radiation-induced apoptosis in hematopoietic cells. In this report, we present data implicating the cyclin B1 protein as a regulator of apoptotic fate following DNA damage. Cyclin B1 is the regulatory subunit of the cdc2 serine/threonine kinase, and accumulation of cyclin B1 in late G2 phase of the cell cycle is a prerequisite for mitotic initiation in mammalian cells. We find that abundance of the cyclin B1 protein rapidly increases in several mouse and human hematopoietic cells (Ramos, DP16, HL60, thymocytes) undergoing gamma-radiation-induced apoptosis. Cyclin B1 accumulation occurs in all phases of the cell cycle. Antisense inhibition of cyclin B1 accumulation decreases apoptosis, and ectopic cyclin B1 expression is sufficient to induce apoptosis. These observations are consistent with the idea that cyclin B1 is both necessary and sufficient for gamma-radiation-induced apoptosis. (Blood. 2000;95:2645-2650)

Breast cancer in NSW women: a shift in tumour size.

OBJECTIVE: To determine whether there has been an increase in the proportion of small (< 1 cm in size) and localised breast cancers in women aged 50-69 (the group actively recruited to mammographic screening) compared with women aged 40-49. DESIGN: Cases of invasive breast cancer in women aged 40-69 notified to the NSW Central Cancer Registry in 1986, 1989 and 1992 were included. Tumour sizes were determined from histopathology reports. RESULTS: A higher percentage of breast cancers were under 1 cm in size in 1992 (10%) than in 1986 and 1989 (7%). The increase in the percentage of small breast cancers was statistically significant in women aged 50-69 (chi 2 for linear trend, 7.9; P = 0.005) but not in those aged 40-49 (chi 2 for linear trend, 2.5; P = 0.12). Slightly more than half the breast cancers (53%) in 1992 were localised to the breast, representing an increase from 49% in both 1986 and 1989. This increase was also statistically significant in women aged 50-69 (chi 2 for linear trend, 3.9; P = 0.05) but not in those aged 40-49 (chi 2 for linear trend, 1.4; P = 0.24). CONCLUSIONS: Breast cancers in 1986, 1989 and 1992 showed a moderately strong shift to smaller tumours and localised disease in women aged 50-69. As women of this age group were targeted by mammographic screening, the widespread availability of mammography may explain this shift.

Patient perceptions of quality of life after coronary artery surgery: was it worth it?

Quality of life and perceptions of the consequences of surgery were examined in 155 individuals having coronary bypass surgery. One year after surgery, subjects believing surgery was worth it because of functional improvement (n = 64) had more positive scores on subjective indicators of life satisfaction and mood than those believing surgery was worth it because it saved them from death (n = 62) or those who were not sure surgery was worth it (n = 23). Differences in perceptions of quality of life between the two groups who believed surgery was worth it are discussed in terms of focus of attention. Individuals who perceive improved functional ability may focus on concrete outcomes of surgery, whereas those who interpret the benefit of surgery in light of the alternative of death may focus their attention on affective aspects of recovery. Findings emphasize the need for using a multidimensional approach to studying quality of life.