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PubMed2005

14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity.

Individual members of the RGK family of Ras-related GTPases, which comprise Rad, Gem/Kir, Rem and Rem2, have been implicated in important functions such as the regulation of voltage-gated calcium channel activity and remodeling of cell shape. The GTPase Kir/Gem inhibits the activity of calcium channels by interacting with the beta-subunit and also regulates cytoskeleton dynamics by inhibiting the Rho-Rho kinase pathway. In addition, Kir/Gem interacts with 14-3-3 and calmodulin, but the significance of this interaction on Kir/Gem function is poorly understood. Here, we present a comprehensive analysis of the binding of 14-3-3 and calmodulin to Kir/Gem. We show that 14-3-3, in conjunction with calmodulin, regulates the subcellular distribution of Kir/Gem between the cytoplasm and the nucleus. In addition, 14-3-3 and calmodulin binding modulate Kir/Gem-mediated cell shape remodeling and downregulation of calcium channel activity. Competition experiments show that binding of 14-3-3, calmodulin and calcium channel beta-subunits to Kir/Gem is mutually exclusive, providing a rationale for the observed regulatory effects of 14-3-3 and calmodulin on Kir/Gem localization and function.

14-3-3 Proteins↗
PubMed2001

Immunolocalization of cytoplasmic dynein and dynactin subunits in cultured macrophages: enrichment on early endocytic organelles.

Cytoplasmic dyneins and their cofactor, dynactin, work together to mediate the movement of numerous cargo organelles toward the minus-ends of microtubules. In many cases, there is compelling evidence that dynactin functions in part to attach dyneins to cargo organelles, but this may not always be the case. We have localized three dynactin subunits (Arp1, p62 and p150(Glued)) and two subunits of conventional cytoplasmic dynein (dynein intermediate chain and dynein heavy chain 1) in murine macrophages using immunogold labeling of thawed cryosections. Using stereological techniques, we have quantified the relative distributions of each of these subunits on specific membrane organelles to generate a comprehensive analysis of the distribution of these proteins in a single cell type. Our results show that each of the subunits tested exhibits the same distribution with respect to different membrane organelles, with highest levels present on early endosomes, and lower levels present on later endocytic organelles, the mitochondrial outer membrane, the plasma membrane and vesicles in the Golgi region. An additional pool of punctate dynactin labeling was detected in the cell periphery, in the absence of dynein labeling. Even when examined closely, membrane organelles could not be detected in association with these dynactin-positive sites; however, double labeling with anti-tubulin antibody revealed that at least some of these sites represent the ends of microtubules. The similarities among the labeling profiles with respect to membrane organelles suggest that dynein and dynactin bind to membrane organelles as an obligate unit. In contrast, our results show that dynactin can associate with microtubule ends in the absence of dynein, perhaps providing sites for subsequent organelle and dynein association to form a functional motility complex.

Animals↗
PubMed2006

Effects of acclimation temperature and cadmium exposure on cellular energy budgets in the marine mollusk Crassostrea virginica: linking cellular and mitochondrial responses.

In order to understand the role of metabolic regulation in environmental stress tolerance, a comprehensive analysis of demand-side effects (i.e. changes in energy demands for basal maintenance) and supply-side effects (i.e. metabolic capacity to provide ATP to cover the energy demand) of environmental stressors is required. We have studied the effects of temperature (12, 20 and 28 degrees C) and exposure to a trace metal, cadmium (50 microg l(-1)), on the cellular energy budget of a model marine poikilotherm, Crassostrea virginica (eastern oysters), using oxygen demand for ATP turnover, protein synthesis, mitochondrial proton leak and non-mitochondrial respiration in isolated gill and hepatopancreas cells as demand-side endpoints and mitochondrial oxidation capacity, abundance and fractional volume as supply-side endpoints. Cadmium exposure and high acclimation temperatures resulted in a strong increase of oxygen demand in gill and hepatopancreas cells of oysters. Cd-induced increases in cellular energy demand were significant at 12 and 20 degrees C but not at 28 degrees C, possibly indicating a metabolic capacity limitation at the highest temperature. Elevated cellular demand in cells from Cd-exposed oysters was associated with a 2-6-fold increase in protein synthesis and, at cold acclimation temperatures, with a 1.5-fold elevated mitochondrial proton leak. Cellular aerobic capacity, as indicated by mitochondrial oxidation capacity, abundance and volume, did not increase in parallel to compensate for the elevated energy demand. Mitochondrial oxidation capacity was reduced in 28 degrees C-acclimated oysters, and mitochondrial abundance decreased in Cd-exposed oysters, with a stronger decrease (by 20-24%) in warm-acclimated oysters compared with cold-acclimated ones (by 8-13%). These data provide a mechanistic basis for synergism between temperature and cadmium stress on metabolism of marine poikilotherms. Exposure to combined temperature and cadmium stress may result in a strong energy deficiency due to the elevated energy demand on one hand and a reduced mitochondrial capacity to cover this demand on the other hand, which may have important implications for surviving seasonally and/or globally elevated temperatures in polluted estuaries.

Acclimatization↗
PubMed2004

Production of secondary metabolites by freshwater cyanobacteria.

Freshwater cyanobacteria produce lethal toxins such as microcystins and anatoxins. During the purification of microcystins in bloom samples we found that a toxic cyanobacterium produced not only microcystins but also other types-peptides in early 1990. Since then we have isolated approximately thirty peptides from freshwater cyanobacteria. In this manuscript we focused on the following topics concerning the isolated peptides: 1) how to isolate desired compounds and to determine their structures, 2) structural classification of isolated compounds, 3) isolation of similar peptides from laboratory strains and bloom materials, 4) structurally related peptides from freshwater and marine origins, 5) beta-amino acid containing peptides from cyanobacteria, 6) comprehensive analysis system for the biosynthetic study of peptides produced by cyanobacteria, 7) biological activities of isolated compounds.

Amino Acids↗
PubMed1987

Variation in repeat rates between 18 radiology departments.

A comprehensive analysis of repeat rates has been obtained from an observational study of radiological practice in diagnostic X-ray departments throughout Wales. Interdepartmental and intradepartmental repeat rates are investigated for chest, abdomen, pelvis, sinus, lumbar spine, cervical spine and intravenous pyelographic examinations. The confounding effects upon observed repeat rates of trainee practitioners and automatic exposure control devices are also considered. The overall proportions of total film cost and patient exposure attributable to repeat radiographs are estimated to be 10% and 14% respectively.

Hospital Departments↗
PubMed2005

An optimized isolation and labeling platform for accurate microRNA expression profiling.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in both plants and animals. miRNA genes have been implicated in a variety of important biological processes, including development, differentiation, apoptosis, fat metabolism, viral infection, and cancer. Similar to protein-coding messenger RNAs, miRNA expression varies between tissues and developmental states. To acquire a better understanding of global miRNA expression in tissues and cells, we have developed isolation, labeling, and array procedures to measure the relative abundance of all of the known human mature miRNAs. The method relies on rapid isolation of RNA species smaller than ~40 nucleotides (nt), direct and homogenous enzymatic labeling of the mature miRNAs with amine modified ribonucleotides, and hybridization to antisense DNA oligonucleotide probes. A thorough performance study showed that this miRNA microarray system can detect subfemtomole amounts of individual miRNAs from <1 mug of total RNA, with 98% correlation between independent replicates. The system has been applied to compare the global miRNA expression profiles in 26 different normal human tissues. This comprehensive analysis identified miRNAs that are preferentially expressed in one or a few related tissues and revealed that human adult tissues have unique miRNA profiles. This implicates miRNAs as important components of tissue development and differentiation. Taken together, these results emphasize the immense potential of microarrays for sensitive and high-throughput analysis of miRNA expression in normal and disease states.

Adult↗
PubMed2007

Protection of psbAII transcript from ribonuclease degradation in vitro by DnaK2 and DnaJ2 chaperones of the cyanobacterium Synechococcus elongatus PCC 7942.

Three dnaK and four dnaJ genes have been identified in the genome of cyanobacterium Synechococcus elongatus PCC 7942. Our comprehensive analysis of yeast two-hybrid screening revealed a specific interaction among DnaK2, DnaJ2, and RNase E, an essential endoribonuclease. We examined the effects of DnaK2 and DnaJ2 on RNase E activity by monitoring the digestion of psbAII transcript in vitro. The addition of DnaK2 and DnaJ2 obviously inhibited RNase E activity in an ATP-dependent manner. These results suggest that DnaK2 and DnaJ2 are involved in RNA degradation through interaction with RNase E.

Bacterial Proteins↗
PubMed2005

A series of crystal structures of a meta-cleavage product hydrolase from Pseudomonas fluorescens IP01 (CumD) complexed with various cleavage products.

Meta-cleavage product hydrolase (MCP-hydrolase) is one of the key enzymes in the microbial degradation of aromatic compounds. MCP-hydrolase produces 2-hydroxypenta-2,4-dienoate and various organic acids, according to the C6 substituent of the substrate. Comprehensive analysis of the substrate specificity of the MCP-hydrolase from Pseudomonas fluorescens IP01 (CumD) was carried out by determining the kinetic parameters for nine substrates and crystal structures complexed with eight cleavage products. CumD preferred substrates with long non-branched C6 substituents, but did not effectively hydrolyze a substrate with a phenyl group. Superimposition of the complex structures indicated that benzoate was bound in a significantly different direction than other aliphatic cleavage products. The directions of the bound organic acids appeared to be related with the k(cat) values of the corresponding substrates. The Ile139 and Trp143 residues on helix alpha4 appeared to cause steric hindrance with the aromatic ring of the substrate, which hampers base-catalyzed attack by water.

Crystallography, X-Ray↗
PubMed2004

Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals.

We developed a DNA microarray to evaluate the estrogen activity of natural estrogens and industrial chemicals. Using MCF-7 cells, we conducted a comprehensive analysis of estrogen-responsive genes among approximately 20,000 human genes. On the basis of reproducible and reliable responses of the genes to estrogen, we selected 172 genes to be used for developing a customized DNA microarray. Using this DNA microarray, we examined estrogen activity among natural estrogens (17beta-estradiol, estriol, estrone, genistein), industrial chemicals (diethylstilbestrol, bisphenol A, nonylphenol, methoxychlor), and dioxin. We obtained results identical to those for other bioassays that are used for detecting estrogen activity. On the basis of statistical correlations analysis, these bioassays have shown more sensitivity for dioxin and methoxychlor.

Biological Assay↗
PubMed2001

Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures.

The efficacy of the atypical antipsychotic risperidone was evaluated in the treatment of aberrant behavior (e.g., aggression, self-injury) in 20 individuals with developmental disabilities. A double-blind, crossover design was used to compare risperidone with placebo in a 22-week trial with a 6-month follow-up phase. Based on a 50% reduction in mean Aberrant Behavior Checklist--Community total scores, 50% of the participants were identified as responders. Naturalistic observations of a subset of five individuals showed that for 4 out of 5 participants, risperidone was effective in reducing aberrant behavior. Side effects included weight gain (84% of participants) and sedation (40% of participants). The advantages of conducting a comprehensive analysis of the effects of medication on aberrant behavior are discussed.

Adolescent↗
PubMed2002

Gene expression alterations in human prostate cancer.

Prostate cancer is a disease with a great degree of variation in biological aggressiveness and clinical prognosis. Although more than 30% of the older-aged male population develops prostate cancer, defined by histologic examination, a large number of these cases does not reach the stage displaying clinical symptoms. Among those patients with clinical prostate cancer, only a fraction of cases demonstrate life-threatening biological aggressiveness. Parallel to the clinical complexity of this disease, abnormalities in the prostate cancer genome have been reported in 21 of 23 pairs of human chromosomes, but none can be accountable for the dominant event in the development of prostate cancer. In order to understand the genetic nature of this disease, a comprehensive analysis of its gene expression patterns is needed. This article will review several recent publications in the area of gene expression analysis using microarray technology. I will discuss some of our findings in the area of gene expression alteration in benign prostate tissue adjacent to prostate cancer. The implication of these studies in potential clinical application will be explored.

Gene Expression Profiling↗
PubMed2004

Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model.

UNLABELLED: The role of androgen receptor-mediated androgen action on bone was investigated in testicular feminized male (Tfm) mice. Cortical bone was found to be unresponsive to testosterone (T) in orchidectomized Tfm mice, whereas cortical thickness as well as trabecular BMD and structure were fully maintained by T in the corresponding Tabby control mice. These data show an essential role for androgen receptor-mediated androgen action in periosteal bone formation. INTRODUCTION: Androgens can affect the male skeleton both directly-through activation of the androgen receptor (AR)-and indirectly-through stimulation of estrogen receptors after aromatization. We assessed the importance of AR-mediated androgen action on bone in a mouse model of androgen resistance. MATERIALS AND METHODS: Eight-week-old androgen-resistant testicular feminized male (Tfm) and Tabby control mice were orchidectomized (ORX) and treated for 4 weeks with a slow-release testosterone (T) pellet (delivering 167 microg/day) or a placebo pellet. A comprehensive analysis of the skeletal effects of androgen deficiency and replacement was performed using histomorphometry, QCT, and biochemical assessment of bone turnover. RESULTS: As expected, T increased trabecular BMD, volume, number, and width in ORX Tabby mice. In ORX Tfm mice, however, T had less effect on trabecular BMD and no effect on trabecular bone structure. T action on trabecular bone was associated with opposite changes in bone turnover: trabecular and endocortical bone turnover and serum levels of osteocalcin were all reduced by T in ORX Tabby mice, but not in ORX Tfm mice. T also increased cortical thickness (+16%), area, and density in ORX Tabby mice, but not in Tfm mice, resulting in greater bone strength in the Tabby control strain. The positive effects of T on cortical bone reflected a stimulatory effect on periosteal bone formation (+137%), which was again absent in Tfm mice. CONCLUSIONS: These data show that, in male mice, AR-mediated T action is essential for periosteal bone formation and contributes to trabecular bone maintenance.

Androgen-Insensitivity Syndrome↗
PubMed2006

Paricalcitol [19-nor-1,25-(OH)2D2] in the treatment of experimental renal bone disease.

UNLABELLED: Paricalcitol is a less hypercalcemic vitamin D analog that has been shown to suppress secondary hyperparathyroidism and to prevent the associated histomorphometric changes in bone. In this study, we show that paricalcitol also ameliorates the renal insufficiency-induced loss of bone mineral and the mechanical competence of bone. INTRODUCTION: Renal bone disease is a common consequence of chronic renal insufficiency and the associated secondary hyperparathyroidism (SH). Paricalcitol [19-nor-1,25(OH)(2)D(2)] has been shown to ameliorate SH and prevent renal failure-induced histomorphometric changes in bone with minimal calcemic and phosphatemic activity. However, information about its efficacy on restoration of bone structural strength is lacking. In this study, we explored the effects of paricalcitol treatment on bone structure and strength in a model of advanced renal disease. MATERIALS AND METHODS: Forty-five 8-week-old rats were randomly assigned to either surgical 5/6 nephrectomy (NTX) or Sham-operation. After a 15-week postoperative disease progression period, the NTX rats were further allocated to uremic control (NTX) and treatment (NTX + paricalcitol) groups, the latter of which received paricalcitol for the subsequent 12 weeks. After 27 weeks, the animals were killed, plasma samples were collected, and both femora were excised for comprehensive analysis of the femoral neck and midshaft (pQCT and biomechanical testing). RESULTS: High mortality that exceeded 30% was observed in both NTX groups. NTX induced over a 13-fold increase in plasma PTH, whereas this increase was only 5-fold after paricalcitol treatment. At the femoral neck, NTX was associated with an 8.1% decrease (p < 0.05) in vBMD and a 16% decrease in breaking load (p < 0.05) compared with the Sham group, whereas paricalcitol treatment completely prevented these changes. At the femoral midshaft, the NTX resulted in a 6.6% decrease in cortical BMD (p < 0.01 versus Sham), and this change was also prevented by paricalcitol. CONCLUSIONS: Paricalcitol administration prevented renal insufficiency-associated decreases in BMD in the femoral neck and the femoral midshaft and restored bone strength in the femoral neck. Therefore, paricalcitol can efficiently ameliorate renal insufficiency-induced loss of bone mineral and mechanical competence of bone.

Animals↗
PubMed2003

The bone gain induced by exercise in puberty is not preserved through a virtually life-long deconditioning: a randomized controlled experimental study in male rats.

To investigate the controversial issue whether exercise-induced positive effects on bone can be maintained after cessation of exercise, 100 5-week-old male Sprague-Dawley rats were used to assess the effects of long-term exercise (EX, treadmill running) and subsequent deconditioning (DC, free cage activity) on the femoral neck and femoral midshaft. At entry, the rats were randomly assigned into eight groups: four control groups (C14, C28, C42, and C56), and four exercise groups (EX, EX + DC14, EX + DC28, and EX + DC42). Rats in the exercise groups were first subjected to a 14-week period of progressively intensifying running, after which the rats of group EX were killed and the remaining exercise groups (EX + DC14, EX + DC28, and EX + DC42) were allowed to move freely in their cages for a subsequent deconditioning period of 14, 28, or 42 weeks, whereas control rats were kept free in their cages for the entire study period (0-56 weeks) and killed with their respective exercise group. At each time point, a comprehensive analysis of the femoral neck and midshaft characteristics (peripheral quantitative computed tomography analysis and fracture load [Fmax]) was performed. In comparison with their age-matched controls, 14 weeks of treadmill training resulted in significant (p < 0.05) increases in all measured femoral neck parameters of the growing male rats (i.e., +25% in total cross-sectional area [tCSA], +28% in total bone mineral content [tBMC], +11% in total bone mineral density [tBMD], and +30% in Fmax). On the contrary, no exercise-induced positive effects were seen in femoral midshaft. The exercise-induced benefits in the femoral neck were partially maintained during the deconditioning period of 14 weeks, the tCSA being + 17%, tBMC + 18% (both p < 0.05), and the Fmax + 11% (p = 0.066) higher in the exercised group than control group. However, after 42 weeks of deconditioning, these benefits were eventually lost. In conclusion, exercise through the period of the fastest skeletal growth results in significant improvements in size, mineral mass, and strength of the femoral neck of male rats. However, these exercise-induced bone benefits are eventually lost if exercise is completely ceased, and thus, continued training is probably needed to maintain the positive effects of youth exercise into adulthood. Further studies should focus on assessing the minimal level of activity needed to maintain the exercise-induced bone gains.

Animals↗
PubMed2003

Femoral neck response to exercise and subsequent deconditioning in young and adult rats.

UNLABELLED: Aged bones have been considered to have reduced capacity to respond to changes in incident loading. By subjecting young and adult rats to increased loading and subsequent deconditioning, we observed quantitatively similar adaptive responses of bone in these two groups, but young skeletons adapted primarily through geometric changes and adult bones through increased volumetric density. Loss of the exercise-induced bone benefits did not depend on age. INTRODUCTION: Aging has been shown to decrease the sensitivity of the mechanosensory cells of bones to loading-induced stimuli, presumably resulting in not only reduced capacity but also different adaptive mechanism of the aged skeleton to altered loading, as well as poorer capacity to preserve exercise-induced bone benefits. MATERIALS AND METHODS: Fifty young (5-week-old) and 50 adult (33-week-old) male rats were randomized into control and exercise (+deconditioning) groups. After a 14-week progressively intensified running program, one-half of the exercised rats (both young and adult) were killed, and the remaining rats underwent subsequent 14-week period of deconditioning (free cage activity). A comprehensive analysis of the femoral neck was performed using peripheral quantitative computed tomography and mechanical testing. RESULTS: In comparison with the controls, both young and adult exercised rats had significant increases in almost all measured parameters: +25% (p < 0.001) and +10% (not significant [NS]) in the cross-sectional area; +28% (p < 0.001) and +18% (p < 0.001) in bone mineral content; +11% (p < 0.05) and +23% (p < 0.001) in bone mineral density; and +30% (p < 0.01) and +28% (p < 0.01) in the breaking load, respectively. The skeletal responses were not statistically different between the young and adult rats. After the 14-week period of deconditioning, the corresponding exercised-to-controls differences were +17% (p < 0.05) and +10% (NS), +18% (p < 0.05) and +13% (p < 0.05), +2% (NS) and +2% (NS), and +11% (NS) and +6% (NS), respectively. Again, the response differences were not significant between the age groups. CONCLUSION: Quantitatively, the capacity of the young and adult skeleton to adapt to increased loading was similar, but the adaptive mechanisms appeared different: growing bones seemed to primarily display geometric changes (increase in bone size), whereas the adult skeleton responded mainly through an increase in density. Despite this apparent difference in the adaptive mechanism, aging did not modulate the ability of the skeleton to preserve the exercise-induced bone gain, because the bone loss was similar in the young and adult rats after cessation of training.

Aging↗
PubMed2002

Polarization optimization in the interference of four umbrellalike symmetric beams for making three-dimensional periodic microstructures.

A systematic and comprehensive analysis of the interference of four umbrellalike beams (lFUB) is provided based on the reciprocal space theory. The concept of pattern contrast is extended to the case of the IFUB, and it is indicated that a uniform contrast for all the interference terms can be obtained by properly choosing the beam ratio and the polarization of each beam. Different polarization combinations, including linear light and linear light, circular light and circular light, and linear light and circular light, have been discussed for the purpose of maximum uniform contrast. It is shown that the use of circular light may generally improve the uniform contrast. This study may lay a theoretical foundation for holographic fabrication of three-dimensional (3D) periodic microstructures, such as simple cubic, body-centered cubic, face-centered cubic, or trigonal lattice.

Journal Article↗
PubMed2005

Scanning near-field optical microscopy as a tool for the characterization of multimode interference devices.

We report the scanning near-field optical microscopy (SNOM) characterization of a 4 x 4 multimode interference (MMI) device working at a wavelength of 1.55 microm and designed for astronomical signal recombination. A comprehensive analysis of the mapped propagating field is presented. We compare SNOM measurements with beam-propagation-method simulations and thus are able to determine the MMI structure's refractive-index contrast and show that the measured value is higher than the expected value. Further investigation allows us to demonstrate that good care must be taken with the refractive-index profile used in simulation when one deals with low-index contrast structures. We show evidence that a step-index contrast is not suitable for adequate simulation of our structure and present a model that permits good agreement between measured and simulated propagating fields.

Journal Article↗
PubMed2006

Picosecond-pulse wavelength conversion based on cascaded second-harmonic generation-difference frequency generation in a periodically poled lithium niobate waveguide.

The wavelength conversion of picosecond optical pulses based on the cascaded second-harmonic generation-difference-frequency generation process in a MgO-doped periodically poled lithium niobate waveguide is studied both experimentally and theoretically. In the experiments, the picosecond pulses are generated from a 40 GHz mode-locked fiber laser and two tunable filters, with which the lasing wavelength can be tuned from 1530 to 1570 nm, and the pulse width can be tuned from 2 to 7 ps. New-frequency pulses, i.e., converted pulses, are generated when the picosecond pulse train and a cw wave interact in the waveguide. The conversion characteristics are systematically investigated when the pulsed and cw waves are alternatively taken as the pump at the quasi-phase-matching wavelength of the device. In particular, the conversion dependences on input pulse width, average power, and pump wavelength are examined quantitatively. Based on the temporal and spectral characteristics of wavelength conversion, a comprehensive analysis on conversion efficiency is presented. The simulation results are in good agreement with the measured data.

Journal Article↗

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