Proxy reporting of health-related quality of life for people with dementia: a psychometric solution.

BACKGROUND: The growing move towards personalised health and social care systems means that every effort needs to be made to generate patient-reported outcome data. However, the deteriorating nature of dementia can make it difficult for people with dementia to complete self-reported questionnaires and it is often necessary to rely on a family member (proxy) to report on their behalf. There is little evidence to guide how the difference between self- and proxy-reports of health reported quality of life (HRQL) in dementia can be interpreted. METHODS: We recruited people with dementia and their family carers from 78 memory Assessment Services in the UK. We used Rasch measurement methods to investigate whether a HRQL questionnaire known as DEMQOL (self-reported by the person with dementia) and DEMQOL-Proxy (proxy-reported by a family carer) can be placed on the same continuum and whether a revised scoring algorithm, based on this equated model, can be developed that takes account of the relationship between self- and proxy-reports. RESULTS: In a sample of 1434 patients and 1030 carers, our findings supported equating DEMQOL/DEMQOL-Proxy (overall fit to the model; no mis-fitting items) after addressing specific issues (eight disordered items requiring re-scoring, four pairs locally dependent items, and five items showing DIF). Cross walk tables have been produced. CONCLUSIONS: We have established for the first time that DEMQOL and DEMQOL-Proxy can be placed on the same continuum and that patients and carer proxies are reporting on the same construct when they complete these questionnaires. Where possible both DEMQOL and DEMQOL-Proxy should still be administered together, using the improved scoring algorithm reported here. Where only DEMQOL-Proxy is available, the cross walk tables provide an estimate of DEMQOL for a particular person from their DEMQOL-Proxy score.

Volumetric bone mineral density of the spine predicts mortality in African-American men with type 2 diabetes.

The study showed that in African-American men with type 2 diabetes mellitus (T2D), vertebral volumetric bone mineral density (vBMD) predicts all-cause mortality, independent of other risk factors for death. INTRODUCTION: Compared to European Americans, African Americans have lower rates of osteoporosis and higher rates of T2D. The relationships between BMD and fractures with mortality are unknown in this population. The aim of this study was to determine relationships between vertebral fractures and vertebral vBMD and mortality in African Americans with T2D. METHODS: Associations between vertebral fractures and vBMD with all-cause mortality were examined in 675 participants with T2D (391 women and 284 men) in the African American-Diabetes Heart Study (AA-DHS). Lumbar and thoracic vBMD were measured using quantitative computed tomography (QCT). Vertebral fractures were assessed on sagittal CT images. Associations of vertebral fractures and vBMD with all-cause mortality were determined in sex-stratified analyses and in the full sample. Covariates in a minimally adjusted model included age, sex, BMI, smoking, and alcohol use; the full model was adjusted for those variables plus cardiovascular disease, hypertension, coronary artery calcified plaque, hormone replacement therapy (women), African ancestry proportion, and eGFR. RESULTS: After mean 7.6 ± 1.8-year follow-up, 59 (15.1%) of women and 58 (20.4%) of men died. In men, vBMD was inversely associated with mortality in the fully adjusted model: lumbar hazard ratio (HR) per standard deviation (SD) = 0.70 (95% CI 0.52-0.95, p = 0.02) and thoracic HR per SD = 0.71 (95% CI 0.54-0.92, p = 0.01). Only trends toward association between vBMD and mortality were observed in the combined sample of men and women, as significant associations were absent in women. Vertebral fractures were not associated with mortality in either sex. CONCLUSIONS: Lower vBMD was associated with increased all-cause mortality in African-American men with T2D, independent of other risk factors for mortality including subclinical atherosclerosis.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

On the mechanism of gas adsorption for pristine, defective and functionalized graphene.

Defects are no longer deemed an adverse aspect of graphene. Contrarily, they can pave ways of extending the applicability of graphene. Herein, we discuss the effects of three types of defects in graphene including carbon deficiency, adatom (single Fe) dopants and the introduction of functional groups (carbonyl, ether group) on the NO2 gas adsorption via density functional theory methods. We have observed that introducing Fe on graphene can enhance the NO2 adsorption process. Adsorption energy calculations suggest that the enhancement in NO2 adsorption is more profound for Fe-doped mono- and tetra-vacant graphene than that for Fe doped bi- and tri-vacant graphene, which is favourable for NO2 gas capture applications. The unsaturated carbons in defected graphene as well as the oxygenated functional groups are very active to attract NO2 molecules. However, though the gas binding strength was not as high as the that found in the Fe-doped graphene structure, the relatively low NO2 gas adsorption energy is suitable for the practical gas sensors both for gas sensitivity and the sensor recovery rate factor. This theoretical study can potentially be useful for developing adsorption-based applications of graphene.

Maternal and neonatal outcomes for pregnancies before and after gastric bypass surgery.

BACKGROUND: Interaction between maternal obesity, intrauterine environment and adverse clinical outcomes of newborns has been described. METHODS: Using statewide birth certificate data, this retrospective, matched-control cohort study compared paired birth weights and complications of infants born to women before and after Roux-en-Y gastric bypass surgery (RYGB) and to matched obese non-operated women in several different groups. Women who had given birth to a child before and after RYGB (group 1; n=295 matches) and women with pregnancies after RYGB (group 2; n=764 matches) were matched to non-operated women based on age, body mass index (BMI) prior to both pregnancy and RYGB, mother's race, year of mother/s birth, date of infant births and birth order. In addition, birth weights of 13 143 live births before and/or after RYGB of their mothers (n=5819) were compared (group 3). RESULTS: Odds ratios (ORs) for having a large-for-gestational-age (LGA) neonate were significantly less after RYGB than for non-surgical mothers: ORs for groups 1 and 2 were 0.19 (0.08-0.38) and 0.33 (0.21-0.51), respectively. In contrast, ORs in all three groups for risk of having a small for gestational age (SGA) neonate were greater for RYGB mothers compared to non-surgical mothers (ORs were 2.16 (1.00-5.04); 2.16 (1.43-3.32); and 2.25 (1.89-2.69), respectively). Neonatal complications were not different for group 1 RYGB and non-surgical women for the first pregnancy following RYGB. Pregnancy-induced hypertension and gestational diabetes were significantly lower for the first pregnancy of mothers following RYGB compared to matched pregnancies of non-surgical mothers. CONCLUSION: Women who had undergone RYGB not only had lower risk for having an LGA neonate compared to BMI-matched mothers, but also had significantly higher risk for delivering an SGA neonate following RYGB. RYGB women were less likely than non-operated women to have pregnancy-related hypertension and diabetes.

Effect of cell-surface components and metabolites of lactic acid bacteria and probiotic organisms on cytokine production and induction of CD25 expression in human peripheral mononuclear cells.

In the current study, the relative contribution of cell-surface components (CSC) and cell-free supernatants (CFS) in the immuno-modulatory properties of 17 strains of probiotic and lactic acid bacteria (LAB) was assessed. The production of pro- and antiinflammatory cytokines including IL-2, IL-4, IL-10, IL-12 p70, IFN-γ, tumor necrosis factor-α (TNF-α), and transforming growth factor-ß was measured at different time points after stimulation of buffy coat derived-peripheral blood mononuclear cells (PBMC) from healthy donors with CSC and CFS of probiotic and LAB. Results showed that CSC of probiotic and LAB strains induced production of T helper 1 and 2 type cytokines. Transforming growth factor-ß was stimulated at highest concentrations, followed by IL-10 and TNF-α. The CFS of all tested bacterial strains induced PBMC for significantly high levels of IL-10 secretion compared with unstimulated cells, but the values were less than lipopolysaccharide-stimulated cells. Cytokines due to CFS stimulation showed declined concentration for IL-2, TNF-α, and IL-4, and complete disappearance of IL-12, IFN-γ, and transforming growth factor-ß in the cultured medium at 96 h of incubation. Results of cytokine data demonstrate proinflammatory TNF-α immune responses are mainly directed through cell-surface structures of probiotic and LAB, but antiinflammatory immune responses are mediated both by metabolites and cell-surfaces of these bacteria. The induction of CD4(+)CD25(+) regulatory T cells after stimulation of PBMC with CSC and CFS of probiotic and LAB showed regulatory T cell activity appeared to be influenced both by the CSC and metabolites, but was principally triggered by cell surfaces of probiotic and LAB strains.

The pigeon (Columba livia) model of spontaneous atherosclerosis.

Multiple animal models have been employed to study human atherosclerosis, the principal cause of mortality in the United States. Each model has individual advantages related to specific pathologies. Initiation, the earliest disease phase, is best modeled by the White Carneau (WC-As) pigeon. Atherosclerosis develops spontaneously in the WC-As without either external manipulation or known risk factors. Furthermore, susceptibility is caused by a single gene defect inherited in an autosomal recessive manner. The Show Racer (SR-Ar) pigeon is resistant to atherosclerosis. Breed differences in the biochemistry and metabolism of celiac foci cells have been described. For example, WC-As have lower oxidative metabolism but higher amounts of chondroitin-6-sulfate and nonesterified fatty acids compared with SR-Ar. Gene expression in aortic smooth muscle cells was compared between breeds using representational difference analysis and microarray analysis. Energy metabolism and cellular phenotype were the chief gene expression differences. Glycolysis and synthetic cell types were related to the WC-As but oxidative metabolism and contractile cell types were related to the SR-Ar. Rosiglitazone, a PPARγ agonist, blocked RNA binding motif (RBMS1) expression in WC-As cells. The drug may act through the c-myc oncogene as RBMS1 is a c-myc target. Proteomic tests of aortic smooth muscle cells supported greater glycosylation in the WC-As and a transforming growth factor ß effect in SR-Ar. Unoxidized fatty acids build up in WC-As cells because of their metabolic deficiency, ultimately preventing the contractile phenotype in these cells. The single gene responsible for the disease is likely regulatory in nature.

Rosiglitazone modulates pigeon atherosclerotic lipid accumulation and gene expression in vitro.

Atherosclerosis is a major contributor to the overall United States mortality rate, primarily in the form of heart attacks and stroke. Unlike the human disease, which is believed to be multifactorial, pigeon atherosclerosis is due to a single gene autosomal recessive trait. The White Carneau (WC-As) strain develops atherosclerotic plaques without the presence of known environmental risk factors such as diet and classic predictors such as blood pressure or blood cholesterol levels. With similar parameters, the Show Racer (SR-Ar) is resistant to plaque development. Thiazolidinediones, including rosiglitazone, activate the peroxisome proliferator-activated receptor gamma (PPARγ) raising cellular sensitivity to insulin. The effect of rosiglitazone was evaluated in aortic smooth muscle cells (SMC) from these 2 pigeon breeds. Primary SMC cultures were prepared from WC-As and SR-Ar squabs. Cell monolayers, which achieved confluence in 7 d, were treated with 0 or 4 µM rosiglitazone for 24 h. Cellular lipid accumulation was evaluated by oil red O staining. Control WC-As cells had significantly higher vacuole scores and lipid content than did the SR-Ar control cells. Rosiglitazone treatment decreased WC-As lipid vacuoles significantly compared with the control cells. On the other hand, lipid vacuoles in the treated and untreated SR-Ar cells did not differ significantly. The effect of rosiglitazone on WC-As SMC gene expression was compared with control SMC using representational difference analysis. Significant transcript increases were found for caveolin and RNA binding motif in the control cells compared with the rosiglitazone-treated cells as well as cytochrome p450 family 17 subfamily A polypeptide 1 (CYP171A) in the rosiglitazone-treated cells compared with the control cells. Although rosiglitazone was selected for these experiments because of its role as a PPARγ agonist, it appears that the drug also tempers c-myc expression, as genes related to this second transcription factor were differentially expressed. Both PPARγ and c-myc appear to affect WC-As SMC gene expression, which may relate to disease development, progression, or both.

Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo.

Spontaneous atherosclerosis in the White Carneau (WC-As) pigeon is inherited as a single gene disorder, and its progression closely mirrors the human disease. Representational difference analysis and microarray were used to identify genes that were differentially expressed between the susceptible WC-As and resistant Show Racer (SR-Ar) aortic tissue. The RNA extracted from 1-d-old squab aortas was used to make cDNA for each experiment. Fifty-six unique genes were found using representational difference analysis, with 25 exclusively expressed in the WC-As, 15 exclusive to the SR-Ar, and 16 nonexclusive genes having copy number variation between breeds. Caveolin and ß-actin were expressed in the WC-As, whereas the proteasome maturation protein and the transcription complex CCR4-NOT were exclusive to the SR-Ar. Microarray analysis revealed 48 genes with differential expression. Vascular endothelial growth factor and p53 binding protein were among the 17 genes upregulated in the WC-As. Thirty-one genes were upregulated in the SR-Ar including the transforming growth factor-ß signaling factor SMAD2 and heat shock protein 90. Genes representing several biochemical pathways were distinctly different between breeds. The most striking divergences were in cytoskeletal remodeling, proteasome activity, cellular respiration, and immune response. Actin cytoskeletal remodeling appears to be one of the first differences between susceptible and resistant breeds, lending support to the smooth muscle cell phenotypic reversion hypothesis of human atherogenesis.

Differentially expressed genes in aortic smooth muscle cells from atherosclerosis-susceptible and atherosclerosis-resistant pigeons.

Susceptibility to spontaneous atherosclerosis in the White Carneau (WC-As) pigeon shows autosomal recessive inheritance. Aortic smooth muscle cells (SMC) cultured from susceptible WC-As and resistant Show Racer (SR-Ar) pigeons exhibit developmental and degenerative features corresponding to the respective SMC at atherosclerosis-prone sites in vivo. We used representational difference analysis to identify differentially expressed genes between WC-As and SR-Ar aortic SMC. Total RNA was extracted from cultured primary SMC of each breed, converted to double-stranded cDNA, followed by direct comparison in reciprocal representational difference analysis experiments. Difference products were cloned, sequenced, and identified by BLAST against the chicken genome. Six putative biochemical pathways were distinctly different between breeds with genes involved in energy metabolism and contractility exhibiting the most striking disparity. Genes associated with glycolysis and a synthetic SMC phenotype were expressed in WC-As cells. In contrast, SR-Ar cells expressed genes indicative of oxidative phosphorylation and a contractile SMC phenotype. In WC-As cells, the alternatives of insufficient ATP production limiting contractile function or the lack of functional contractile elements downregulating ATP synthesis cannot be distinguished due to the compressed in vitro versus in vivo developmental time frame. However, the genetic potential for effectively coupling energy production to muscle contraction present in the resistant SR-Ar was lacking in the susceptible WC-As.

Anatomy of the S(1D) + H2 reaction: the dynamics on two new potential energy surfaces from quantum dynamics calculations.

We present exact quantum integral and differential cross sections for the title reaction from a time-dependent wavepacket method which takes account of all Coriolis couplings. We employ two new potential energy surfaces fitted using the double many-body expansion (DMBE) method. The difference between the two surfaces is that for the first the data was extrapolated to the complete basis set limit (CBS) and for the second the data was corrected semi-empirically (SEC). While the DMBE/CBS surface is, on first impressions, regarded as the most accurate, our results show that this surface gives consistent smaller cross section when compared to previous results employing an earlier surface, named Ho after its first author. We also find that the DMBE/CBS surface features an unphysical barrier for contracted H(2) distances which explains the smaller results. The DMBE/SEC surface, which is based on the same data, does not show the same barrier and the results compare much better to previous theoretical results as well as those from experiment. While we find that overall the differential cross sections from the DMBE/SEC surface are forward scattered, which is in line with experiment, the cross sections do not rise steeply enough with decreasing energy showing that this surface is not sufficiently attractive at low energies. We find this is due to a shallow van der Waals well present for the Ho surface but not on the DMBE surfaces.

Energy dependent dynamics of the O(1D) + HCl reaction: a quantum, quasiclassical and statistical study.

The dynamics of the reaction O((1)D) + HCl → ClO + H, OH + Cl has been investigated in detail by means of a time-dependent wave packet (TDWP) method in comparison with quasiclassical trajectory (QCT) and statistical approaches on the ground potential energy surface by Martínez et al. [Phys. Chem. Chem. Phys., 2000, 2, 589]. Fully coupled quantum mechanical (QM) reaction probabilities for high values of the total angular momentum (J≤ 50) are reported for the first time. At the low collision energy regime (E(c)≤ 0.4 eV) the TDWP probabilities are well reproduced by the QCT and statistical results for the ClO forming product channel, but for the OH + Cl arrangement, only QCT probabilities are found to agree with the QM values. The good accordance found between the rigorous statistical models and the dynamical QM and QCT calculations for the O + HCl → ClO + H process underpins the assumption that the reaction pathway leading to ClO is predominantly governed by a complex-forming mechanism. In addition, to further test the statistical character of this reaction channel, the laboratory angular distribution and time-of-flight spectra obtained in a crossed molecular beam study by Balucani et al. [Chem. Phys. Lett. 1991, 180, 34] at a collision energy as high as 0.53 eV have been simulated using the state resolved differential cross section obtained with the statistical approaches yielding a satisfactory agreement with the experimental results. For the other channel, O + HCl → OH + Cl, noticeable differences between the statistical results and those found with the QCT calculation suggest that the dynamics of the reaction are controlled by a direct mechanism. The comparison between the QCT and QM-TDWP results in the whole range of collision energies lends credence to the QCT description of the dynamics of this reaction.

Myocarditis-inducing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart.

Immune interactions in the heart were studied using a murine model of myosin-induced autoimmune myocarditis. A T cell hybridoma specific for mouse cardiac myosin was generated from A/J mice and used to demonstrate that endogenous myosin/I-Ak complexes are constitutively expressed on antigen-presenting cells in the heart. This T cell hybridoma, Seu.5, was used as a functional probe to identify a myocarditis-inducing epitope of cardiac myosin. Overlapping peptides based on the cardiac myosin heavy chain alpha (myhc alpha) sequences were synthesized and tested for their ability to stimulate Seu.5 T cells. One peptide, myhc alpha (325-357) strongly stimulated the Seu.5 T cells, localizing the epitope to this region of the myhc alpha molecule. Using truncated peptides, the epitope was further localized to residues 334-352. The myhc alpha (334-352) peptide strongly induced myocarditis when administered to A/J mice, which was histologically indistinguishable from that induced by myosin. The myhc alpha (334-352) epitope was present in cardiac myosin and not skeletal muscle myosins, providing a biochemical basis for the cardiac specificity of this autoimmune disease. Induction of myocarditis by this epitope was restricted to the myhc alpha isoform and not the myhc beta isoform, suggesting there may be a difference in the efficiency of generating tolerance to these isoforms of cardiac myosin, which are differentially developmentally regulated. The myhc alpha (334-352) epitope bound to purified I-Ak molecules in a similar manner to other I-Ak-restricted immunogenic epitopes, HEL(48-61) and RNase(43-56). Importantly, the myhc alpha (334-352) epitope was able to bind to I-Ak molecules on the surface of antigen-presenting cells in a stable manner. These findings demonstrate that autoantigenic epitopes can behave in a dominant manner and constitutively bind to class II molecules in the target organ in a similar manner to foreign immunogenic epitopes.

Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin.

Mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs.

Integral and differential cross sections for the S(1D)+HD reaction employing the ground adiabatic electronic state.

We present converged quantum mechanical calculations for the title reaction employing a time-dependent wavepacket method. We obtained integral and differential cross sections over an energy range from 0.23 to 0.35 eV total energy as well as product state distributions for both product channels. The excitation functions decrease with energy and point to statistical dynamics as do the cold vibrational distributions and highly inverted rotational distributions. The differential cross sections oscillate strongly with energy for both product channels. Our differential cross sections for both product channels at 2.5 kcal/mol, one of the experimental energies, compare well to the experimental results. The quantum results obtained in this study are similar to what has been found employing QCT methods, implying that the differences between the experimental and theoretical results are due to the potential energy surface or non-adiabatic effects rather than due to quantum effects or the methods employed.

Psoas and Paraspinous Muscle Measurements on Computed Tomography Predict Mortality in European Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations. OBJECTIVES: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D). DESIGN: Single-center observational study. SETTING: Diabetes Heart Study. PARTICIPANTS: 839 European Americans with T2D. METHODS: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015. RESULTS: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p<0.001), psoas muscle index (HR 0.82, p=0.008), and paraspinous muscle density (HR 0.85, p=0.003) were inversely associated with mortality. Paraspinous muscle index was not significantly associated with mortality (HR 0.90, p=0.08). Results did not differ significantly between men and women. CONCLUSIONS: In addition to established risk factors for mortality and CVD, higher psoas muscle index, psoas muscle density, and paraspinous muscle density were significantly associated with lower all-cause mortality in European Americans with T2D.

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector.

Although the monomeric GTPases RalA and RalB have been shown to regulate a variety of transcription factors, little is known regarding the differences or similarities in transcriptional programs regulated by RalA compared to RalB. Further, the association of these transcriptional pathways to human carcinogenesis and progression remains unclear. Here, we studied the role of RalA and/or RalB in transcriptional regulation by combining short interfering RNA depletion of Ral with gene expression profiling via microarray in the human bladder cancer cell line, UMUC-3. A large number of genes were found to be similarly modulated in cells with RalA and RalB depletion, suggesting that RalA and RalB impinge on overlapping transcriptional signaling pathways. However, smaller sets of genes were modulated by depletion of RalA or RalB, indicating that these closely related proteins also regulate nonoverlapping transcriptional pathways. Computational analysis of upstream sequences of genes modulated by Ral depletion identified Ras-responsive element-binding protein (RREB)-1, as a putative Ral transcriptional target, which we verified experimentally. Importantly, as a group, Ral-regulated probe sets identified here were disproportionally represented among those differentially expressed as a function of human bladder transformation. Taken together, these data strongly suggest that Ral family members mediate both common and specific transcriptional programs that are associated with human cancer and identify RREB-1 as a novel transcriptional effector of Ral.

Theoretical study of liquid-immersed exposed-core microstructured optical fibers for sensing.

The absorption and fluorescence sensing properties of liquid-immersed exposed-core microstructured optical fibers are explored for the regime where these structures act as supported nanowires with direct access to the sensing environment. For absorption-based sensing we demonstrate that the amount of power propagating in the sensing region of the exposed-core fiber can compete with that of traditional MOFs. For fluorescence-based sensing, we see that in addition to the enhanced fluorescence capture efficiency already predicted for small-core, high refractive index contrast fibers, an improvement of up to 29% can be gained by using liquid-immersed exposed-core fibers. Additionally, calculation of the losses associated with interfaces between filled and unfilled sections predict significant benefit in using high refractive index substrate glasses for liquid-immersed exposed-core fiber sensing. This work demonstrates that, for fiber dimensions of interest, the exposed-core fiber is an attractive new sensor technology.

Differentially expressed soluble proteins in aortic cells from atherosclerosis-susceptible and resistant pigeons.

Soluble proteins in aortic smooth muscle cells cultured from atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons were extracted and separated on 2-dimensional electrophoresis gels. Spots were analyzed with Phoretix software and compared between the 2 breeds. Proteins differentially expressed were arrayed on a map, plotting molecular weight against isoelectric point. Eight discrete zones were identified, 5 that included only proteins unique to susceptible cells and 3 that included proteins unique to resistant cells. Of the 88 differentially expressed proteins from susceptible cells, 41 were located in unique zones, whereas 29 of 82 differentially expressed proteins from resistant cells were in unique zones. Selected proteins from susceptibility, and resistance zones were annotated by peptide mass fragments, molecular weights, isoelectric points, and correspondence with genes differentially expressed between cells from the 2 breeds. Some of the annotated proteins (such as smooth muscle myosin phosphatase, myosin heavy chain, fatty acid-binding protein, ribophorin, heat shock protein, and tumor necrosis factor alpha-inducing factor) corresponded to the current hypotheses to explain atherogenesis. In addition, the unique electrophoretic migration zones of proteins associated with susceptibility or resistance should prove useful as a diagnostic tool in clinical settings where species or phenotypes, or both, susceptible or resistant to atherosclerosis can be identified.