Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse.

Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia

Dilaton Contact Terms in the Bosonic and Heterotic Strings

Dilaton contact terms in the bosonic and heterotic strings are examined following the recent work of Distler and Nelson on the bosonic and semirigid strings. In the bosonic case dilaton two-point functions on the sphere are calculated as a stepping stone to constructing a `good' coordinate family for dilaton calculations on higher genus surfaces. It is found that dilaton-dilaton contact terms are improperly normalized, suggesting that the interpretation of the dilaton as the first variation of string coupling breaks down when other dilatons are present. It seems likely that this can be attributed to the tachyon divergence found in \TCCT. For the heterotic case, it is found that there is no tachyon divergence and that the dilaton contact terms are properly normalized. Thus, a dilaton equation analogous to the one in topological gravity is derived and the interpretation of the dilaton as the string coupling constant goes through.Comment: 44 pages, Figures now included. This replacement version includes the 7 figures as PostScript files appended to the end and the macros to insert them into the text. Also some typos in intermediate formulae were correcte

World-Sheet Supersymmetry Without Contact Terms

Green and Seiberg showed that, in simple treatments of fermionic string theory, it is necessary to introduce contact interactions when vertex operators collide. Otherwise, certain superconformal Ward identities would be violated. In this note, we show how these contact terms arise naturally when proper account is taken of the superconformal geometry involved when punctures collide. More precisely, we show that there is no contact term at all! Rather, corrections arise to the ``na\"\i ve" formula when the boundary of moduli space is described correctly.Comment: 14pp., 2 figures (included

The Dilaton Theorem and Closed String Backgrounds

The zero-momentum ghost-dilaton is a non-primary BRST physical state present in every bosonic closed string background. It is given by the action of the BRST operator on another state \x, but remains nontrivial in the semirelative BRST cohomology. When local coordinates arise from metrics we show that dilaton and \x insertions compute Riemannian curvature and geodesic curvature respectively. A proper definition of a CFT deformation induced by the dilaton requires surface integrals of the dilaton and line integrals of \x. Surprisingly, the ghost number anomaly makes this a trivial deformation. While dilatons cannot deform conformal theories, they actually deform conformal string backgrounds, showing in a simple context that a string background is not necessarily the same as a CFT. We generalize the earlier proof of quantum background independence of string theory to show that a dilaton shift amounts to a shift of the string coupling in the field-dependent part of the quantum string action. Thus the ``dilaton theorem'', familiar for on-shell string amplitudes, holds off-shell as a consequence of an exact symmetry of the string action.Comment: 51 pages, plain tex with phyzzx, two uuencoded figure

Quantization from an exponential distribution of infinitesimal action

A statistical model of quantization based on an exponential distribution of infinitesimal action is proposed. Trajectory which does not extremize the action along an infinitesimal short segment of path is allowed to occur with a very small probability following an exponential law. Planck constant is argued to give the average deviation from the infinitesimal stationary action.Comment: 15 pages, accepted for publication in Physica

Telomere lengths in human oocytes, cleavage stage embryos and blastocysts

Telomeres are repeated sequences that protect the ends of chromosomes and harbour DNA-repair proteins. Telomeres shorten during each cell division in the absence of telomerase. When telomere length becomes critically short, cell senescence occurs. Telomere length therefore reflects both cellular ageing and capacity for division. We have measured telomere length in human germinal vesicle (GV) oocytes and pre-implantation embryos, by quantitative fluorescence in-situ hybridisation (Q-FISH), providing baseline data towards our hypothesis that telomere length is a marker of embryo quality. The numbers of fluorescent foci suggest that extensive clustering of telomeres occurs in mature GV stage oocytes, and in pre-implantation embryos. When calculating average telomere length by assuming that each signal presents one telomere, the calculated telomere length decreased from the oocyte to the cleavage stages, and increased between the cleavage stages and the blastocyst (11.12 vs 8.43 vs 12.22kb respectively, p<0.001). Other methods of calculation, based upon expected maximum and minimum numbers of telomeres, confirm that telomere length in blastocysts is significantly longer than cleavage stages. Individual blastomeres within an embryo showed substantial variation in calculated average telomere length. This study implies that telomere length changes according to the stage of pre-implantation embryo development

Change in well-being amongst participants in a four-month pedometer-based workplace health program

Background: There is increasing uptake of workplace physical activity programs to prevent chronic disease. While they are frequently evaluated for improvement in biomedical risk factors there has been little evaluation of additional benefits for psychosocial health. We aimed to evaluate whether participation in a four-month, team-based, pedometer-based workplace health program known to improve biomedical risk factors is associated with an improvement in well-being, immediately after the program and eight-months after program completion.Methods. At baseline (2008), 762 adults (aged 40 ± 10 SD years, 42% male) employed in primarily sedentary occupations and voluntarily enrolled in a physical activity program were recruited from ten Australian worksites. Data was collected at baseline, at the completion of the four-month program and eight-months after program completion. The outcome was the WHO-Five Well-being Index (WHO-5), a self-administered five-item scale that can be dichotomised as 'poor' (less than 52%) or 'positive' (more than or equal to 52%) well-being.Results: At baseline, 75% of participants had positive well-being (mean: 60 ± 19 SD WHO-5 units). On average, well-being improved immediately after the health program (+3.5 units, p < 0.001) and was sustained eight-months later (+3.4 units from baseline, p < 0.001). In the 25% with poor well-being at baseline, 49.5% moved into the positive well-being category immediately after program completion, sustained eight-months later (p < 0.001).Conclusions: Clinically relevant immediate and sustained improvements in well-being were observed after participation in the health program. These results suggest that participation in workplace programs, such as the one evaluated here, also has the potential to improve well-being

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p&lt;0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p&lt;0.001), age (OR=1.1, p&lt;0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p&lt;0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis

Experimental arthritis is dependent on mouse mast cell protease-5

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The constitutive heparin+ (HP) mast cells (MCs) in mice express mouseMCprotease (mMCP)-5 and carboxypeptidaseA (mMC-CPA). The amino acid sequence ofmMCP-5is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralisinfected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis ofmMCP-5from theMCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wildtype mice in two disease models