Dysfunction of the 140 aa protein alpha-synuclein plays a central role in Lewy body disorders, including Parkinson's disease, as well as in multiple system atrophy. Here, we show that the expression ...of truncated human alpha-synuclein(1-120), driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.
Abnormalities in microtubule-associated tau protein are a key neuropathological feature of both Alzheimer's disease and many frontotemporal dementias (FTDs), including hereditary FTD with ...Parkinsonism linked to chromosome 17 (FTDP-17). In these disorders, tau becomes aberrantly phosphorylated, leading to the development of filamentous neurofibrillary tangles in the brain. Here we report, in a longitudinal ageing study, the sensorimotor and cognitive assessment of transgenic mice expressing the human tauV337M ('Seattle Family A') FTDP-17 mutation, which we have previously shown to demonstrate abnormalities in brain tau phosphorylation. The data indicated highly specific effects of transgene expression on the ability to withhold responding in a murine version of the 5-choice serial reaction time task, behaviour consistent with deficits in impulse control. Ageing exacerbated these effects. In young tauV337M mice, increased impulsivity was present under task conditions making inhibition of premature responding more difficult (longer inter-trial intervals) but not under baseline conditions. However, when older, the tauV337M mice showed further increases in premature responding, including under baseline conditions. These impulse control deficits were fully dissociable from sensorimotor or motivation effects on performance. The findings recapitulate core abnormalities in impulsive responding observed in both frontal variant FTD and FTDP-17 linked to the tauV337M mutation in humans.
Abnormalities in microtubule-associated tau protein are a key neuropathological feature of both Alzheimer's disease and many frontotemporal dementias (FTDs), including hereditary FTD with ...Parkinsonism linked to chromosome 17 (FTDP-17). In these disorders, tau becomes aberrantly phosphorylated, leading to the development of filamentous neurofibrillary tangles in the brain. Here we report, in a longitudinal ageing study, the sensorimotor and cognitive assessment of transgenic mice expressing the human tauV337M ('Seattle Family A') FTDP-17 mutation, which we have previously shown to demonstrate abnormalities in brain tau phosphorylation. The data indicated highly specific effects of transgene expression on the ability to withhold responding in a murine version of the 5-choice serial reaction time task, behaviour consistent with deficits in impulse control. Ageing exacerbated these effects. In young tauV337M mice, increased impulsivity was present under task conditions making inhibition of premature responding more difficult (longer inter-trial intervals) but not under baseline conditions. However, when older, the tauV337M mice showed further increases in premature responding, including under baseline conditions. These impulse control deficits were fully dissociable from sensorimotor or motivation effects on performance. The findings recapitulate core abnormalities in impulsive responding observed in both frontal variant FTD and FTDP-17 linked to the tauV337M mutation in humans.
A measurement and a search, both involving high transverse momentum bosons decaying to b-quarks, are performed using a dataset of proton-proton collisions at √s = 8 TeV, collected in 2012 with the ...ATLAS detector at the LHC, corresponding to an integrated luminosity of 19.5 inverse fb. The production cross section of Z → bb is measured, where the Z boson has high transverse momentum. The measured value of the fiducial cross section is found to be in good agreement with next-to-leading-order Standard Model predictions. A search is made for TeV-scale resonances decaying via a pair of Higgs bosons to the b ̄bb ̄b final state. The graviton excitation, G*, in the bulk Randall-Sundrum model is used as a baseline signal model. No evidence of a resonance is found. Upper limits are set on σ(pp→G*) x BR(G*→HH→bbbb).
A measurement and a search, both involving high transverse momentum bosons decaying to b-quarks, are performed using a dataset of proton-proton collisions at √s = 8 TeV, collected in 2012 with the ...ATLAS detector at the LHC, corresponding to an integrated luminosity of 19.5 inverse fb. The production cross section of Z → bb is measured, where the Z boson has high transverse momentum. The measured value of the fiducial cross section is found to be in good agreement with next-to-leading-order Standard Model predictions. A search is made for TeV-scale resonances decaying via a pair of Higgs bosons to the b ̄bb ̄b final state. The graviton excitation, G*, in the bulk Randall-Sundrum model is used as a baseline signal model. No evidence of a resonance is found. Upper limits are set on σ(pp→G*) x BR(G*→HH→bbbb).
A site-specific recombination system that probes the relative probabilities that pairs of chromosomal loci collide with one another in living cells of budding yeast was used to explore the relative ...contributions of pairing, recombination, synaptonemal complex formation, and telomere clustering to the close juxtaposition of homologous chromosome pairs during meiosis. The level of Cre-mediated recombination between a pair of loxP sites located at an allelic position on homologous chromosomes was 13-fold greater than that between a pair of loxP sites located at ectopic positions on nonhomologous chromosomes. Mutations affecting meiotic recombination initiation and the processing of DNA double-strand breaks (DSBs) into single-end invasions (SEIs) reduced the levels of allelic Cre-mediated recombination levels by three- to sixfold. The severity of Cre/loxP phenotypes is presented in contrast to relatively weak DSB-independent pairing defects as assayed using fluorescence in situ hybridization for these mutants. Mutations affecting synaptonemal complex (SC) formation or crossover control gave wild-type levels of allelic Cre-mediated recombination. A delay in attaining maximum levels of allelic Cre-mediated recombination was observed for a mutant defective in telomere clustering. None of the mutants affected ectopic levels of recombination. These data suggest that stable, close homolog juxtaposition in yeast is distinct from pre-DSB pairing interactions, requires both DSB and SEI formation, but does not depend on crossovers or SC.
Pneumoperitoneum has been shown to reduce hepatic portal blood flow and alter postoperative hepatic transaminases. This study evaluated the changes in hepatic function after laparoscopic and open ...gastric bypass (GBP).
Thirty-six morbidly obese patients were randomly assigned to undergo either laparoscopic (n = 18) or open (n = 18) GBP. Liver function tests—total bilirubin (T Bil), gamma GT (GGT), albumin, alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT)—and creatine kinase levels were obtained preoperatively and at 1, 24, 48, and 72 hours postoperatively.
The two groups were similar in age, sex, and body mass index. Albumin and ALP levels decreased while T Bil and GGT levels remained unchanged from baseline in both groups without significant difference between the two groups. After laparoscopic GBP, ALT and AST transiently increased by sixfold and returned to near baseline levels at 72 hours. After open GBP, ALT and AST transiently increased by fivefold to eightfold and returned to near baseline levels by 72 hours. Creatine kinase level was significantly lower after laparoscopic GBP than after open GBP at 48 and 72 hours postoperatively. There was no postoperative liver failure or mortality in either group.
Laparoscopic GBP resulted in transient postoperative elevation of hepatic transaminase (ALT, AST) but did not adversely alter hepatic function to any greater extent than open GBP. Creatine kinase levels were lower after laparoscopic GBP reflecting its lesser degree of abdominal wall trauma.
Nonmetabolizable glucose analogs inhibit the growth of Escherichia coli on a wide variety of carbon sources. This phenomenon was investigated with particular reference to the effect of 2-deoxyglucose ...(2DG) on growth on fructose as sole carbon source. When the inhibitor is supplied in sufficiently low concentrations, the initial arrest of growth is overcome; this relief of inhibition is aided by means that increase the availability of phosphoenolpyruvate (PEP) to the growing cells, such as the use of L-aspartate instead of ammonium chloride as sole nitrogen source for growth, and the introduction of the pps+allele into a pps-strain. Studies with 14C2DG showed that the analog or its 6-phosphate as such did not inhibit growth but that 2DG exerted its effect by competing for intracellular PEP and lowering its concentration below that needed to sustain growth. Direct measurements of the PEP-dependent phosphorylation of 2DG and of fructose by permeabilized E. coli showed that the apparent Kmfor PEP was nearly 7 times higher for 2DG than it was for fructose, although the apparent Vmaxfor 2DG was nearly 3 times that for fructose; this explains the ability of cells to overcome the inhibition by low, but not by high, concentrations of 2DG.
PDF
