559 research outputs found
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload
Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson’s disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1^{-/-}) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca^{2+}]_{c} esponses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca^{2+} uptake was reduced in gba1^{−/−} cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1^{−/−} neurons. Behavior of gba1^{+/−} neurons was similar to gba1^{−/−} in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca^{2+}]_{c} dysregulation as mechanisms driving neurodegeneration
Exercise respiratory cycle time components in patients with emphysema
Background: We have recently demonstrated that in patients with COPD the severity of emphysema (E) measured by high resolution computed tomography (HRCT) correlated with: ratio VTpeak/FEV1; VE/VCO2 slope and PETCO2 values at peak exercise. The aim of this study was to further investigate if exercise respiratory cycle time components correlated with % of E measured by HRCT. Method: Twelve patients (age = 65±8 yrs; FEV1 = 55±17%pred) with moderate to severe E (quantified by lung HRCT as % voxels < −910 HU) were evaluated with incremental cardiopulmonary exercise testing (CPET). Mean inspiratory time (TiM), mean total respiratory cycle time (TtotM), mean expiratory time during exercise (TeM) and mean expiratory time during the last third of exercise (TeM-end), has been calculated.
Results: Both TeM and TeM-end had a good linear correlation with % of E (r = 0,61; p = 0,004 and r = 0,63; p = 0,003). Moreover, by dividing the patients in two groups based on the % of E (>50% and <50%), we observed that patients with higher % of E had longer TeM (TeM: 1,72±0,26sec vs 1,34±0,27sec, p = 0,005) and TeM-end. A good linear correlation has been observed also between TeM and PETCO2 and VE/VCO2 (r = 0,64; p = 0,002 and r = 0,7; p = 0,0005). TeM did not correlated with resting lung function values or inspiratory capacity (IC).
Conclusion: The data confirm that distinct physiologic response pattern can be detected at CPET in these patients
Exercise intolerance at high altitude (5050 m): critical power and W'
The relationship between work rate (WR) and its tolerable duration (t(LIM)) has not been investigated at high altitude (HA). At HA (5050 m) and at sea level (SL), six subjects therefore performed symptom-limited cycle-ergometry: an incremental test (IET) and three constant-WR tests (% of IET WR(max), HA and SL respectively: WR(1) 70±8%, 74±7%; WR(2) 86±14%, 88±10%; WR(3) 105±13%, 104±9%). The power asymptote (CP) and curvature constant (W') of the hyperbolic WR-t(LIM) relationship were reduced at HA compared to SL (CP: 81±21 vs. 123±38 W; W': 7.2±2.9 vs. 13.1±4.3 kJ). HA breathing reserve (estimated maximum voluntary ventilation minus end-exercise ventilation) was also compromised (WR(1): 25±25 vs. 50±18 l min(-1); WR(2): 4±23 vs. 38±23 l min(-1); WR(3): -3±18 vs. 32±24 l min(-1)) with near-maximal dyspnea levels (Borg) (WR(1): 7.2±1.2 vs. 4.8±1.3; WR(2): 8.8±0.8 vs. 5.3±1.2; WR(3): 9.3±1.0 vs. 5.3±1.5). The CP reduction is consistent with a reduced O(2) availability; that of W' with reduced muscle-venous O(2) storage, exacerbated by ventilatory limitation and dyspnea. Copyright © 2011 Elsevier B.V. All rights reserved
Factorial Economic Planning Applied to Agricultural Experimentation
Innovation may be limited by the scarceness of resources, such as financial, homogeneous area, skilled labor or other research needs, for example the difficulty in experimental control of large areas in the field. In research areas such as chemistry and physics, designs are used in such a way that when compared to the agronomic designs, they result in a reduced number of experimental units, which in this work are called economic designs. Thus, the objective of this study was to identify significant factors and effects (p-valu
A Serum Resistin and Multicytokine Inflammatory Pathway Is Linked With and Helps Predict All-cause Death in Diabetes
Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1 beta, IL-6, IL-8, and TNF-alpha, that is associated with cardiovascular disease.Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D.Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification.Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase=1.34, P<.001). In CEA patients, REMAP was associated with mortality (HR=1.64, P=.04) and a modest change was observed when plaque stability was taken into account (HR=1.58; P=.07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P<.05-<.001).Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1 beta monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested
Search for the Higgs boson in events with missing transverse energy and b quark jets produced in proton-antiproton collisions at s**(1/2)=1.96 TeV
We search for the standard model Higgs boson produced in association with an
electroweak vector boson in events with no identified charged leptons, large
imbalance in transverse momentum, and two jets where at least one contains a
secondary vertex consistent with the decay of b hadrons. We use ~1 fb-1
integrated luminosity of proton-antiproton collisions at s**(1/2)=1.96 TeV
recorded by the CDF II experiment at the Tevatron. We find 268 (16) single
(double) b-tagged candidate events, where 248 +/- 43 (14.4 +/- 2.7) are
expected from standard model background processes. We place 95% confidence
level upper limits on the Higgs boson production cross section for several
Higgs boson masses ranging from 110 GeV/c2 to 140 GeV/c2. For a mass of 115
GeV/c2 the observed (expected) limit is 20.4 (14.2) times the standard model
prediction.Comment: 8 pages, 2 figures, submitted to Phys. Rev. Let
Measurements of branching fraction ratios and CP-asymmetries in suppressed B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^- decays
We report the first reconstruction in hadron collisions of the suppressed
decays B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^-, sensitive to the
CKM phase gamma, using data from 7 fb^-1 of integrated luminosity collected by
the CDF II detector at the Tevatron collider. We reconstruct a signal for the
B^- -> D(-> K^+ pi^-)K^- suppressed mode with a significance of 3.2 standard
deviations, and measure the ratios of the suppressed to favored branching
fractions R(K) = [22.0 \pm 8.6(stat)\pm 2.6(syst)]\times 10^-3, R^+(K) =
[42.6\pm 13.7(stat)\pm 2.8(syst)]\times 10^-3, R^-(K)= [3.8\pm 10.3(stat)\pm
2.7(syst]\times 10^-3, as well as the direct CP-violating asymmetry A(K) =
-0.82\pm 0.44(stat)\pm 0.09(syst) of this mode. Corresponding quantities for
B^- -> D(-> K^+ pi^-)pi^- decay are also reported.Comment: 8 pages, 1 figure, accepted by Phys.Rev.D Rapid Communications for
Publicatio
Measurement of Ratios of Fragmentation Fractions for Bottom Hadrons in p-pbar Collisions at sqrt{s}=1.96 TeV
This paper describes the first measurement of b-quark fragmentation fractions
into bottom hadrons in Run II of the Tevatron Collider at Fermilab. The result
is based on a 360 pb-1 sample of data collected with the CDF II detector in
p-pbar collisions at sqrt{s}=1.96 TeV. Semileptonic decays of B0, B+, and B_s
mesons, as well as Lambda_b baryons, are reconstructed. For an effective bottom
hadron p_T threshold of 7 GeV/c, the fragmentation fractions are measured to be
f_u/f_d=1.054 +/- 0.018 (stat) +0.025-0.045(sys) +/- 0.058 (Br),
f_s/(f_u+f_d)=0.160 +/- 0.005 (stat) +0.011-0.010 (sys) +0.057-0.034 (Br), and
f_{Lambda_b}/(f_u+f_d)=0.281\pm0.012 (stat) +0.058-0.056 (sys) +0.128-0.086
(Br), where the uncertainty (Br) is due to uncertainties on measured branching
ratios. The value of f_s/(f_u+f_d) agrees within one standard deviation with
previous CDF measurements and the world average of this quantity, which is
dominated by LEP measurements. However, the ratio f_{Lambda_b}/(f_u+f_d) is
approximately twice the value previously measured at LEP. The approximately 2
sigma discrepancy is examined in terms of kinematic differences between the two
production environments.Comment: Submitted to PRD, 54 pages, 53 plot
Evidence for t\bar{t}\gamma Production and Measurement of \sigma_t\bar{t}\gamma / \sigma_t\bar{t}
Using data corresponding to 6.0/fb of ppbar collisions at sqrt(s) = 1.96 TeV
collected by the CDF II detector, we present a cross section measurement of
top-quark pair production with an additional radiated photon. The events are
selected by looking for a lepton, a photon, significant transverse momentum
imbalance, large total transverse energy, and three or more jets, with at least
one identified as containing a b quark. The ttbar+photon sample requires the
photon to have 10 GeV or more of transverse energy, and to be in the central
region. Using an event selection optimized for the ttbar+photon candidate
sample we measure the production cross section of, and the ratio of cross
sections of the two samples. Control samples in the dilepton+photon and
lepton+photon+\met, channels are constructed to aid in decay product
identification and background measurements. We observe 30 ttbar+photon
candidate events compared to the standard model expectation of 26.9 +/- 3.4
events. We measure the ttbar+photon cross section to be 0.18+0.08 pb, and the
ratio of the cross section of ttbar+photon to ttbar to be 0.024 +/- 0.009.
Assuming no ttbar+photon production, we observe a probability of 0.0015 of the
background events alone producing 30 events or more, corresponding to 3.0
standard deviations.Comment: 9 pages, 3 figure
Search for Pair Production of Scalar Top Quarks Decaying to a tau Lepton and a b Quark in ppbar Collisions at sqrt{s}=1.96 TeV
We search for pair production of supersymmetric top quarks (~t_1), followed
by R-parity violating decay ~t_1 -> tau b with a branching ratio beta, using
322 pb^-1 of ppbar collisions at sqrt{s}=1.96 TeV collected by the CDF II
detector at Fermilab. Two candidate events pass our final selection criteria,
consistent with the standard model expectation. We set upper limits on the
cross section sigma(~t_1 ~tbar_1)*beta^2 as a function of the stop mass
m(~t_1). Assuming beta=1, we set a 95% confidence level limit m(~t_1)>153
GeV/c^2. The limits are also applicable to the case of a third generation
scalar leptoquark (LQ_3) decaying LQ_3 -> tau b.Comment: 7 pages, 2 eps figure
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