The role of atrial natriuretic peptide (ANP) in regulating fetal cardiac growth is poorly understood. Angiotensin II (Ang II) stimulates proliferation in fetal sheep cardiomyocytes when growth is ...dependent on the activity of the mitogen‐activated protein kinase (MAPK) and phosphoinositol‐3‐kinase (PI3K) pathways. We hypothesized that ANP would suppress near‐term fetal cardiomyocyte proliferation in vitro and inhibit both the MAPK and PI3K pathways. Forty‐eight hour 5‐bromodeoxyuridine (BrdU) uptake (used as an index of proliferation) was measured in cardiomyocytes isolated from fetal sheep (135 day gestational age) in response to 100 nm Ang II with or without ANP (0.003–100 nm) or 1 μm 8‐bromo‐cGMP. The effects of these compounds on the MAPK and PI3K pathways were assessed by measuring extracellular signal‐regulated kinase (ERK) and AKT phosphorylation following 10 min of treatment with Ang II, ANP or 8‐bromo‐cGMP. In right ventricular myocytes (RV), the lowest dose of ANP (0.003 nm) inhibited Ang II‐stimulated BrdU uptake by 68%. Similarly, 8‐bromo‐cGMP suppressed Ang II‐stimulated proliferation by 62%. The same effects were observed in left ventricular (LV) cardiomyoytes but the RV was more sensitive to the inhibitory effects of ANP than the LV (P < 0.0001). Intracellular cGMP was increased by 4‐fold in the presence of 100 nm ANP. Ang II‐stimulated ERK and Akt phosphorylation was inhibited by 100 nm ANP. The activity of ANP may in part be cGMP dependent, as 8‐bromo‐cGMP had similar effects on the cardiomyocytes.
Atrial natriuretic peptide (ANP) plays an important role in regulating blood pressure and heart growth in adult mammals. It is not known how ANP affects heart growth in the fetus, though ANP levels are very high at this stage of development. We show here that ANP inhibits fetal heart cell proliferation in sheep following stimulation by a growth factor, angiotensin II (Ang II). ANP blocks the downstream cell growth signalling pathways stimulated by Ang II. These data are important because heart cell numbers are determined in the perinatal period and have lifelong consequences for cardiovascular health.
To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl).
We studied 314 patients with a ...pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria.
We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant.
Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.
The fetal heart is highly sensitive to changes in mechanical load. We have previously demonstrated that increased cardiac load can stimulate cell cycle activity and maturation of immature ...cardiomyocytes, but the effects of reduced load are not known. Sixteen fetal sheep were given either continuous intravenous infusion of lactated Ringer solution (LR) or enalaprilat, an angiotensin-converting enzyme inhibitor beginning at 127 days gestational age. After 8 days, fetal arterial pressure in the enalaprilat-infused fetuses (23.8 +/- 2.8 mmHg) was lower than that of control fetuses (47.5 +/- 4.7 mmHg) (P < 0.0001). Although the body weights of the two groups of fetuses were similar, the heart weight-to-body weight ratios of the enalaprilat-infused fetuses were less than those of the LR-infused fetuses (5.6 +/- 0.5 g/kg vs. 7.0 +/- 0.6 g/kg, P < 0.0001). Dimensions of ventricular myocytes were not different between control and enalaprilat-infused fetuses. However, there was a significant decrease in cell cycle activity in both the right ventricle (P < 0.005) and the left ventricle (P < 0.002) of the enalaprilat-infused fetuses. Thus, we conclude a sustained reduction in systolic pressure load decreases hyperplastic growth in the fetal heart.
The control on the deformation of the ATLAS barrel toroid warm structure Bauer, F.; Foussat, A.; Giraud, P.F. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2007, Letnik:
572, Številka:
1
Journal Article
Recenzirano
The ATLAS barrel toroid warm structure supports the barrel toroid and the muon detectors. The warm structure is about 26 meters long with an outer diameter of 20 meters. In order to ensure the ...physics performance of the muon detectors, the deformation of the warm structure is minimised during the design phase.
The barrel toroid assembly has been carried out in the cavern of the ATLAS experiment since end of 2004. In September 2005, the warm structure has been completely released. The release has been followed-up in real time using optical alignment sensors. Good agreement has been found within 1
mm, between the alignment system measurement, the geometer survey and the predicted values according to the finite element analyses results.
We describe the software chain for the Atlas muon optical alignment system, dedicated to the measurement of geometry corrections for the Muon Spectrometer chambers positions. The corrections are then ...used inside the reconstruction software. We detail in particular the architecture of the monitoring application, deployed in a J2EE server, and the monitoring tools that have been developed for the daily follow up. The system has been in production during the whole Run 1 period (2010-2013).
ATLAS detector is designed to exploit the full discovery potential of the LHC proton–proton collider at CERN, at an energy of 14
TeV. The detector, which is optimized for operating at high ...luminosity, features an inner tracker, Electromagnetic and Hadronic calorimeters and a Muon Spectrometer. The ATLAS Muon Spectrometer is composed of tracking and trigger detectors, which span a total area of 5500
m
2. The design of the spectrometer provides very good momentum resolution that varies between 2% and 10% for momentum ranging from 5
GeV to 1
TeV. To achieve this resolution, the 1200 individual tracking chambers composed of Monitored Drift Tubes (MDT) are constructed with mechanical precision better than 20
μm, while the position and deformation of individual chambers will be monitored with an optical alignment system to be better than 40
μm during data taking. In 2004, a combined systems test of a
ϕ sector of the following ATLAS sub-detectors: the Inner Detector, the Liquid Argon Calorimeter, the Tile Hadronic Calorimeter and the Muon Spectrometer, was performed in the H8 beam line at the CERN SPS. Results obtained on the alignment of the MDT chambers in the Muon Spectrometer setup, the performance of the MDT chambers and the reconstruction of Muon tracks using the combined information from both the Inner Detector and the Muon Spectrometer are presented here.
The DIRC particle identification system for the BaBar experiment Aleksan, R.; Amerman, L.; Aston, D. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2005, Letnik:
538, Številka:
1-3
Journal Article
Recenzirano
Odprti dostop
A new type of ring-imaging Cherenkov detector is being used for hadronic particle identification in the BABAR experiment at the SLAC B Factory (PEP-II). This detector is called DIRC, an acronym for ...Detection of Internally Reflected Cherenkov (Light). This paper will discuss the construction, operation and performance of the BABAR DIRC in detail.
A search for the decay of the tau lepton to seven charged pions and one or zero pizero mesons was performed using the BaBar detector at the PEP-II asymmetric-energy e+e- collider. The analysis uses ...232.2 fb-1 of data at center-of-mass energies on or near the Y(4S) resonance. We observe 24 events with an expected background of 21.6+-1.3 events. Without evidence for a signal, we calculate an upper limit of BR(tau- --> 4pi- 3pi+ (pizero) nu_tau) < 3.0*10^-7 at 90 % confidence level. This is an improvement by nearly an order of magnitude over the previously established limit. In addition, we set upper limits for the exclusive decays tau- --> 4pi- 3pi+ nu_tau and tau- --> 4pi- 3pi+ pizero nu_tau.
In order to investigate how calcium on the cytosolic side of human erythrocytes induces the transmembrane redistribution of
phospholipids, we studied the effect of this cation on the transmembrane ...movements of spin-labeled phospholipids (phosphatidylserine
(PS) and phosphatidylcholine (PC)) incorporated into inside-out vesicles derived from human erythrocytes. We found that the
extent of the Ca(2+)-induced lipid scrambling was dependent upon the level of phosphatidylinositol 4,5-bisphosphate (PIP2)
contained in the external leaflet of inside-out vesicles. The level of PIP2 in this leaflet, which normally accounts for 80%
of the total membrane PIP2, was manipulated either by ATP depletion of the original erythrocytes or by incorporation of exogenous
PIP2. Similarly, loading the outer monolayer of the membrane of intact erythrocytes with exogenous PIP2 caused, in a dose-dependent
way, the scrambling of spin-labeled phosphatidylethanolamine, sphingomyelin, PC, and PS and in parallel the stomatocytic conversion
of the cells. Both scrambling and stomatocytosis were strictly dependent on the presence of divalent cations in the medium.
Mg2+ could replace Ca2+ but required a 10 times higher concentration. The effect was specific for PIP2, the other phosphoinositides
being unable to induce the lipid redistribution. The shape change, but not the scrambling, required a normal ATP level. These
results show that Ca2+ or Mg2+ trigger the lipid redistribution either from the internal or the external side of the membrane,
provided that enough PIP2 is present on that side. Thus, no specific protein is required for this process. We infer that the
ATP-dependent shape change of erythrocytes after incubation with PIP2 and Ca2+ results from the bilayer imbalance due to the
activity of the aminophospholipid translocase which relocates PS and phosphatidylethanolamine to the inner monolayer without
simultaneous outward diffusion of PC and sphingomyelin.
Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, ...and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-trans-retinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.
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