Gravity Probe B, launched 20 April 2004, is a space experiment testing two fundamental predictions of Einstein's theory of general relativity (GR), the geodetic and frame-dragging effects, by means ...of cryogenic gyroscopes in Earth orbit. Data collection started 28 August 2004 and ended 14 August 2005. Analysis of the data from all four gyroscopes results in a geodetic drift rate of -6601.8±18.3 mas/yr and a frame-dragging drift rate of -37.2±7.2 mas/yr, to be compared with the GR predictions of -6606.1 mas/yr and -39.2 mas/yr, respectively ("mas" is milliarcsecond; 1 mas=4.848×10(-9) rad).
Fibrocytes (FC) are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO). FCs express high levels of thyrotropin receptor (TSHR) ...and insulin-like growth factor-1 receptor (IGF-1R). These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH) or M22 (activating antibody to TSHR) induces the production of numerous cytokines, including tumor necrosis factor α (TNFα). Teprotumumab (TMB) is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs.
To characterize the molecular mechanisms underlying TSH-induced TNFα production by FCs, and the role of IGF-1R blockade by TMB.
FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-κB and Akt, respectively), and TMB. TNFα protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR.
Treatment with TSH/M22 induced TNFα protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001). TMB decreased TSH-induced TNFα protein production in circulating FCs from mean fluorescent index (MFI) value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001). TMB also decreased M22-induced TNFα protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001).
TSH/M22 stimulates FC production of TNFα mRNA and protein. This process involves the transcription factor NF-κB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFα production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFα production, TMB may be a promising therapeutic agent for GO.
The Gravity Probe B mission provided two new quantitative tests of Einstein's theory of gravity, general relativity (GR), by cryogenic gyroscopes in Earth's orbit. Data from four gyroscopes gave a ...geodetic drift-rate of −6601.8 18.3 marc-s yr−1 and a frame-dragging of −37.2 7.2 marc-s yr−1, to be compared with GR predictions of −6606.1 and −39.2 marc-s yr−1 (1 marc-s = 4.848 × 10−9 radians). The present paper introduces the science, engineering, data analysis, and heritage of Gravity Probe B, detailed in the accompanying 20 CQG papers.
Following the revision of the International System of Units (SI), that takes effect on 20 May 2019, the unit mole is defined by using a fixed number of elementary entities. This number is the fixed ...numerical value of the Avogadro constant, which is the defining constant of the unit mole. This definition was made possible because the determination of the Avogadro constant had reached a level of relative uncertainty that allowed its value to be fixed and, at the same time, safeguard continuity of measurement results before and after the definition. The motivation for the revision of the SI and the mole in particular will be explained and the experimental work that allowed it is summarized.
Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to ...designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.
Gravity Probe B Data Analysis Everitt, C. W. F.; Adams, M.; Bencze, W. ...
Space science reviews,
12/2009, Letnik:
148, Številka:
1-4
Journal Article
Recenzirano
This is the first of five connected papers detailing progress on the Gravity Probe B (GP-B) Relativity Mission. GP-B, launched 20 April 2004, is a landmark physics experiment in space to test two ...fundamental predictions of Einstein’s general relativity theory, the geodetic and frame-dragging effects, by means of cryogenic gyroscopes in Earth orbit. Data collection began 28 August 2004 and science operations were completed 29 September 2005. The data analysis has proven deeper than expected as a result of two mutually reinforcing complications in gyroscope performance: (1) a changing polhode path affecting the calibration of the gyroscope scale factor
C
g
against the aberration of starlight and (2) two larger than expected manifestations of a Newtonian gyro torque due to patch potentials on the rotor and housing. In earlier papers, we reported two methods, ‘geometric’ and ‘algebraic’, for identifying and removing the first Newtonian effect (‘misalignment torque’), and also a preliminary method of treating the second (‘roll-polhode resonance torque’). Central to the progress in both torque modeling and
C
g
determination has been an extended effort on “Trapped Flux Mapping” commenced in November 2006. A turning point came in August 2008 when it became possible to include a detailed history of the resonance torques into the computation. The East-West (frame-dragging) effect is now plainly visible in the processed data. The current
statistical uncertainty
from an analysis of 155 days of data is 5.4 marc-s/yr (∼14% of the predicted effect), though it must be emphasized that this is a preliminary result requiring rigorous investigation of systematics by methods discussed in the accompanying paper by Muhlfelder et al. A covariance analysis incorporating models of the patch effect torques indicates that a 3–5% determination of frame-dragging is possible with more complete, computationally intensive data analysis.
Fibrocytes (FC) are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO). FCs express high levels of thyrotropin receptor (TSHR) ...and insulin-like growth factor-1 receptor (IGF-1R). These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH) or M22 (activating antibody to TSHR) induces the production of numerous cytokines, including tumor necrosis factor alpha (TNFalpha). Teprotumumab (TMB) is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs. To characterize the molecular mechanisms underlying TSH-induced TNFalpha production by FCs, and the role of IGF-1R blockade by TMB. FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-kappaB and Akt, respectively), and TMB. TNFalpha protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR. Treatment with TSH/M22 induced TNFalpha protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001). TMB decreased TSH-induced TNFalpha protein production in circulating FCs from mean fluorescent index (MFI) value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001). TMB also decreased M22-induced TNFalpha protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001). TSH/M22 stimulates FC production of TNFalpha mRNA and protein. This process involves the transcription factor NF-kappaB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFalpha production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFalpha production, TMB may be a promising therapeutic agent for GO.
A full-field hard-x-ray microscope at SSRL has successfully imaged samples of biological and environmental origin at 40 nm resolution. Phase contrast imaging of trabeculae from a female mouse tibia, ...loaded in vivo to study the effects of weight-bearing on bone structure, revealed a complex network of osteocytes and canaliculi. Imaging of cordgrass roots exposed to mercury revealed nanoparticles with strong absorption contrast. 3D tomography of yeast cells grown in selenium rich media showed internal structure.
In-tube solid phase microextraction (SPME) is an on-line extraction technique for compounds in aqueous samples, in which analytes are extracted and concentrated from the sample directly into a coated ...capillary by repeated aspirate/dispense steps. In this paper, a polypyrrole (PPY) coated capillary and several commercially available capillaries (used for GC separation) were used to examine their extraction efficiencies to the organoarsenic compounds studied. Compared with commercial capillaries that were currently used for in-tube SPME, the PPY coated capillary has shown better extraction efficiency to most of the compounds studied, especially to the anionic species, due to the inherent multi-functionality of pyrrole polymer. For the first time, this PPY coated capillary has been used for automated in-tube SPME and speciation of organoarsenic species in aqueous samples when coupled with liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS). Organoarsenic compounds in water samples and arsenobetaine in a certified reference material (DORM-2) were analyzed by this method.
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