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- 2019
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Tidskriftsartikel (refereegranskat)
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- Karamyshev, Andrey L., et al.
(författare)
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Inefficient SRP Interaction with a Nascent Chain Triggers a mRNA Quality Control Pathway
- 2014
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 156:1-2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded. Severity of signal sequence mutations correlated with increased proximity of Ago2 to nascent chain and mRNA degradation. Ago2 knockdown inhibited degradation of the mutant mRNA, while overexpression of Ago2 or knockdown of SRP54 promoted degradation of secretory protein mRNA. The results reveal a previously unappreciated general mechanismof translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP).
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- Pasche, Boris, et al.
(författare)
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Somatic acquisition and signaling of TGFBR1*6A in cancer
- 2005
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 294:13, s. 1634-1646
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Tidskriftsartikel (refereegranskat)abstract
- Context: TGFBR1*6A is a common polymorphism of the type I transforming growth factor 0 receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown.. Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients: Tumor And germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004, In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
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- Ballabriga, R., et al.
(författare)
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Medipix3 : A 64 k pixel detector readout chip working in single photon counting mode with improved spectrometric performance
- 2011
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 633:SUPPL. 1, s. S15-S18
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Tidskriftsartikel (refereegranskat)abstract
- Medipix3 is a 256×256 channel hybrid pixel detector readout chip working in a single photon counting mode with a new inter-pixel architecture, which aims to improve the energy resolution in pixelated detectors by mitigating the effects of charge sharing between channels. Charges are summed in all 2×2 pixel clusters on the chip and a given hit is allocated locally to the pixel summing circuit with the biggest total charge on an event-by-event basis. Each pixel contains also two 12-bit binary counters with programmable depth and overflow control. The chip is configurable such that either the dimensions of each detector pixel match those of one readout pixel or detector pixels are four times greater in area than the readout pixels. In the latter case, event-by-event summing is still possible between the larger pixels. Each pixel has around 1600 transistors and the analog static power consumption is below 15 μW in the charge summing mode and 9 μW in the single pixel mode. The chip has been built in an 8-metal 0.13 μm CMOS technology. This paper describes the chip from the pixel to the periphery and first electrical results are summarized.
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- Ballabriga, Rafael, et al.
(författare)
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The Medipix3RX: a high resolution, zero dead-time pixel detector readout chip allowing spectroscopic imaging
- 2013
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 8:2, s. C02016-
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Tidskriftsartikel (refereegranskat)abstract
- The Medipix3 chips have been designed to permit spectroscopic imaging in highly segmented hybrid pixel detectors. Spectral degradation due to charge sharing in the sensor has been addressed by means of an architecture in which adjacent pixels communicate in the analog and digital domains on an event-by-event basis to reconstruct the deposited charge in a neighbourhood prior to the assignation of the hit to a single pixel. The Medipix3RX chip architecture is presented. The first results for the characterization of the chip with 300 μm thick Si sensors are given. ~ 72e− r.m.s. noise and ~ 40e− r.m.s. of threshold dispersion after chip equalization have been measured in Single Pixel Mode of operation. The homogeneity of the image in Charge Summing mode is comparable to the Single Pixel Mode image. This demonstrates both modes are suitable for X-ray imaging applications.
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- Campbell, M, et al.
(författare)
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Detection of single electrons by means of a Micromegas-covered Medipix2 pixel CMOS readout circuit
- 2005
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 540:2-3, s. 295-304
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Tidskriftsartikel (refereegranskat)abstract
- A small drift chamber was read out by means of a MediPix2 readout chip as a direct anode. A Micromegas foil was placed above the chip, and electron multiplication occurred in the gap. With a He/isobutane 80/20 mixture, gas multiplication factors up to tens of thousands were achieved, resulting in an efficiency for detecting single electrons of better than 90%. We recorded many frames containing 2D images with tracks from cosmic muons. Along these tracks, electron clusters were observed, as well as δ-rays.
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| 10. |
- Campbell, M., et al.
(författare)
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Towards a new generation of pixel detector readout chips
- 2016
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The Medipix3 Collaboration has broken new ground in spectroscopic X-ray imaging and in single particle detection and tracking. This paper will review briefly the performance and limitations of the present generation of pixel detector readout chips developed by the Collaboration. Through Silicon Via technology has the potential to provide a significant improvement in the tile-ability and more flexibility in the choice of readout architecture. This has been explored in the context of 3 projects with CEA-LETI using Medipix3 and Timepix3 wafers. The next generation of chips will aim to provide improved spectroscopic imaging performance at rates compatible with human CT. It will also aim to provide full spectroscopic images with unprecedented energy and spatial resolution. Some of the opportunities and challenges posed by moving to a more dense CMOS process will be discussed.
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