RESUMEN
Obstacles in elucidating the role of oxidative stress in aging include difficulties in (1) tracking in vivo oxidants, in (2) identifying affected proteins, and in (3) correlating changes in oxidant levels with life span. Here, we used quantitative redox proteomics to determine the onset and the cellular targets of oxidative stress during Caenorhabditis elegans' life span. In parallel, we used genetically encoded sensor proteins to determine peroxide levels in live animals in real time. We discovered that C. elegans encounters significant levels of oxidants as early as during larval development. Oxidant levels drop rapidly as animals mature, and reducing conditions prevail throughout the reproductive age, after which age-accompanied protein oxidation sets in. Long-lived daf-2 mutants transition faster to reducing conditions, whereas short-lived daf-16 mutants retain higher oxidant levels throughout their mature life. These results suggest that animals with improved capacity to recover from early oxidative stress have significant advantages later in life.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Longevidad , Estrés Oxidativo , Animales , Caenorhabditis elegans/citología , Oxidación-Reducción , Peróxidos/análisis , ProteómicaRESUMEN
The signal-to-noise properties of active matrix, flat-panel imagers (AMFPIs) limit the imaging performance of this x-ray imaging technology under conditions of low dose per image frame. This limitation can affect cone-beam computed tomography (CBCT) procedures where an AMFPI is used to acquire hundreds of image frames to form a single volumetric data set. An approach for overcoming this limitation is to replace the energy-integrating pixel circuits of AMFPI arrays with photon counting pixel circuits which examine the energy of each x-ray interaction and count those events whose signals exceed user-defined energy thresholds. A promising material for fabricating the circuits of such photon-counting detectors (PCDs) is polycrystalline silicon (poly-Si)-a semiconductor that facilitates economic manufacture of large area, monolithic arrays of the size presently provided by AMFPIs as well as provides good radiation damage resistance. In this paper, results are reported from a theoretical investigation of the potential for poly-Si PCDs to satisfy the count rate needs, while maintaining good energy resolution, of two CBCT applications-CBCT used for breast imaging and kilo-voltage CBCT used for providing localization information in image guided radiotherapy (referred to as BCT and kV-CBCT, respectively). The study focused on the performance of the critical first component of a PCD pixel circuit, the amplifier, under conditions relevant to the two applications. The study determined that, compared to the average input fluxes associated with BCT and kV-CBCT, a promising amplifier design employing poly-Si thin-film transistors can provide count rates two and four times in excess of those levels, respectively, assuming a dead time loss of 10%. In addition, calculational estimates based on foreseeable poly-Si circuit densities suggest that it should be possible to include sufficient circuitry to support 2 and 3 energy thresholds per pixel, respectively. Finally, prospects for further improvements are discussed.
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Tomografía Computarizada de Haz Cónico/instrumentación , Tomografía Computarizada de Haz Cónico/métodos , Modelos Teóricos , Fotones , Semiconductores , Silicio/química , Humanos , Rayos XRESUMEN
PURPOSE: In the spirit of overcoming the signal-to-noise limitations of active matrix, flat-panel imagers (AMFPIs) which employ array circuits based on a-Si:H thin-film transistors (TFTs), an empirical investigation of the noise properties of prototype active pixel arrays based on polycrystalline silicon (poly-Si) TFTs is reported. Like a-Si:H, poly-Si supports fabrication of large area, monolithic x-ray imaging arrays and offers good radiation damage resistance, while providing electron and hole mobility orders of magnitude higher. Compared to pixel circuits typically consisting of a single addressing switch in an AMFPI array, the pixel circuit of an active pixel array includes an amplifier that magnifies the imaging signal prior to readout by external acquisition electronics. Also, while readout erases signal stored in the pixels for AMFPI arrays, active pixel arrays allow multiple nondestructive readout, which can be used to reduce noise. The prototype arrays investigated in this paper were developed to explore the effect of variation in amplifier design on noise. METHODS: A pair of prototype arrays incorporating single-stage and two-stage poly-Si pixel amplifiers were examined. The arrays incorporate various amplifier designs in which dimensions of some of the three (or four) poly-Si TFTs per pixel circuit for the single-stage array, and some of the five poly-Si TFTs for the two-stage array, were varied. The arrays were operated using a recently developed electronic data acquisition system that allows variation of operational conditions such as voltages and timing of control signals. The arrays were operated in the absence of radiation in various correlated multiple sampling modes, with and without the injection of charge directly into the pixel circuits for measurements of in-pixel gain and pixel noise. Pixel noise, referred back to the input of the pixel amplifier, was compared to predictions generated by a sophisticated circuit simulation model. RESULTS: Across the various pixel circuit designs, the median in-pixel gain for the single-stage and two-stage arrays was measured to be ×9.3 and ×25, respectively. These gain levels were sufficient to reduce the contribution of external noise, defined as the electronic additive noise in the absence of noise contributions from circuitry in the pixel and referred back to the input of the pixel amplifier, to less than 340 e. As a result, median pixel noise results as low as ~695 e and 866 e, acquired using eight samples, were observed from the best-performing single-stage and two-stage designs, respectively. While the magnitude of pixel noise predicted by simulation was lower than the measured results, there was generally good agreement between simulation and measurement for the functional dependence of noise on operating voltages, timing, and sampling mode. CONCLUSIONS: The single-stage and two-stage arrays examined in this study demonstrated pixel noise well below that typically demonstrated by AMFPIs. Through proper design, it should be possible to maintain the noise levels observed in this study irrespective of the size and pitch of an active pixel array. Further reduction in pixel noise may be possible through more optimized pixel circuit design, faster readout, or improvements in fabrication.
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Amplificadores Electrónicos , Silicio , Simulación por Computador , Electrónica , Diseño de EquipoRESUMEN
Active matrix, flat-panel imagers (AMFPIs) employing a 2D matrix of a-Si addressing TFTs have become ubiquitous in many x-ray imaging applications due to their numerous advantages. However, under conditions of low exposures and/or high spatial resolution, their signal-to-noise performance is constrained by the modest system gain relative to the electronic additive noise. In this article, a strategy for overcoming this limitation through the incorporation of in-pixel amplification circuits, referred to as active pixel (AP) architectures, using polycrystalline-silicon (poly-Si) TFTs is reported. Compared to a-Si, poly-Si offers substantially higher mobilities, enabling higher TFT currents and the possibility of sophisticated AP designs based on both n- and p-channel TFTs. Three prototype indirect detection arrays employing poly-Si TFTs and a continuous a-Si photodiode structure were characterized. The prototypes consist of an array (PSI-1) that employs a pixel architecture with a single TFT, as well as two arrays (PSI-2 and PSI-3) that employ AP architectures based on three and five TFTs, respectively. While PSI-1 serves as a reference with a design similar to that of conventional AMFPI arrays, PSI-2 and PSI-3 incorporate additional in-pixel amplification circuitry. Compared to PSI-1, results of x-ray sensitivity demonstrate signal gains of approximately 10.7 and 20.9 for PSI-2 and PSI-3, respectively. These values are in reasonable agreement with design expectations, demonstrating that poly-Si AP circuits can be tailored to provide a desired level of signal gain. PSI-2 exhibits the same high levels of charge trapping as those observed for PSI-1 and other conventional arrays employing a continuous photodiode structure. For PSI-3, charge trapping was found to be significantly lower and largely independent of the bias voltage applied across the photodiode. MTF results indicate that the use of a continuous photodiode structure in PSI-1, PSI-2, and PSI-3 results in optical fill factors that are close to unity. In addition, the greater complexity of PSI-2 and PSI-3 pixel circuits, compared to that of PSI-1, has no observable effect on spatial resolution. Both PSI-2 and PSI-3 exhibit high levels of additive noise, resulting in no net improvement in the signal-to-noise performance of these early prototypes compared to conventional AMFPIs. However, faster readout rates, coupled with implementation of multiple sampling protocols allowed by the nondestructive nature of pixel readout, resulted in a significantly lower noise level of approximately 560 e (rms) for PSI-3.
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Amplificadores Electrónicos , Radiografía/instrumentación , Compuestos de Silicona , Transistores Electrónicos , Diseño de Equipo , Fotomicrografía , Intensificación de Imagen Radiográfica/instrumentación , Factores de TiempoRESUMEN
PURPOSE: Photon counting arrays (PCAs), capable of measuring the spectral information of individual x-ray photons and recording that information digitally, provide a number of advantages compared to conventional, energy-integrating active matrix flat-panel imagers - such as reducing the undesirable effects of electronic readout noise and Swank noise. While contemporary PCAs are based on crystalline silicon, our group has been examining the use of polycrystalline silicon (poly-Si, a semiconductor material better-suited for the manufacture of large-area devices) for such arrays. In this study, a theoretical investigation of the front-end amplifiers of array pixels incorporating photon counting circuits is described - building upon circuit simulation techniques developed in a previous study. Results for amplifier circuit designs corresponding to prototype PCAs currently under development, as well as for hypothetical circuit designs identified in the study, are reported. In the simulations, performance metrics (such as signal gain, linearity of signal response, and energy resolution) as well as various measures of count rate are determined. METHODS: The simulations employed various input energy distributions (i.e., a 72 kVp spectrum as well as monoenergetic x rays) in order to determine circuit performance. To make the results representative of the properties of poly-Si, the simulations incorporated transistor characteristics that were empirically obtained from test devices. Optimal operating conditions for the circuits were determined by applying criteria to the performance metrics and identifying which conditions minimized settling time. Once the optimal operating conditions were identified, trains of input pulses simulating x-ray flux were used to determine two measures of count rate corresponding to dead time losses of 10% and 30% (referred to as CR10 and CR30 , respectively). RESULTS: The best-performing prototype amplifier design (implemented at a pixel pitch of 1 mm) exhibited CR10 and CR30 values (expressed in counts per second per pixel) of 8.4 and 21.6 kcps/pixel, respectively. A hypothetical amplifier design was derived by modifying transistor, resistor, and capacitor elements of the prototype amplifier designs. This hypothetical design (implemented at a pitch of 1 mm) exhibited CR10 and CR30 values of 154 and 381 kcps/pixel, respectively. When implemented at a pitch of 0.25 mm, the performance of that design increased to 210 and 491 kcps/pixel, respectively (corresponding to counts per second per unit area of 3.4 and 7.9 Mcps/mm2 ). CONCLUSIONS: The simulation methodology described in this paper represents a useful tool for identifying promising designs for the amplifier component of photon counting arrays, as well as evaluating the analog signal and noise performance of those designs. The results obtained from the current study support the hypothesis that large-area, photon counting arrays based on poly-Si transistors can provide clinically useful count rates. Encouraged by these early results, further development of the methodology to assist in the identification and evaluation of even more promising designs, along with development and empirical characterization of prototype designs, is planned.
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Amplificadores Electrónicos , Modelos Teóricos , Fotones , Conteo por Cintilación/instrumentación , Silicio/químicaRESUMEN
PURPOSE: Active matrix flat-panel imagers, which typically incorporate a pixelated array with one a-Si:H thin-film transistor (TFT) per pixel, have become ubiquitous by virtue of many advantages, including large monolithic construction, radiation tolerance, and high DQE. However, at low exposures such as those encountered in fluoroscopy, digital breast tomosynthesis and breast computed tomography, DQE is degraded due to the modest average signal generated per interacting x-ray relative to electronic additive noise levels of ~1000 e, or greater. A promising strategy for overcoming this limitation is to introduce an amplifier into each pixel, referred to as the active pixel (AP) concept. Such circuits provide in-pixel amplification prior to readout as well as facilitate correlated multiple sampling, enhancing signal-to-noise and restoring DQE at low exposures. In this study, a methodology for theoretically investigating the signal and noise performance of imaging array designs is introduced and applied to the case of AP circuits based on low-temperature polycrystalline silicon (poly-Si), a semiconductor suited to manufacture of large area, radiation tolerant arrays. METHODS: Computer simulations employing an analog circuit simulator and performed in the temporal domain were used to investigate signal characteristics and major sources of electronic additive noise for various pixel amplifier designs. The noise sources include photodiode shot noise and resistor thermal noise, as well as TFT thermal and flicker noise. TFT signal behavior and flicker noise were parameterized from fits to measurements performed on individual poly-Si test TFTs. The performance of three single-stage and three two-stage pixel amplifier designs were investigated under conditions relevant to fluoroscopy. The study assumes a 20 × 20 cm2 , 150 µm pitch array operated at 30 fps and coupled to a CsI:Tl x-ray converter. Noise simulations were performed as a function of operating conditions, including sampling mode, of the designs. The total electronic additive noise included noise contributions from each circuit component. RESULTS: The total noise results were found to exhibit a strong dependence on circuit design and operating conditions, with TFT flicker noise generally found to be the dominant noise contributor. For the single-stage designs, significantly increasing the size of the source-follower TFT substantially reduced flicker noise - with the lowest total noise found to be ~574 e [rms]. For the two-stage designs, in addition to tuning TFT sizes and introducing a low-pass filter, replacing a p-type TFT with a resistor (under the assumption in the study that resistors make no flicker noise contribution) resulted in significant noise reduction - with the lowest total noise found to be ~336 e [rms]. CONCLUSIONS: A methodology based on circuit simulations which facilitates comprehensive explorations of signal and noise characteristics has been developed and applied to the case of poly-Si AP arrays. The encouraging results suggest that the electronic additive noise of such devices can be substantially reduced through judicious circuit design, signal amplification, and multiple sampling. This methodology could be extended to explore the noise performance of arrays employing other pixel circuitry such as that for photon counting as well as other semiconductor materials such as a-Si:H and a-IGZO.
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Neoplasias de la Mama/diagnóstico por imagen , Mamografía/instrumentación , Silicio , Diseño de Equipo , Femenino , Fluoroscopía , Humanos , Rayos XRESUMEN
Photon counting arrays (PCAs), defined as pixelated imagers which measure the absorbed energy of x-ray photons individually and record this information digitally, are of increasing clinical interest. A number of PCA prototypes with a 1 mm pixel-to-pixel pitch have recently been fabricated with polycrystalline silicon (poly-Si)-a thin-film technology capable of creating monolithic imagers of a size commensurate with human anatomy. In this study, analog and digital simulation frameworks were developed to provide insight into the influence of individual poly-Si transistors on pixel circuit performance-information that is not readily available through empirical means. The simulation frameworks were used to characterize the circuit designs employed in the prototypes. The analog framework, which determines the noise produced by individual transistors, was used to estimate energy resolution, as well as to identify which transistors contribute the most noise. The digital framework, which analyzes how well circuits function in the presence of significant variations in transistor properties, was used to estimate how fast a circuit can produce an output (referred to as output count rate). In addition, an algorithm was developed and used to estimate the minimum pixel pitch that could be achieved for the pixel circuits of the current prototypes. The simulation frameworks predict that the analog component of the PCA prototypes could have energy resolution as low as 8.9% full width at half maximum (FWHM) at 70 keV; and the digital components should work well even in the presence of significant thin-film transistor (TFT) variations, with the fastest component having output count rates as high as 3 MHz. Finally, based on conceivable improvements in the underlying fabrication process, the algorithm predicts that the 1 mm pitch of the current PCA prototypes could be reduced significantly, potentially to between ~240 and 290 µm.