MRI-based 3-dimensional volumetric assessment of fatty infiltration and muscle atrophy in rotator cuff tears.

BACKGROUND: The Goutallier and Warner Classification systems are useful in determining rotator cuff reparability. Data are limited on how accurately the scapular-Y view used in both systems reflects the 3-dimensional (3-D) changes in fatty infiltration (FI) and muscle atrophy (MA). Tendon retraction in the setting of a cuff tear may also influence the perception of these changes. This study's objectives were to (1) measure the 3-D volume of the supraspinatus muscle in intact rotator cuffs, and with varying magnitudes of retraction; (2) measure the 3-D volume of FI in the supraspinatus muscle in these conditions; and (3) determine the influence of tendon retraction on measured FI and MA using the Goutallier and Warner Classification Systems. METHODS: Between August 2015 and February 2016, all shoulder magnetic resonance images (MRIs) at the Portland VA Medical Center were standardized to include the medial scapular border. MRIs and charts were reviewed for inclusion/exclusion criteria. Included MRIs were categorized into 4 groups based on rotator cuff retraction. Supraspinatus muscle and fossa were traced to create 3-D volumes. FI and MA were measured within the supraspinatus. The supraspinatus muscle was graded among 6 physicians using the Goutallier and Warner classification systems. These grades were compared to 3-D measured FI and MA. The influence of tendon retraction on the measured grades were also evaluated. RESULTS: One hundred nine patients met inclusion/exclusion criteria. Ten MRIs for each group (N = 40) were included for image analysis. Supraspinatus volume tracings were highly reproducible and consistent between tracers. Supraspinatus muscle volumes decreased while global FI and MA increased with greater degrees of tendon retraction. In muscles with less than 10% global fat, fat concentrated in the lateral third of the muscle. In muscle with more than 10% global fat content, it distributed more diffusely throughout the muscle from medial to lateral. In comparing the scapular-Y to a medial cut, there was no consistent trend in FI whereas MA was more accurate at the medial cut. CONCLUSION: Parasagittal imaging location did not significantly influence the Goutallier score; however, assessment of MA using the Warner score leads readers to perceive less MA medially regardless of the magnitude of tendon retraction. The pattern of FI within the supraspinatus muscle changes from a laterally based location around the muscle-tendon junction to a more diffuse, global infiltration pattern when the whole muscle fat content exceeds 10%.

Transcriptomic response of Gordonia sp. strain NB4-1Y when provided with 6:2 fluorotelomer sulfonamidoalkyl betaine or 6:2 fluorotelomer sulfonate as sole sulfur source.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are environmental contaminants of concern. We previously described biodegradation of two PFAS that represent components and transformation products of aqueous film-forming foams (AFFF), 6:2 fluorotelomer sulfonamidoalkyl betaine (6:2 FTAB) and 6:2 fluorotelomer sulfonate (6:2 FTSA), by Gordonia sp. strain NB4-1Y. To identify genes involved in the breakdown of these compounds, the transcriptomic response of NB4-1Y was examined when grown on 6:2 FTAB, 6:2 FTSA, a non-fluorinated analog of 6:2 FTSA (1-octanesulfonate), or MgSO4, as sole sulfur source. Differentially expressed genes were identified as those with ± 1.5 log2-fold-differences (± 1.5 log2FD) in transcript abundances in pairwise comparisons. Transcriptomes of cells grown on 6:2 FTAB and 6:2 FTSA were most similar (7.9% of genes expressed ± 1.5 log2FD); however, several genes that were expressed in greater abundance in 6:2 FTAB treated cells compared to 6:2 FTSA treated cells were noted for their potential role in carbon-nitrogen bond cleavage in 6:2 FTAB. Responses to sulfur limitation were observed in 6:2 FTAB, 6:2 FTSA, and 1-octanesulfonate treatments, as 20 genes relating to global sulfate stress response were more highly expressed under these conditions compared to the MgSO4 treatment. More highly expressed oxygenase genes in 6:2 FTAB, 6:2 FTSA, and 1-octanesulfonate treatments were found to code for proteins with lower percent sulfur-containing amino acids compared to both the total proteome and to oxygenases showing decreased expression. This work identifies genetic targets for further characterization and will inform studies aimed at evaluating the biodegradation potential of environmental samples through applied genomics.

Analysis of closed versus operating dairies in the southeastern United States.

This study analyzed differences between dairies that have closed compared with dairies still operating in the southeastern United States. Significant changes have occurred in the US dairy industry in the last decade, involving the number of dairy farms, herd size, milk quality, and management practices, yet the dairy industry remains the fourth leading agricultural sector in the United States, with $38 billion of milk sales in 2017. Although the number of dairy cows in the United States has remained relatively constant over the past decade, at approximately 9 million head, the number of dairy operations has decreased by 30%, resulting in larger dairies. This trend is even more prevalent in the southeastern United States, where the number of dairies has decreased by 39% from 5,315 in 2008 to only 3,235 in 2017. Additionally, downward pressure on bulk tank somatic cell count, which is used as a milk quality metric and has implications regarding animal health, intensified with US processors' introduction of incentive and penalty systems for quality milk production, necessitating better management of mastitis in dairy herds. In this context, this study examines factors that affect southeastern US dairy farms' persistence in the industry by using primary survey data collected in 2013 through a mail survey of Grade A dairies in Georgia, Mississippi, Kentucky, North Carolina, South Carolina, Tennessee, and Virginia. Dairies that were no longer operational had exited the industry from 2007 through 2014. A probit regression was used to determine which farm and operator characteristics were associated with the dairy's operational status. Dairy farms with more cows and higher average milk production per cow were more likely to be operational. For an additional 10 kg/d of milk production per cow, the dairy was 1.5% more likely to be operational. For each 100 additional cows a dairy had, it was 4% more likely to be operational. The analysis also identifies nonpecuniary determinants of operational status for southeastern US dairies, such as mastitis management practices. Findings suggest that operations capable of leveraging scale effects are more likely to remain operational, with results affirming the consolidation of the US dairy industry and demonstrating that more productive farms are more likely to stay in operation. Results also suggest that factors other than farm size affect a dairy's operational status.

Autophagy function and its relationship to pathology, clinical applications, drug metabolism and toxicity.

Autophagy is a cellular process that facilitates nutrient turnover and removal of expended macromolecules and organelles to maintain homeostasis. The recycling of cytosolic macromolecules and damaged organelles by autophagosomes occurs through the lysosomal degradation pathway. Autophagy can also be upregulated as a prosurvival pathway in response to stress stimuli such as starvation, hypoxia or cell damage. Over the last two decades, there has been a surge in research revealing the basic molecular mechanisms of autophagy in mammalian cells. A corollary of an advanced understanding of autophagy has been a concurrent expansion of research into understanding autophagic function and dysfunction in pathology. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets in treating disease and cancer. In this review, advances in understanding the molecular basis of mammalian autophagy, methods used to induce and evaluate autophagy, and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis are discussed. Copyright © 2016 John Wiley & Sons, Ltd.

The role of surface chemistry in the cytotoxicity profile of graphene.

Graphene and its derivative, because of their unique physical, electrical and chemical properties, are an important class of nanomaterials being proposed as foundational materials in nanomedicine as well as for a variety of industrial applications. A major limitation for graphene, when used in biomedical applications, is its poor solubility due to its rather hydrophobic nature. Therefore, chemical functionalities are commonly introduced to alter both its surface chemistry and biochemical activity. Here, we show that surface chemistry plays a major role in the toxicological profile of the graphene structures. To demonstrate this, we chemically increased the oxidation level of the pristine graphene and compared the corresponding toxicological effects along with those for the graphene oxide. X-ray photoelectron spectroscopy revealed that pristine graphene had the lowest amount of surface oxygen, while graphene oxide had the highest at 2.5% and 31%, respectively. Low and high oxygen functionalized graphene samples were found to have 6.6% and 24% surface oxygen, respectively. Our results showed a dose-dependent trend in the cytotoxicity profile, where pristine graphene was the most cytotoxic, with decreasing toxicity observed with increasing oxygen content. Increased surface oxygen also played a role in nanomaterial dispersion in water or cell culture medium over longer periods. It is likely that higher dispersity might result in graphene entering into cells as individual flakes ~1 nm thick rather than as more cytotoxic aggregates. In conclusion, changes in graphene's surface chemistry resulted in altered solubility and toxicity, suggesting that a generalized toxicity profile would be rather misleading. Copyright © 2016 John Wiley & Sons, Ltd.

p53-competent cells and p53-deficient cells display different susceptibility to oxygen functionalized graphene cytotoxicity and genotoxicity.

Due to the distinctive physical, electrical, and chemical properties of graphene nanomaterials, numerous efforts pursuing graphene-based biomedical and industrial applications are underway. Oxidation of pristine graphene surfaces mitigates its otherwise hydrophobic characteristic thereby improving its biocompatibility and functionality. Yet, the potential widespread use of oxidized graphene derivatives raises concern about adverse impacts on human health. The p53 tumor suppressor protein maintains cellular and genetic stability after toxic exposures. Here, we show that p53 functional status correlates with oxygen functionalized graphene (f-G) cytotoxicity and genotoxicity in vitro. The f-G exposed p53-competent cells, but not p53-deficient cells, initiated G0 /G1 phase cell cycle arrest, suppressed reactive oxygen species, and entered apoptosis. There was p53-dependent f-G genotoxicity evident as increased structural chromosome damage, but not increased gene mutation or chromatin loss. In conclusion, the cytotoxic and genotoxic potential for f-G in exposed cells was dependent on the p53 functional status. These findings have broad implications for the safe and effective implementation of oxidized graphene derivatives into biomedical and industrial applications. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Farm business and operator variables associated with bulk tank somatic cell count from dairy herds in the southeastern United States.

Mastitis is a worldwide problem in dairy cows and results in reduced milk production, the culling of cows, and other economic losses. Bulk tank somatic cell count (BTSCC) over 200,000 cells/mL often indicates underlying subclinical mastitis in dairy herds. Several preventative measures that can be implemented to help improve the incidence of mastitis exist, but surveys find these practices not fully adopted by producers. The goal of this research was to analyze the farm and operator characteristics associated with BTSCC in dairy herds by analyzing a survey of dairy producers in the southeastern United States. We examined this region because it has experienced a decline in the number of dairy farms, dairy cows, and milk production over the past 2 decades. The southeast region is also associated with higher BTSCC levels than the national average. Dairy farms in Georgia, Mississippi, Kentucky, North Carolina, South Carolina, Tennessee, and Virginia were surveyed. Producers were asked questions about the BTSCC at which they take action to address BTSCC, the information sources they use to learn about and manage BTSCC, farm structure and management characteristics, and attitudinal variables associated with profitability, managerial control, and planning horizon. Least squares regression was used to determine how these factors were associated with BTSCC levels across the 7-state region. Concern over mastitis, financial consequences of mastitis, and increased previous-year BTSCC were associated with higher current BTSCC levels. Obtaining information about mastitis from veterinarians and extension personnel, taking action against mastitis at a BTSCC less than 300,000 cells/mL, and perceived ability to control processes and mastitis incidence were associated with reduced BTSCC. We found average BTSCC was lower in North Carolina and Virginia. These results suggest that proactive producers (i.e., those that perceive they can control BTSCC and seek information from reliable sources), were more likely to report lower BTSCC. As a result, it may be possible to achieve improved milk quality, evident from lowered BTSCC, across the region.

Measurement of Hydrodynamic Growth near Peak Velocity in an Inertial Confinement Fusion Capsule Implosion using a Self-Radiography Technique.

First measurements of hydrodynamic growth near peak implosion velocity in an inertial confinement fusion (ICF) implosion at the National Ignition Facility were obtained using a self-radiographing technique and a preimposed Legendre mode 40, λ=140 µm, sinusoidal perturbation. These are the first measurements of the total growth at the most unstable mode from acceleration Rayleigh-Taylor achieved in any ICF experiment to date, showing growth of the areal density perturbation of ∼7000×. Measurements were made at convergences of ∼5 to ∼10× at both the waist and pole of the capsule, demonstrating simultaneous measurements of the growth factors from both lines of sight. The areal density growth factors are an order of magnitude larger than prior experimental measurements and differed by ∼2× between the waist and the pole, showing asymmetry in the measured growth factors. These new measurements significantly advance our ability to diagnose perturbations detrimental to ICF implosions, uniquely intersecting the change from an accelerating to decelerating shell, with multiple simultaneous angular views.

Confirmation of Pig-a mutation in flow cytometry-identified CD48-deficient T-lymphocytes from F344 rats.

The Pig-a assay is used for monitoring somatic cell mutation in laboratory animals and humans. The assay detects haematopoietic cells deficient in glycosylphosphatidylinositol (GPI)-anchored protein surface markers using flow cytometry. However, given that synthesis of the protein markers (and the expression of their genes) is independent of the expression of the X-linked Pig-a gene and the function of its enzyme product, the deficiency of markers at the surface of the cells may be caused by a number of events (e.g. by mutation or epigenetic silencing in the marker gene itself or in any of about two dozen autosomal genes involved in the synthesis of GPI). Here we provide direct evidence that the deficiency of the GPI-anchored surface marker CD48 in rat T-cells is accompanied by mutation in the endogenous X-linked Pig-a gene. We treated male F344 rats with N-ethyl-N-nitrosourea (ENU), and established colonies from flow cytometry-identified and sorted CD48-deficient spleen T-lymphocytes. Molecular analysis confirmed that the expanded sorted cells have mutations in the Pig-a gene. The spectrum of Pig-a mutation in our model was consistent with the spectrum of ENU-induced mutation determined in other in vivo models, mostly base-pair substitutions at A:T with the mutated T on the non-transcribed strand of Pig-a genomic DNA. We also used next generation sequencing to derive a similar mutational spectrum from a pool of 64 clones developed from flow-sorted CD48-deficient lymphocytes. Our findings confirm that Pig-a assays detect what they are designed to detect-gene mutation in the Pig-a gene.

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate.

Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low- (P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until ∼5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent.

Time-resolved X-ray diffraction diagnostic development for the National Ignition Facility.

We present the development of an experimental platform that can collect four frames of x-ray diffraction data along a single line of sight during laser-driven, dynamic-compression experiments at the National Ignition Facility. The platform is comprised of a diagnostic imager built around ultrafast sensors with a 2-ns integration time, a custom target assembly that serves also to shield the imager, and a 10-ns duration, quasi-monochromatic x-ray source produced by laser-generated plasma. We demonstrate the performance with diffraction data for Pb ramp compressed to 150 GPa and illuminated by a Ge x-ray source that produces ∼7 × 1011, 10.25-keV photons/ns at the 400 µm diameter sample.

Potential value of animal microphysiological systems.

Microphysiological systems (MPS) are designed to recapitulate aspects of tissue/organ physiology in vivo, thereby providing potential value in safety and efficacy assessments of FDA-regulated products and regulatory decision-making. While there have been significant advances in the development, use, and proposals of qualification criteria for human organ MPS, there remains a gap in the development using animal tissues. Animal MPS may be of value in many areas including the study of zoonotic diseases, assessment of the safety and efficacy of animal therapeutics, and possibly reduction of the use of animals in regulatory submissions for animal therapeutics. In addition, the development of MPS from various animal species enables comparison to animal in vivo data. This comparison, while not always critical for all contexts of use, could help gain confidence in the use and application of human MPS data for regulatory decision-making and for the potential identification of species-specific effects. The use of animal MPS is consistent with the replacement, reduction, and refinement (3Rs) principles of animal use by identifying toxic compounds before conducting in vivo studies and identifying the appropriate species for testing.

Microphysiological systems (MPS) mimic aspects of organs in humans or animals. These systems may provide information useful for FDA-regulated products. While there have been significant advances in the development of MPS made from human cells, there remains a gap in the development of MPS using animal cells. FDA believes animal MPS may be of value in many areas including the study of diseases transmitted from animals to humans, assessment of the safety and efficacy of animal drugs, and reduction of the use of animals in regulatory submissions. The development of animal MPS enables comparison to data from studies conducted in animals. This comparison provides confidence in the use of human MPS data for regulatory decision-making. The use of animal MPS is consistent with the 3Rs principles of animal use by allowing identification of toxic compounds before conducting animal studies and by helping select the appropriate species for further testing.

Analysis and mitigation of an oscillating background on hybrid complementary metal-oxide semiconductor (hCMOS) imaging sensors at the National Ignition Facility.

Nanosecond-gated hybrid complementary metal-oxide semiconductor imaging sensors are a powerful tool for temporally gated and spatially resolved measurements in high energy density science, including inertial confinement fusion, and in laser diagnostics. However, a significant oscillating background excited by photocurrent has been observed in image sequences during testing and in experiments at the National Ignition Facility (NIF). Characterization measurements and simulation results are used to explain the oscillations as the convolution of the pixel-level sensor response with a sensor-wide RLC circuit ringing. Data correction techniques are discussed for NIF diagnostics, and for diagnostics where these techniques cannot be used, a proof-of-principle image correction algorithm is presented.

In vivo genotoxicity of furan in F344 rats at cancer bioassay doses.

Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 and 16mg/kg. Rats were killed 3h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single-cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity.

Evaluation of p53 genotype on gene expression in the testis, liver, and heart from male C57BL/6 mice.

Our laboratory is conducting experiments designed to characterize the role of p53 in gene expression in the TSG-p53® mouse model. In the study reported here, gene expression levels in tissue derived from the testis, liver, and heart of male, 8-9 week old, p53 wild-type (WT), heterozygous (HET) or knockout (KO) mice were determined utilizing a targeted qPCR 84-gene array. The heart, liver and testis were selected because of the unique function and rate of cell division of each tissue. The genes on the arrays were categorized into three Functional Gene Groups, Apoptosis, Cell-Cycle and DNA Repair. Differences in expression of the functional groups were determined by multivariate analysis of variance (MANOVA) and significant (P < 0.05) differences in their expression were found among the heart, liver and testis. Further, the expression of the Functional Gene Groups in each of these tissues was also significantly affected by p53 genotype. These data indicate that gene expression in unperturbed tissue is influenced by the status of p53 genotype, and relates, at least partially, to the function of the tissue.

The genetic toxicity of methylphenidate: a review of the current literature.

Attention deficit/hyperactivity disorder (ADHD), a common children's behavioral disorder, is characterized by inattention, hyperactivity and impulsivity. The disorder is thought to stem from abnormalities in the catecholamine pathway and the symptoms of the disorder have been successfully treated with methylphenidate (MPH) since the FDA approved the drug in the 1950s. MPH underwent the appropriate safety testing as part of the FDA approval process; however, a publication in 2005 that reported significant increases in cytogenetic damage in the lymphocytes of MPH-treated pediatric patients caused concern for patients and their families, the pharmaceutical industry and regulatory agencies. This communication will review the many studies that were subsequently initiated worldwide to address the genetic safety of MPH in both animal models and human subjects. Animal experiments broadened the study protocols used in the 2005 investigation to include a wider dose-range, a longer treatment period and automated scoring of biological endpoints, where possible, to reduce observer bias. The human subject studies replicated the experimental design used in the 2005 study, but increased the treatment periods and the sizes of the study populations. Neither the laboratory animal nor human subject studies found an increase in any of the measures of genetic damage that were evaluated. Taken together, these new studies are consistent with the original safety evaluation of the FDA and do not support the hypothesis that MPH treatment increases the risk of genetic damage in ADHD patients. Published 2012. This article is a US Government work and is in the public domain in the USA.

A study of space charge induced non-linearity in the Single Line Of Sight camera.

A new generation of gated x-ray detectors at the National Ignition Facility has brought faster, enhanced imaging capabilities. Their performance is currently limited by the amount of signal they can be operated with before space charge effects in their electron tube start to compromise their temporal and spatial response. We present a technique to characterize this phenomenon and apply it to a prototype of such a system, the Single Line Of Sight camera. The results of this characterization are used to benchmark particle-in-cell simulations of the electrons drifting inside the detector, which are found to well reproduce the experimental data. These simulations are then employed to predict the optimum photon flux to the camera, with the goal to increase the quality of the images obtained on an experimental campaign while preventing the appearance of deleterious effects. They also offer some insights into some of the improvements that can be brought to the new pulse-dilation systems being built at Lawrence Livermore National Laboratory.

Characterization of the hardened single line of sight camera at the National Ignition Facility.

The hardened single line of sight camera has been recently characterized in preparation for its deployment on the National Ignition Facility. The latest creation based on the pulse-dilation technology leads to many new features and improvements over the previous-generation cameras to provide better quality measurements of inertial confinement fusion experiments, including during high neutron yield implosions. Here, we present the characterization data that illustrate the main performance features of this instrument, such as extended dynamic range and adjustable internal magnification, leading to improved spatial resolution.

MAPK signaling and a mobile scaffold complex regulate AMPA receptor transport to modulate synaptic strength.

Synaptic plasticity depends on rapid experience-dependent changes in the number of neurotransmitter receptors. Previously, we demonstrated that motor-mediated transport of AMPA receptors (AMPARs) to and from synapses is a critical determinant of synaptic strength. Here, we describe two convergent signaling pathways that coordinate the loading of synaptic AMPARs onto scaffolds, and scaffolds onto motors, thus providing a mechanism for experience-dependent changes in synaptic strength. We find that an evolutionarily conserved JIP-protein scaffold complex and two classes of mitogen-activated protein kinase (MAPK) proteins mediate AMPAR transport by kinesin-1 motors. Genetic analysis combined with in vivo, real-time imaging in Caenorhabditis elegans revealed that CaMKII is required for loading AMPARs onto the scaffold, and MAPK signaling is required for loading the scaffold complex onto motors. Our data support a model where CaMKII signaling and a MAPK-signaling pathway cooperate to facilitate the rapid exchange of AMPARs required for early stages of synaptic plasticity.

Timing characterization of fast hCMOS sensors.

We describe a method of analyzing gate profile data for ultrafast x-ray imagers that allows pixel-by-pixel determination of temporal sensitivity in the presence of substantial background oscillations. With this method, systematic timing errors in gate width and gate arrival time of up to 1 ns (in a 2 ns wide gate) can be removed. In-sensor variations in gate arrival and gate width are observed, with variations in each up to 0.5 ns. This method can be used to estimate the coarse timing of the sensor, even if errors up to several ns are present.