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1.  The Part Task of the Part-Spacing Paradigm Is Not a Pure Measurement of Part-Based Information of Faces 
PLoS ONE  2009;4(7):e6239.
Background
Faces are arguably one of the most important object categories encountered by human observers, yet they present one of the most difficult challenges to both the human and artificial visual systems. A variety of experimental paradigms have been developed to study how faces are represented and recognized, among which is the part-spacing paradigm. This paradigm is presumed to characterize the processing of both the featural and configural information of faces, and it has become increasingly popular for testing hypotheses on face specificity and in the diagnosis of face perception in cognitive disorders.
Methodology/Principal Findings
In two experiments we questioned the validity of the part task of this paradigm by showing that, in this task, measuring pure information about face parts is confounded by the effect of face configuration on the perception of those parts. First, we eliminated or reduced contributions from face configuration by either rearranging face parts into a non-face configuration or by removing the low spatial frequencies of face images. We found that face parts were no longer sensitive to inversion, suggesting that the previously reported inversion effect observed in the part task was due in fact to the presence of face configuration. Second, self-reported prosopagnosic patients who were selectively impaired in the holistic processing of faces failed to detect part changes when face configurations were presented. When face configurations were scrambled, however, their performance was as good as that of normal controls.
Conclusions/Significance
In sum, consistent evidence from testing both normal and prosopagnosic subjects suggests the part task of the part-spacing paradigm is not an appropriate task for either measuring how face parts alone are processed or for providing a valid contrast to the spacing task. Therefore, conclusions from previous studies using the part-spacing paradigm may need re-evaluation with proper paradigms.
doi:10.1371/journal.pone.0006239
PMCID: PMC2706049  PMID: 19603077
2.  Noise correlation in PET, CT, SPECT and PET/CT data evaluated using autocorrelation function: a phantom study on data, reconstructed using FBP and OSEM 
Background
Positron Emission Tomography (PET), Computed Tomography (CT), PET/CT and Single Photon Emission Tomography (SPECT) are non-invasive imaging tools used for creating two dimensional (2D) cross section images of three dimensional (3D) objects. PET and SPECT have the potential of providing functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules, whereas CT visualizes X-ray density in tissues in the body. PET/CT provides fused images representing both functional and anatomical information with better precision in localization than PET alone.
Images generated by these types of techniques are generally noisy, thereby impairing the imaging potential and affecting the precision in quantitative values derived from the images. It is crucial to explore and understand the properties of noise in these imaging techniques. Here we used autocorrelation function (ACF) specifically to describe noise correlation and its non-isotropic behaviour in experimentally generated images of PET, CT, PET/CT and SPECT.
Methods
Experiments were performed using phantoms with different shapes. In PET and PET/CT studies, data were acquired in 2D acquisition mode and reconstructed by both analytical filter back projection (FBP) and iterative, ordered subsets expectation maximisation (OSEM) methods. In the PET/CT studies, different magnitudes of X-ray dose in the transmission were employed by using different mA settings for the X-ray tube. In the CT studies, data were acquired using different slice thickness with and without applied dose reduction function and the images were reconstructed by FBP. SPECT studies were performed in 2D, reconstructed using FBP and OSEM, using post 3D filtering. ACF images were generated from the primary images, and profiles across the ACF images were used to describe the noise correlation in different directions. The variance of noise across the images was visualised as images and with profiles across these images.
Results
The most important finding was that the pattern of noise correlation is rotation symmetric or isotropic, independent of object shape in PET and PET/CT images reconstructed using the iterative method. This is, however, not the case in FBP images when the shape of phantom is not circular. Also CT images reconstructed using FBP show the same non-isotropic pattern independent of slice thickness and utilization of care dose function. SPECT images show an isotropic correlation of the noise independent of object shape or applied reconstruction algorithm. Noise in PET/CT images was identical independent of the applied X-ray dose in the transmission part (CT), indicating that the noise from transmission with the applied doses does not propagate into the PET images showing that the noise from the emission part is dominant. The results indicate that in human studies it is possible to utilize a low dose in transmission part while maintaining the noise behaviour and the quality of the images.
Conclusion
The combined effect of noise correlation for asymmetric objects and a varying noise variance across the image field significantly complicates the interpretation of the images when statistical methods are used, such as with statistical estimates of precision in average values, use of statistical parametric mapping methods and principal component analysis. Hence it is recommended that iterative reconstruction methods are used for such applications. However, it is possible to calculate the noise analytically in images reconstructed by FBP, while it is not possible to do the same calculation in images reconstructed by iterative methods. Therefore for performing statistical methods of analysis which depend on knowing the noise, FBP would be preferred.
doi:10.1186/1471-2342-5-5
PMCID: PMC1208889  PMID: 16122383
3.  A Quantitative Study of Airway Changes on Micro-CT in a Mouse Asthma Model: Comparison With Histopathological Findings 
Purpose
To evaluate airway changes in ovalbumin-induced asthmatic mice in terms of postmortem micro-CT images and pathological findings.
Methods
Asthma was induced in mice by intraperitoneal injection and nasal instillation of ovalbumin aluminium hydroxide into mice (experimental group, n=6), and another group of mice received intraperitoneal injection and nasal instillation of distilled phosphate-buffered saline (control group, n=6). Bronchial lumen area was measured in the main bronchial lumen of the distal third bronchial branch level (6 parts per each mouse) on axial scans of Micro-CT, using a Lucion's smart pen (semi-automated) and a curve pen (manual). Bronchial wall thickness was obtained in 4 sections (2 levels on either side) after the third bronchial branch by measuring the diameter which was perpendicular to the longitudinal axis of the main bronchus on curved Multi-planar reconstruction (MPR) images. Histologic slides were obtained from the lesion that was matched with its CT images, and bronchial wall thicknesses were determined.
Results
The mean bronchial lumen area was 0.196±0.072 mm2 in the experimental group and 0.243±0.116 mm2 in the control group; the difference was significant. Bronchial wall thickness on micro-CT images (mean, 0.119±0.01 vs. 0.108±0.013 mm) and in pathological specimens (mean, 0.066±0.011 vs. 0.041±0.009 mm) were thicker in the experimental group than in the control group; bronchial wall thickness on micro-CT images correlated well with pathological thickness (for the experimental group, r=0.712; for the control group, r=0.46). The thick bronchial wall in the experimental group demonstrated submucosal hypertrophy along with goblet cell hyperplasia and smooth muscle hyperplasia.
Conclusions
The results of this study suggest that asthma may induce thickening of bronchial wall and narrowing of the lumen area on micro-CT images and that these results may significantly correlate with pathological findings.
doi:10.4168/aair.2014.6.1.75
PMCID: PMC3881405  PMID: 24404397
Bronchial asthma; mice Laboratory; x-ray Micro-CT scans; airway remodeling; quantitative evaluation; histopathology; case comparison studies
4.  Hierarchical spatio-temporal extraction of models for moving rigid parts 
Pattern Recognition Letters  2011;32(16-2):2239-2249.
Highlights
► Extract part-based model based on trajectories of features. ► Model consists of rigid parts connected via points of articulation. ► Analyze movement in triangulated graph. ► Filter triangles which are not relevant. ► Group triangles which undergo similar motion.
This paper presents a method to extract a part-based model of an observed scene from a video sequence. Independent motion is a strong cue that two points belong to different “rigid” entities. Conversely, things that move together throughout the whole video belong together and define a “rigid” object or part. Successfully tracked features indicate trajectories of salient points in the scene. A triangulated graph connects the salient points and encodes their local neighborhood in the first frame. The length variation of the triangle edges is used to label them as relevant (on an object) or separating (connecting different objects). A following grouping process uses the motion of the triangles marked as relevant as a cue to identify the “rigid” parts of the foreground or the background. The choice of the motion-based grouping criterion depends on the type of motion: in the image plane or out of the image plane. The result is a hierarchical description (graph pyramid) of the scene, where each vertex in the top level of the pyramid represents a “rigid” part of the foreground or the background, and encloses to the salient features used to describe it. Promising experimental results show the potential of the approach.
doi:10.1016/j.patrec.2011.05.005
PMCID: PMC3223567  PMID: 22199412
Rigid parts; Articulated objects; Model extraction; Graph pyramid
5.  Magnetoacoustic Tomography with Magnetic Induction (MAT-MI) 
Physics in medicine and biology  2005;50(21):5175-5187.
We report our theoretical and experimental investigations on a new imaging modality, magnetoacoustic tomography with magnetic induction (MAT-MI). In MAT-MI, the sample is located in a static magnetic field and a time-varying (μs ) magnetic field. The time-varying magnetic field induces eddy current in the sample. Consequently, the sample will emit ultrasonic waves by the Lorentz force. The ultrasonic signals are collected around the object to reconstruct images related with the electrical impedance distribution in the sample. MAT-MI combines the good contrast of electrical impedance tomography with the good spatial resolution of sonography. In principle, MAT-MI mainly has two unique features due to the solenoid nature of the induced electrical field. Firstly, MAT-MI could provide explicit or simple quantitative reconstruction algorithm for the electrical impedance distribution. Secondly, it promises to eliminate the shielding effects of other imaging modalities in which the current is applied directly with electrodes. In the theoretical part, we provide the formulas for both the forward and inverse problems of MAT-MI and estimate the signal amplitude in biological tissues. In the experimental part, the experiment setup and methods are introduced and the signals and the image of a metal object by means of MAT-MI are presented. The promising pilot experimental results suggest the feasibility of the proposed MAT-MI approach.
doi:10.1088/0031-9155/50/21/015
PMCID: PMC1815477  PMID: 16237248
6.  Synchronized Drumming Enhances Activity in the Caudate and Facilitates Prosocial Commitment - If the Rhythm Comes Easily 
PLoS ONE  2011;6(11):e27272.
Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter “accidentally” dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system.
doi:10.1371/journal.pone.0027272
PMCID: PMC3217964  PMID: 22110623
7.  The Mysterious Noh Mask: Contribution of Multiple Facial Parts to the Recognition of Emotional Expressions 
PLoS ONE  2012;7(11):e50280.
Background
A Noh mask worn by expert actors when performing on a Japanese traditional Noh drama is suggested to convey countless different facial expressions according to different angles of head/body orientation. The present study addressed the question of how different facial parts of a Noh mask, including the eyebrows, the eyes, and the mouth, may contribute to different emotional expressions. Both experimental situations of active creation and passive recognition of emotional facial expressions were introduced.
Methodology/Principal Findings
In Experiment 1, participants either created happy or sad facial expressions, or imitated a face that looked up or down, by actively changing each facial part of a Noh mask image presented on a computer screen. For an upward tilted mask, the eyebrows and the mouth shared common features with sad expressions, whereas the eyes with happy expressions. This contingency tended to be reversed for a downward tilted mask. Experiment 2 further examined which facial parts of a Noh mask are crucial in determining emotional expressions. Participants were exposed to the synthesized Noh mask images with different facial parts expressing different emotions. Results clearly revealed that participants primarily used the shape of the mouth in judging emotions. The facial images having the mouth of an upward/downward tilted Noh mask strongly tended to be evaluated as sad/happy, respectively.
Conclusions/Significance
The results suggest that Noh masks express chimeric emotional patterns, with different facial parts conveying different emotions This appears consistent with the principles of Noh which highly appreciate subtle and composite emotional expressions, as well as with the mysterious facial expressions observed in Western art. It was further demonstrated that the mouth serves as a diagnostic feature in characterizing the emotional expressions. This indicates the superiority of biologically-driven factors over the traditionally formulated performing styles when evaluating the emotions of the Noh masks.
doi:10.1371/journal.pone.0050280
PMCID: PMC3503996  PMID: 23185595
8.  The Effect of Body Image Threat on Smoking Motivation Among College Women: Mediation by Negative Affect 
Previous descriptive, correlational, and quasi-experimental research has established that weight concerns and negative body image are associated with tobacco smoking, cessation, and relapse among young women. A recent experimental study found that activation of negative body image cognitions produced urges to smoke (Lopez, Drobes, Thompson, & Brandon, 2008). The current study intended to replicate and extend these experimental findings by examining the role of negative affect as a mediator of the relationship between body dissatisfaction and smoking urges. Female college smokers (N = 133) were randomly assigned to a body image challenge (trying on a bathing suit) or a control condition (evaluating a purse). State levels of urge to smoke, mood, and body dissatisfaction were assessed both pre- and post-manipulation. Trying on a bathing suit increased body dissatisfaction and reported urges to smoke, particularly those urges related to reducing negative affect. Additionally, state negative affect mediated the relationship between the body image manipulation and smoking urge. This study provides additional support, through an experimental design, that situational challenges to body image influence smoking motivation, and that this effect occurs, at least in part, via increases in negative affect. Theoretical and applied implications are discussed.
doi:10.1037/a0014291
PMCID: PMC3989068  PMID: 19586144
9.  Investigating Effective Brain Connectivity from fMRI Data: Past Findings and Current Issues with Reference to Granger Causality Analysis 
Brain Connectivity  2012;2(5):235-245.
Abstract
Interactions between brain regions have been recognized as a critical ingredient required to understand brain function. Two modes of interactions have held prominence—synchronization and causal influence. Efforts to ascertain causal influence from functional magnetic resonance imaging (fMRI) data have relied primarily on confirmatory model-driven approaches, such as dynamic causal modeling and structural equation modeling, and exploratory data-driven approaches such as Granger causality analysis. A slew of recent articles have focused on the relative merits and caveats of these approaches. The relevant studies can be classified into simulations, theoretical developments, and experimental results. In the first part of this review, we will consider each of these themes and critically evaluate their arguments, with regard to Granger causality analysis. Specifically, we argue that simulations are bounded by the assumptions and simplifications made by the simulator, and hence must be regarded only as a guide to experimental design and should not be viewed as the final word. On the theoretical front, we reason that each of the improvements to existing, yet disparate, methods brings them closer to each other with the hope of eventually leading to a unified framework specifically designed for fMRI. We then review latest experimental results that demonstrate the utility and validity of Granger causality analysis under certain experimental conditions. In the second part, we will consider current issues in causal connectivity analysis—hemodynamic variability, sampling, instantaneous versus causal relationship, and task versus resting states. We highlight some of our own work regarding these issues showing the effect of hemodynamic variability and sampling on Granger causality. Further, we discuss recent techniques such as the cubature Kalman filtering, which can perform blind deconvolution of the hemodynamic response robustly well, and hence enabling wider application of Granger causality analysis. Finally, we discuss our previous work on the less-appreciated interactions between instantaneous and causal relationships and the utility and interpretation of Granger causality results obtained from task versus resting state (e.g., ability of causal relationships to provide a mode of connectivity between regions that are instantaneously dissociated in resting state). We conclude by discussing future directions in this area.
doi:10.1089/brain.2012.0091
PMCID: PMC3621319  PMID: 23016794
brain networks; blind hemodynamic deconvolution; effective connectivity; functional connectivity; Granger causality
10.  Parental inconsistency, impulsive choice and neural value representations in healthy adolescents 
Translational Psychiatry  2014;4(4):e382-.
A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13–15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention.
doi:10.1038/tp.2014.20
PMCID: PMC4012284  PMID: 24736798
11.  Induction of malignant nasal cavity tumours in Wistar rats fed Chinese salted fish. 
British Journal of Cancer  1989;60(2):198-201.
Epidemiological evidence has implicated Chinese salted fish as a human nasopharyngeal carcinogen. In the present study, 221 Wistar-Kyoto rats aged 21 days were randomly assigned to one of three experimental groups. Rats in group 1 (high dose group) were fed a powder diet of one part Chinese salted fish to three parts certified rat chow during the first 18 months. Similarly, rats in group 2 (low dose group) were fed a powder diet of one part salted fish to five parts rat chow for 18 months. Rats in group 3 were given rat chow only throughout the 3-year experiment. Four malignant tumours of the nasal cavity were observed among rats fed the experimental diets (three and one respectively in the high and low dose groups). No comparable tumours were observed in controls, compatible with the historical control rate of zero. Our results, therefore, further strengthen the hypothesis that Chinese salted fish is a human nasopharyngeal carcinogen; they also establish Wistar rats as a viable animal model for carcinogenicity studies of this food in the laboratory.
Images
PMCID: PMC2247048  PMID: 2765365
12.  Bayesian reconstruction of P(r) directly from two-dimensional detector images via a Markov chain Monte Carlo method 
Journal of Applied Crystallography  2013;46(Pt 2):404-414.
A new method for reconstruction of the interatomic distance distribution, P(r), directly from two-dimensional detector images of solution scattering data is developed and tested. This method employs Bayesian inference and a Markov chain Monte Carlo method to simultaneously estimate indirect transform coefficients and beam and detector parameters, while also evaluating the covariance among all parameters.
The interatomic distance distribution, P(r), is a valuable tool for evaluating the structure of a molecule in solution and represents the maximum structural information that can be derived from solution scattering data without further assumptions. Most current instrumentation for scattering experiments (typically CCD detectors) generates a finely pixelated two-dimensional image. In contin­uation of the standard practice with earlier one-dimensional detectors, these images are typically reduced to a one-dimensional profile of scattering inten­sities, I(q), by circular averaging of the two-dimensional image. Indirect Fourier transformation methods are then used to reconstruct P(r) from I(q). Substantial advantages in data analysis, however, could be achieved by directly estimating the P(r) curve from the two-dimensional images. This article describes a Bayesian framework, using a Markov chain Monte Carlo method, for estimating the parameters of the indirect transform, and thus P(r), directly from the two-dimensional images. Using simulated detector images, it is demonstrated that this method yields P(r) curves nearly identical to the reference P(r). Furthermore, an approach for evaluating spatially correlated errors (such as those that arise from a detector point spread function) is evaluated. Accounting for these errors further improves the precision of the P(r) estimation. Experimental scattering data, where no ground truth reference P(r) is available, are used to demonstrate that this method yields a scattering and detector model that more closely reflects the two-dimensional data, as judged by smaller residuals in cross-validation, than P(r) obtained by indirect transformation of a one-dimensional profile. Finally, the method allows concurrent estimation of the beam center and D max, the longest interatomic distance in P(r), as part of the Bayesian Markov chain Monte Carlo method, reducing experimental effort and providing a well defined protocol for these parameters while also allowing estimation of the covariance among all parameters. This method provides parameter estimates of greater precision from the experimental data. The observed improvement in precision for the traditionally problematic D max is particularly noticeable.
doi:10.1107/S002188981300109X
PMCID: PMC3627411  PMID: 23596342
structure analysis; small-angle X-ray scattering; small-angle neutron scattering; Bayesian inference; Markov chain Monte Carlo methods
13.  Animal Models of Human Disease: Severe and Mild Lead Encephalopathy in the Neonatal Rat* 
Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.
A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet.
We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (5HT), norepinephrine (NE), dopamine (DA), and γ-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of “encephalopathy” consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain 5HT, GABA, or NE, but a 15–20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.
The experimental design as discribed provides a model of CNS dysfunction due to lead exposure without debilitating histopathologies. It is possible that our findings on increased motor activity and changes in brain dopamine may correspond to early responses to lead exposure before recognized overt signs of toxicity.
Images
PMCID: PMC1475133  PMID: 4831141
14.  Studies on the Mechanism of Oliguria in a Model of Unilateral Acute Renal Failure 
Journal of Clinical Investigation  1974;53(6):1546-1558.
To further evaluate the mechanism of the oliguria of acute renal failure, a model was utilized in which intense and prolonged vasoconstriction produced the unilateral cessation of urine flow. The radioactive microsphere method was used to measure total and regional blood flow before and after the intrarenal infusion of norepinephrine, 0.75 μg/kg/min, for 2 h in the dog. In the control kidney, renal blood flow increased 32% 48 h after norepinephrine in association with a fall in the fractional distribution of flow to the outer cortex. In the experimental kidney, total renal blood flow fell from 190 ml/min before norepinephrine to 116 ml/min at 48 h (P < 0.025) with a uniform reduction in cortical blood flow. After the administration of 10% body wt Ringer's solution, there was a marked redistribution of flow to inner cortical nephrons in both the control and experimental kidney. In addition, there was a marked increase in total blood flow in both kidneys. On the experimental side, flow rose to 235 ml/min, a value greater than in either the control period (P < 0.05) or at 48 h after norepinephrine (P < 0.001). However, in spite of this marked increase in blood flow, there was essentially no urine flow from the experimental kidney. In separate studies, the animals were prepared for micropuncture. In all studies, the surface tubules were collapsed, and there was no evidence of tubular obstruction or leakage of filtrate. Over 99% of the 15-μM spheres were extracted in one pass through the experimental kidney. An analysis of the forces affecting filtration suggested that an alteration in the ultrafiltration coefficient may be responsible, at least in part, for the anuria in this model. In this regard, transmission and scanning electron microscopy revealed a marked abnormality in the epithelial structure of the glomerulus. It is suggested that a decrease in glomerular capillary permeability may be present in this model of acute renal failure.
Images
PMCID: PMC302650  PMID: 4830221
15.  Tamper Detection and Restoring System for Medical Images Using Wavelet-based Reversible Data Embedding 
Journal of Digital Imaging  2007;21(1):77-90.
Over the past few years, the billows of the digital trends and the exploding growth of electronic networks, such as worldwide web, global mobility networks, etc., have drastically changed our daily lifestyle. In view of the widespread applications of digital images, medical images, which are produced by a wide variety of medical appliances, are stored in digital form gradually. These digital images are very easy to be modified imperceptively by malicious intruders for illegal purposes. The well-known adage that “seeing is believing” seems not always a changeless truth. Therefore, protecting images from being altered becomes an important issue. Based on the lossless data-embedding techniques, two detection and restoration systems are proposed to cope with forgery of medical images in this paper. One of them has the ability to recover the whole blocks of the image and the other enables to recover only a particular region where a physician will be interested in, with a better visual quality. Without the need of comparing with the original image, these systems have a great advantage of detecting and locating forged parts of the image with high possibility. And then it can also restore the counterfeited parts. Furthermore, once an image is announced authentic, the original image can be derived from the stego-image losslessly. The experimental results show that the restored version of a tampered image in the first method is extremely close to the original one. As to the second method, the region of interest selected by a physician can be recovered without any loss, when it is tampered.
doi:10.1007/s10278-007-9012-0
PMCID: PMC3043826  PMID: 17333416
Tamper detection; restoring; wavelet; reversible data embedding
16.  Clustering phenotype populations by genome-wide RNAi and multiparametric imaging 
How to predict gene function from phenotypic cues is a longstanding question in biology.Using quantitative multiparametric imaging, RNAi-mediated cell phenotypes were measured on a genome-wide scale.On the basis of phenotypic ‘neighbourhoods', we identified previously uncharacterized human genes as mediators of the DNA damage response pathway and the maintenance of genomic integrity.The phenotypic map is provided as an online resource at http://www.cellmorph.org for discovering further functional relationships for a broad spectrum of biological module
Genetic screens for phenotypic similarity have made key contributions for associating genes with biological processes. Aggregating genes by similarity of their loss-of-function phenotype has provided insights into signalling pathways that have a conserved function from Drosophila to human (Nusslein-Volhard and Wieschaus, 1980; Bier, 2005). Complex visual phenotypes, such as defects in pattern formation during development, greatly facilitated the classification of genes into pathways, and phenotypic similarities in many cases predicted molecular relationships. With RNA interference (RNAi), highly parallel phenotyping of loss-of-function effects in cultured cells has become feasible in many organisms whose genome have been sequenced (Boutros and Ahringer, 2008). One of the current challenges is the computational categorization of visual phenotypes and the prediction of gene function and associated biological processes. With large parts of the genome still being in unchartered territory, deriving functional information from large-scale phenotype analysis promises to uncover novel gene–gene relationships and to generate functional maps to explore cellular processes.
In this study, we developed an automated approach using RNAi-mediated cell phenotypes, multiparametric imaging and computational modelling to obtain functional information on previously uncharacterized genes. To generate broad, computer-readable phenotypic signatures, we measured the effect of RNAi-mediated knockdowns on changes of cell morphology in human cells on a genome-wide scale. First, the several million cells were stained for nuclear and cytoskeletal markers and then imaged using automated microscopy. On the basis of fluorescent markers, we established an automated image analysis to classify individual cells (Figure 1A). After cell segmentation for determining nuclei and cell boundaries (Figure 1C), we computed 51 cell descriptors that quantified intensities, shape characteristics and texture (Figure 1F). Individual cells were categorized into 1 of 10 classes, which included cells showing protrusion/elongation, cells in metaphase, large cells, condensed cells, cells with lamellipodia and cellular debris (Figure 1D and E). Each siRNA knockdown was summarized by a phenotypic profile and differences between RNAi knockdowns were quantified by the similarity between phenotypic profiles. We termed the vector of scores a phenoprint (Figure 3C) and defined the phenotypic distance between a pair of perturbations as the distance between their corresponding phenoprints.
To visualize the distribution of all phenoprints, we plotted them in a genome-wide map as a two-dimensional representation of the phenotypic similarity relationships (Figure 3A). The complete data set and an interactive version of the phenotypic map are available at http://www.cellmorph.org. The map identified phenotypic ‘neighbourhoods', which are characterized by cells with lamellipodia (WNK3, ANXA4), cells with prominent actin fibres (ODF2, SOD3), abundance of large cells (CA14), many elongated cells (SH2B2, ELMO2), decrease in cell number (TPX2, COPB1, COPA), increase in number of cells in metaphase (BLR1, CIB2) and combinations of phenotypes such as presence of large cells with protrusions and bright nuclei (PTPRZ1, RRM1; Figure 3B).
To test whether phenotypic similarity might serve as a predictor of gene function, we focused our further analysis on two clusters that contained genes associated with the DNA damage response (DDR) and genomic integrity (Figure 3A and C). The first phenotypic cluster included proteins with kinetochore-associated functions such as NUF2 (Figure 3B) and SGOL1. It also contained the centrosomal protein CEP164 that has been described as an important mediator of the DNA damage-activated signalling cascade (Sivasubramaniam et al, 2008) and the largely uncharacterized genes DONSON and SON. A second phenotypically distinct cluster included previously described components of the DDR pathway such as RRM1 (Figure 3A–C), CLSPN, PRIM2 and SETD8. Furthermore, this cluster contained the poorly characterized genes CADM1 and CD3EAP.
Cells activate a signalling cascade in response to DNA damage induced by exogenous and endogenous factors. Central are the kinases ATM and ATR as they serve as sensors of DNA damage and activators of further downstream kinases (Harper and Elledge, 2007; Cimprich and Cortez, 2008). To investigate whether DONSON, SON, CADM1 and CD3EAP, which were found in phenotypic ‘neighbourhoods' to known DDR components, have a role in the DNA damage signalling pathway, we tested the effect of their depletion on the DDR on γ irradiation. As indicated by reduced CHEK1 phosphorylation, siRNA knock down of DONSON, SON, CD3EAP or CADM1 resulted in impaired DDR signalling on γ irradiation. Furthermore, knock down of DONSON or SON reduced phosphorylation of downstream effectors such as NBS1, CHEK1 and the histone variant H2AX on UVC irradiation. DONSON depletion also impaired recruitment of RPA2 onto chromatin and SON knockdown reduced RPA2 phosphorylation indicating that DONSON and SON presumably act downstream of the activation of ATM. In agreement to their phenotypic profile, these results suggest that DONSON, SON, CADM1 and CD3EAP are important mediators of the DDR. Further experiments demonstrated that they are also required for the maintenance of genomic integrity.
In summary, we show that genes with similar phenotypic profiles tend to share similar functions. The power of our computational and experimental approach is demonstrated by the identification of novel signalling regulators whose phenotypic profiles were found in proximity to known biological modules. Therefore, we believe that such phenotypic maps can serve as a resource for functional discovery and characterization of unknown genes. Furthermore, such approaches are also applicable for other perturbation reagents, such as small molecules in drug discovery and development. One could also envision combined maps that contain both siRNAs and small molecules to predict target–small molecule relationships and potential side effects.
Genetic screens for phenotypic similarity have made key contributions to associating genes with biological processes. With RNA interference (RNAi), highly parallel phenotyping of loss-of-function effects in cells has become feasible. One of the current challenges however is the computational categorization of visual phenotypes and the prediction of biological function and processes. In this study, we describe a combined computational and experimental approach to discover novel gene functions and explore functional relationships. We performed a genome-wide RNAi screen in human cells and used quantitative descriptors derived from high-throughput imaging to generate multiparametric phenotypic profiles. We show that profiles predicted functions of genes by phenotypic similarity. Specifically, we examined several candidates including the largely uncharacterized gene DONSON, which shared phenotype similarity with known factors of DNA damage response (DDR) and genomic integrity. Experimental evidence supports that DONSON is a novel centrosomal protein required for DDR signalling and genomic integrity. Multiparametric phenotyping by automated imaging and computational annotation is a powerful method for functional discovery and mapping the landscape of phenotypic responses to cellular perturbations.
doi:10.1038/msb.2010.25
PMCID: PMC2913390  PMID: 20531400
DNA damage response signalling; massively parallel phenotyping; phenotype networks; RNAi screening
17.  A Multispectral Photon-Counting Double Random Phase Encoding Scheme for Image Authentication 
Sensors (Basel, Switzerland)  2014;14(5):8877-8894.
In this paper, we propose a new method for color image-based authentication that combines multispectral photon-counting imaging (MPCI) and double random phase encoding (DRPE) schemes. The sparsely distributed information from MPCI and the stationary white noise signal from DRPE make intruder attacks difficult. In this authentication method, the original multispectral RGB color image is down-sampled into a Bayer image. The three types of color samples (red, green and blue color) in the Bayer image are encrypted with DRPE and the amplitude part of the resulting image is photon counted. The corresponding phase information that has nonzero amplitude after photon counting is then kept for decryption. Experimental results show that the retrieved images from the proposed method do not visually resemble their original counterparts. Nevertheless, the original color image can be efficiently verified with statistical nonlinear correlations. Our experimental results also show that different interpolation algorithms applied to Bayer images result in different verification effects for multispectral RGB color images.
doi:10.3390/s140508877
PMCID: PMC4063078  PMID: 24854208
optical security and encryption; pattern recognition; multispectral photon counting imaging; double random phase encryption; nonlinear correlators; color images
18.  Learning Sparse Representations for Fruit-Fly Gene Expression Pattern Image Annotation and Retrieval 
BMC Bioinformatics  2012;13:107.
Background
Fruit fly embryogenesis is one of the best understood animal development systems, and the spatiotemporal gene expression dynamics in this process are captured by digital images. Analysis of these high-throughput images will provide novel insights into the functions, interactions, and networks of animal genes governing development. To facilitate comparative analysis, web-based interfaces have been developed to conduct image retrieval based on body part keywords and images. Currently, the keyword annotation of spatiotemporal gene expression patterns is conducted manually. However, this manual practice does not scale with the continuously expanding collection of images. In addition, existing image retrieval systems based on the expression patterns may be made more accurate using keywords.
Results
In this article, we adapt advanced data mining and computer vision techniques to address the key challenges in annotating and retrieving fruit fly gene expression pattern images. To boost the performance of image annotation and retrieval, we propose representations integrating spatial information and sparse features, overcoming the limitations of prior schemes.
Conclusions
We perform systematic experimental studies to evaluate the proposed schemes in comparison with current methods. Experimental results indicate that the integration of spatial information and sparse features lead to consistent performance improvement in image annotation, while for the task of retrieval, sparse features alone yields better results.
doi:10.1186/1471-2105-13-107
PMCID: PMC3434040  PMID: 22621237
19.  Information management for high content live cell imaging 
BMC Bioinformatics  2009;10:226.
Background
High content live cell imaging experiments are able to track the cellular localisation of labelled proteins in multiple live cells over a time course. Experiments using high content live cell imaging will generate multiple large datasets that are often stored in an ad-hoc manner. This hinders identification of previously gathered data that may be relevant to current analyses. Whilst solutions exist for managing image data, they are primarily concerned with storage and retrieval of the images themselves and not the data derived from the images. There is therefore a requirement for an information management solution that facilitates the indexing of experimental metadata and results of high content live cell imaging experiments.
Results
We have designed and implemented a data model and information management solution for the data gathered through high content live cell imaging experiments. Many of the experiments to be stored measure the translocation of fluorescently labelled proteins from cytoplasm to nucleus in individual cells. The functionality of this database has been enhanced by the addition of an algorithm that automatically annotates results of these experiments with the timings of translocations and periods of any oscillatory translocations as they are uploaded to the repository. Testing has shown the algorithm to perform well with a variety of previously unseen data.
Conclusion
Our repository is a fully functional example of how high throughput imaging data may be effectively indexed and managed to address the requirements of end users. By implementing the automated analysis of experimental results, we have provided a clear impetus for individuals to ensure that their data forms part of that which is stored in the repository. Although focused on imaging, the solution provided is sufficiently generic to be applied to other functional proteomics and genomics experiments. The software is available from:
doi:10.1186/1471-2105-10-226
PMCID: PMC2723092  PMID: 19622144
20.  Partner-specific interpretation of maintained referential precedents during interactive dialog 
Journal of memory and language  2009;61(2):171-190.
In dialog settings, conversational partners converge on similar names for referents. These lexically entrained terms (Garrod & Anderson, 1987) are part of the common ground between the particular individuals who established the entrained term (Brennan & Clark, 1996), and are thought to be encoded in memory with a partner-specific cue. Thus far, analyses of the time-course of interpretation suggest that partner-specific information may not constrain the initial interpretation of referring expressions (Kronmüller & Barr, 2007; Barr & Keysar, 2002). However, these studies used non-interactive paradigms, which may limit the use of partner-specific representations. This article presents the results of three eye-tracking experiments. Experiment 1a used an interactive conversation methodology in which the experimenter and participant jointly established entrained terms for various images. On critical trials, the same experimenter, or a new experimenter described a critical image using an entrained term, or a new term. The results demonstrated an early, on-line partner-specific effect for interpretation of entrained terms, as well as preliminary evidence for an early, partner-specific effect for new terms. Experiment 1b used a non-interactive paradigm in which participants completed the same task by listening to image descriptions recorded during Experiment 1a; the results showed that partner-specific effects were eliminated. Experiment 2 replicated the partner-specific findings of Experiment 1a with an interactive paradigm and scenes that contained previously unmentioned images. The results suggest that partner-specific interpretation is most likely to occur in interactive dialog settings; the number of critical trials and stimulus characteristics may also play a role. The results are consistent with a large body of work demonstrating that the language processing system uses a rich source of contextual and pragmatic representations to guide on-line processing decisions.
doi:10.1016/j.jml.2009.04.003
PMCID: PMC2740920  PMID: 20161117
conceptual pact; entrainment; precedent; perspective; reference; common ground; conversation; eye-tracking
21.  dxtbx: the diffraction experiment toolbox 
Journal of Applied Crystallography  2014;47(Pt 4):1459-1465.
A Python/C++ library for reading image data and experimental geometry for X-ray diffraction experiments from arbitrary data sources is presented.
Data formats for recording X-ray diffraction data continue to evolve rapidly to accommodate new detector technologies developed in response to more intense light sources. Processing the data from single-crystal X-ray diffraction experiments therefore requires the ability to read, and correctly interpret, image data and metadata from a variety of instruments employing different experimental representations. Tools that have previously been developed to address this problem have been limited either by a lack of extensibility or by inconsistent treatment of image metadata. The dxtbx software package provides a consistent interface to both image data and experimental models, while supporting a completely generic user-extensible approach to reading the data files. The library is written in a mixture of C++ and Python and is distributed as part of the cctbx under an open-source licence at http://cctbx.sourceforge.net.
doi:10.1107/S1600576714011996
PMCID: PMC4119952  PMID: 25242914
single-crystal X-ray diffraction; data processing; computer programs
22.  Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury 
Background
Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.
Methods
One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.
Results
Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.
Conclusion
Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.
doi:10.1186/1742-2094-9-43
PMCID: PMC3308916  PMID: 22373400
Traumatic brain injury; microglia; metabotropic glutamate receptor 5; delayed treatment; neuroprotection
23.  Finite volume analysis of temperature effects induced by active MRI implants: 2. Defects on active MRI implants causing hot spots 
Background
Active magnetic resonance imaging implants, for example stents, stent grafts or vena cava filters, are constructed as wireless inductively coupled transmit and receive coils. They are built as a resonator tuned to the Larmor frequency of a magnetic resonance system. The resonator can be added to or incorporated within the implant. This technology can counteract the shielding caused by eddy currents inside the metallic implant structure. This may allow getting diagnostic information of the implant lumen (in stent stenosis or thrombosis for example). The electro magnetic rf-pulses during magnetic resonance imaging induce a current in the circuit path of the resonator. A by material fatigue provoked partial rupture of the circuit path or a broken wire with touching surfaces can set up a relatively high resistance on a very short distance, which may behave as a point-like power source, a hot spot, inside the body part the resonator is implanted to. This local power loss inside a small volume can reach ¼ of the total power loss of the intact resonating circuit, which itself is proportional to the product of the resonator volume and the quality factor and depends as well from the orientation of the resonator with respect to the main magnetic field and the imaging sequence the resonator is exposed to.
Methods
First an analytical solution of a hot spot for thermal equilibrium is described. This analytical solution with a definite hot spot power loss represents the worst case scenario for thermal equilibrium inside a homogeneous medium without cooling effects. Starting with this worst case assumptions additional conditions are considered in a numerical simulation, which are more realistic and may make the results less critical. The analytical solution as well as the numerical simulations use the experimental experience of the maximum hot spot power loss of implanted resonators with a definite volume during magnetic resonance imaging investigations. The finite volume analysis calculates the time developing temperature maps for the model of a broken linear metallic wire embedded in tissue. Half of the total hot spot power loss is assumed to diffuse into both wire parts at the location of a defect. The energy is distributed from there by heat conduction. Additionally the effect of blood perfusion and blood flow is respected in some simulations because the simultaneous appearance of all worst case conditions, especially the absence of blood perfusion and blood flow near the hot spot, is very unlikely for vessel implants.
Results
The analytical solution as worst case scenario as well as the finite volume analysis for near worst case situations show not negligible volumes with critical temperature increases for part of the modeled hot spot situations. MR investigations with a high rf-pulse density lasting below a minute can establish volumes of several cubic millimeters with temperature increases high enough to start cell destruction. Longer exposure times can involve volumes larger than 100 mm3. Even temperature increases in the range of thermal ablation are reached for substantial volumes. MR sequence exposure time and hot spot power loss are the primary factors influencing the volume with critical temperature increases. Wire radius, wire material as well as the physiological parameters blood perfusion and blood flow inside larger vessels reduce the volume with critical temperature increases, but do not exclude a volume with critical tissue heating for resonators with a large product of resonator volume and quality factor.
Conclusion
The worst case scenario assumes thermal equilibrium for a hot spot embedded in homogeneous tissue without any cooling due to blood perfusion or flow. The finite volume analysis can calculate the results for near and not close to worst case conditions. For both cases a substantial volume can reach a critical temperature increase in a short time. The analytical solution, as absolute worst case, points out that resonators with a small product of inductance volume and quality factor (Q Vind < 2 cm3) are definitely save. Stents for coronary vessels or resonators used as tracking devices for interventional procedures therefore have no risk of high temperature increases. The finite volume analysis shows for sure that also conditions not close to the worst case reach physiologically critical temperature increases for implants with a large product of inductance volume and quality factor (Q Vind > 10 cm3). Such resonators exclude patients from exactly the MRI investigation these devices are made for.
doi:10.1186/1475-925X-5-35
PMCID: PMC1513583  PMID: 16729878
24.  Large size three-dimensional video by electronic holography using multiple spatial light modulators 
Scientific Reports  2014;4:6177.
In this paper, we propose a new method of using multiple spatial light modulators (SLMs) to increase the size of three-dimensional (3D) images that are displayed using electronic holography. The scalability of images produced by the previous method had an upper limit that was derived from the path length of the image-readout part. We were able to produce larger colour electronic holographic images with a newly devised space-saving image-readout optical system for multiple reflection-type SLMs. This optical system is designed so that the path length of the image-readout part is half that of the previous method. It consists of polarization beam splitters (PBSs), half-wave plates (HWPs), and polarizers. We used 16 (4 × 4) 4K×2K-pixel SLMs for displaying holograms. The experimental device we constructed was able to perform 20 fps video reproduction in colour of full-parallax holographic 3D images with a diagonal image size of 85 mm and a horizontal viewing-zone angle of 5.6 degrees.
doi:10.1038/srep06177
PMCID: PMC4141271  PMID: 25146685
25.  Modeling of Dispersion in a Polymeric Chromatographic Monolith 
Journal of Chromatography. a  2012;1237:55-63.
Dispersion in a commercial polymeric monolith was simulated on a sample geometry obtained by direct imaging using high-resolution electron microscopy. A parallelized random walk algorithm, implemented using a velocity field obtained previously by the lattice-Boltzmann method, was used to model mass transfer. Both point particles and probes of finite size were studied.
Dispersion simulations with point particles using periodic boundaries resulted in plate heights that varied almost linearly with flow rate, at odds with the weaker dependence suggested by the experimental observations and predicted by theory. This discrepancy resulted from the combined effect of the artificial symmetry in the velocity field and the periodic boundaries implemented to emulate macroscopic column lengths. Eliminating periodicity and simulating a single block length instead resulted in a functional dependence of plate heights on flow rate more in accord with experimental trends and theoretical predictions for random media. The lower values of the simulated plate heights than experimental ones are attributed in part to the presence of walls in real systems, an effect not modeled by the algorithm. On the other hand, analysis of transient dispersion coefficients and comparison of lateral particle positions at the entry and exit hinted at non-asymptotic behavior and a strong degree of correlation that was presumably a consequence of preferential high-velocity pathways in the raw sample block.
Simulations with finite-sized probes resulted in particle trajectories that frequently terminated at narrow constrictions of the geometry. The amount of entrapment was predicted to increase monotonically with flow rate, evidently due to the relative contributions to transport of convection that carries particles to choke-points and diffusion that dislodges these entrapped particles. The overall effect is very similar to a flow-dependent entrapment phenomenon previously observed experimentally for adenovirus.
doi:10.1016/j.chroma.2012.03.005
PMCID: PMC3327764  PMID: 22465685
Monolith; CIM disk; dispersion; random walk; image-based simulation; entrapment

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