System-dependent Effects Research Articles

Motor System-Dependent Effects of Amygdala and Ventral Striatum Lesions on Explore-Exploit Behaviors.

Deciding whether to forego immediate rewards or explore new opportunities is a key component of flexible behavior and is critical for the survival of the species. Although previous studies have shown that different cortical and subcortical areas, including the amygdala and ventral striatum (VS), are implicated in representing the immediate (exploitative) and future (explorative) value of choices, the effect of the motor system used to make choices has not been examined. Here, we tested male rhesus macaques with amygdala or VS lesions on two versions of a three-arm bandit task where choices were registered with either a saccade or an arm movement. In both tasks we presented the monkeys with explore-exploit tradeoffs by periodically replacing familiar options with novel options that had unknown reward probabilities. We found that monkeys explored more with saccades but showed better learning with arm movements. VS lesions caused the monkeys to be more explorative with arm movements and less explorative with saccades, although this may have been due to an overall decrease in performance. VS lesions affected the monkeys' ability to learn novel stimulus-reward associations in both tasks, while after amygdala lesions this effect was stronger when choices were made with saccades. Further, on average, VS and amygdala lesions reduced the monkeys' ability to choose better options only when choices were made with a saccade. These results show that learning reward value associations to manage explore-exploit behaviors is motor system dependent and they further define the contributions of amygdala and VS to reinforcement learning.

Recent Advances in Attenuation Estimation.

This chapter reviews some of the recent advances in the estimation of the local and the total attenuation, with an emphasis on reducing the bias and variance of the estimates. A special focus is put on describing the effect of power spectrum estimation on bias and variance, the introduction of regularization strategies, as well as on eliminating the need to use reference phantoms for compensating for system dependent effects.

Performance comparison of commonly used photoacoustic tomography reconstruction algorithms under various blurring conditions

A reconstructed image in photoacoustic tomography (PAT) imaging modality can be blurred because of some system-dependent effects – broad laser pulse, the limited bandwidth of the sensors, acoustically attenuating medium and transducers with finite-size apertures having Gaussian sensitivity profile. A robust deblurring method involving a system matrix is presented in this work. Image reconstruction was accomplished by using the backprojection (BP), interpolated time reversal (ITR), Tikhonov regularization (TH) and total variation minimization (TV) schemes. A modified version of the BP algorithm was also explored for image reconstruction for finite transducers. Each factor of blurring was considered at a time. For the model-based methods, the system matrix was constructed in presence of such a factor. Subsequently, the model matrix inversion method was deployed for image formation. Quantitative values of some standard metrics were computed to assess the performance of the reconstruction protocols. The visual inspection of the reconstructed images as well as numerical values of the figures of merit revealed that the BP and ITR techniques generally fail to remove blurring; however, the model-based methods can provide distortion-free images under various conditions. For example, the numerical values of the Pearson correlation coefficient (PCC) for all the cases showed a strong correlation between the nominal and reconstructed images for the TH and TV techniques compared to the BP and ITR methods. The TV method can be utilized in practice to facilitate the PAT image reconstruction free from system-dependent blurring.

Noise Suppression for Ultrasound Attenuation Coefficient Estimation Based on Spectrum Normalization.

Ultrasound attenuation coefficient estimation (ACE) has great diagnostic potential for fatty liver detection and assessment. In a previous study, we proposed a reference phantom-free ACE method, called reference frequency method (RFM), which does not require a calibrated phantom for normalization. The power of each frequency component can be normalized by the power of an adjacent frequency component in the spectrum to cancel system-dependent effects such as focusing and time gain compensation (TGC). RFM demonstrated accurate ACE in both phantom and in in-vivo liver studies. However, our study also showed that the robustness and penetration of RFM were affected by noise in the ACE signals. Here we propose a noise suppression (NS) and a signal-to-noise ratio (SNR) quality control method to reduce the influence of noise on ACE-RFM performance. The proposed methods were tested in harmonic ACE because harmonic imaging is a more frequently used mode than fundamental imaging for abdominal applications. After applying the NS and SNR control methods, the noise-induced bias for attenuation estimation in harmonic ACE was effectively reduced, leading to significantly improved effective penetration depth. The proposed methods directly measure the noise spectrum of the ultrasound system, which can also be adapted to other spectrum-based ACE methods, such as the reference phantom method and the spectra shift method.

Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate

Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.

System-Independent Ultrasound Attenuation Coefficient Estimation Using Spectra Normalization.

Ultrasound attenuation coefficient estimation (ACE) has diagnostic potential for clinical applications such as differentiating tumors and quantifying fat content in the liver. The two commonly used ACE methods in the ultrasound array imaging system are the spectral shift method and the reference-phantom-based methods. The spectra shift method estimates the central frequency downshift along depth, whereas the reference-phantom-based methods use a well-calibrated phantom to cancel system dependent effects in attenuation estimation. In this study, we propose a novel system-independent ACE technique based on spectra normalization of different frequencies. This technique does not require a reference phantom for normalization. The power of each frequency component is normalized by the power of an adjacent frequency component in the spectrum to cancel system-dependent effects, such as focusing and time gain compensation (TGC). This method is referred to as the reference frequency method (RFM), and its performance has been evaluated in phantoms and in vivo liver studies. The RFM technique can be applied to various transducer geometries (e.g., linear or curved arrays) with different beam patterns (e.g., focused or unfocused).

Direct comparison of UDP-glucuronosyltransferase and cytochrome P450 activities in human liver microsomes, plated and suspended primary human hepatocytes from five liver donors

UDP-glucuronosyltransferases (UGTs) and cytochrome P450s (CYPs) are the major enzymes involved in hepatic metabolism of drugs. Hepatic drug metabolism is commonly investigated using human liver microsomes (HLM) or primary human hepatocytes (PHH). We describe the development of a sensitive assay to phenotype activities of six major hepatic UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7) in intact PHH by analysis of glucuronidation of selective probe substrates. The non-selective, general substrate 7-hydroxycoumarin was included for comparison. For each liver donor preparation (five donors) UGT activities in cryopreserved suspended and plated PHH were compared to HLM prepared from the same donors. Standard CYP reaction phenotyping of seven major isoforms was performed in parallel. For all donors, CYP- and UGT-isoforms activity profiles were comparable in PHH and HLM, indicating that reaction phenotyping with selective probe substrates in intact cells primarily reflects respective CYP or UGT activity. System-dependent effects on UGT and CYP isoform activity were still found. While UGT activity of UGT1A1 was equivalent in plated and suspended PHH, UGT1A3, UGT1A6 and UGT2B7 activity was higher in suspended PHH and UGT1A9 and UGT1A4 activity was higher in plated PHH. The well-known decrease in activity of most CYP isoforms in plated compared to suspended PHH was confirmed. Importantly, we found a significant loss in CYP2C19 and CYP2B6 in HLM, activity being lower than in intact cells. Taken together, these findings implicate that, dependent on the UGT or CYP isoforms involved in the metabolism of a given compound, the outcome of metabolic assays is strongly dependent on the choice of the in vitro system. The currently described UGT- and CYP- activity profiling method can be used as a standard assay in intact cells and can especially aid in reaction phenotyping of in vitro systems for which a limited number of cells are available.

Two heterozygous Cav3.2 channel mutations in a pediatric chronic pain patient: recording condition-dependent biophysical effects.

We report expression system-dependent effects of heterozygous mutations (P769L and A1059S) in the Cav3.2 CACNA1H gene identified in a pediatric patient with chronic pain and absence seizures. The mutations were introduced individually into recombinant channels and then analyzed by means of electrophysiology. When both mutants were co-expressed in tsA-201 cells, we observed a loss of channel function, with significantly smaller current densities across a wide range of voltages (-40 to +20 mV). In addition, when both mutant channels were co-expressed, the channels opened at a more depolarizing potential with a ~5-mV right shift in the half-activation potential, with no changes in half-inactivation potential and the rate of recovery from inactivation. Interestingly, when both mutants were co-expressed in the neuronal-derived CAD cells in a different extracellular milieu, the effect was remarkably different. Although not statistically significant (p < 0.07), current densities appeared augmented compared to wild-type channels and the difference in the half-activation potential was lost. This could be attributed to the replacement of extracellular sodium and potassium with tetraethylammonium chloride. Our results show that experimental conditions can be a confounding factor in the biophysical effects of T-type calcium channel mutations found in certain neurological disorders.

Platelet-activating factor receptor contributes to antileishmanial function of miltefosine.

Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system-dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor-deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor-deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor-deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage-T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.

In vitro inhibition of human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effects on inhibitory potential

1. Rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) is being developed for the treatment of cutaneous melanoma and hepatocellular carcinoma. Interestingly, rose bengal can generate singlet oxygen species upon exposure to light.2. We evaluated rose bengal as an in vitro inhibitor of cytochrome P450 (CYP) or UDP-glucuronosyltransferase (UGT) enzymes in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHHs) under both yellow light and dark conditions.3. Rose bengal directly inhibited CYP3A4/5 and UGT1A6 in HLM under yellow light with inhibitor concentration that causes 50% inhibition (IC50) values of 0.072 and 0.035 μM, respectively; whereas much less inhibition was observed in the dark with the IC50 values increasing 43- and 120-fold, respectively. To determine if a more physiologically-relevant test system could be protected from such an effect, rose bengal was evaluated as an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5 and UGT enzymes in CHH. All IC50 values were similar (64 ± 8 μM) and little to no effect of light on inhibitory potential was observed.4. Given the IC50 values in CHH increased an order of magnitude compared to HLM and the atypical pharmacokinetics of the drug, the risk of rose bengal to cause clinically relevant drug–drug interactions is likely low, particularly when administered to cancer patients on an intermittent schedule.

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism. Differences in pharmacokinetic outcomes in guinea pig and rat, with the same metabolic clearance mechanism, show how species differences in the systemic clearance mechanism can affect the in vivo outcome. Overall, to gain from the application of deuteration as a strategy to alter drug pharmacokinetics, these studies demonstrate the importance of understanding the systemic clearance mechanism and knowing the identity of the metabolic enzymes involved, the extent to which they contribute to metabolic clearance, and the extent to which metabolism contributes to the systemic clearance.

Predictive Deconvolution and Hybrid Feature Selection for Computer-Aided Detection of Prostate Cancer

Computer-aided detection (CAD) schemes are decision making support tools, useful to overcome limitations of problematic clinical procedures. Trans-rectal ultrasound image based CAD would be extremely important to support prostate cancer diagnosis. An effective approach to realize a CAD scheme for this purpose is described in this work, employing a multi-feature kernel classification model based on generalized discriminant analysis. The mutual information of feature value and tissue pathological state is used to select features essential for tissue characterization. System-dependent effects are reduced through predictive deconvolution of the acquired radio-frequency signals. A clinical study, performed on ground truth images from biopsy findings, provides a comparison of the classification model applied before and after deconvolution, showing in the latter case a significant gain in accuracy and area under the receiver operating characteristic curve.

Unravelling the brain targets of gamma-hydroxybutyric acid.

Gamma-hydroxybutyric acid (GHB) is a naturally occurring gamma-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).

Printing-based performance analysis of the engineering test stand set-2 optic using a synchrotron exposure station with variable sigma

While interferometry is routinely used for the characterization and alignment of lithographic optics, the ultimate measure of performance for these optical systems is the transfer of an image or pattern into photoresist. Simple yet flexible exposure systems play an important role in this task because they allow complex system-dependent effects to be isolated from the printing results. One such tool has been implemented for alpha-class extreme ultraviolet (EUV) optics at Lawrence Berkeley National Laboratory using a synchrotron-based illumination source with programmable coherence. This static microfield exposure system has been used to characterize a four-mirror optical system designed for the EUV engineering test stand prototype stepper. Here we present a detailed performance analysis based on the large volume of lithographic data collected from this 0.1 NA system. Process window results are presented for dark field and bright field nested features down to a half pitch of 70 nm (k1 factor of 0.52) where a depth of focus of approximately 1 μm with 10% exposure latitude is demonstrated.

High-frequency ultrasonic attenuation and backscatter coefficients of in vivo normal human dermis and subcutaneous fat

In vivo attenuation and backscatter coefficients of normal human forearm dermis and subcutaneous fat were determined in the ranges 14 to 50 MHz and 14 to 34 MHz, respectively. Data were collected using three different transducers to ensure that results were independent of the measurement system. Attenuation coefficient was obtained by computing spectral slopes vs. depth, with the transducers axially translated to minimize diffraction effects. Backscatter coefficient was obtained by compensating recorded backscatter spectra for system-dependent effects and, additionally, for one transducer using the reference phantom technique. Good agreement was seen between the computed attenuation and backscatter results from the different transducers/methods. The attenuation coefficient of the forearm dermis was well described by a linear dependence with a slope that ranged between 0.08 to 0.39 (median = 0.21) dB mm −1 MHz −1. The backscatter coefficient of the dermis was generally in the range 10 −3 to 10 −1 Sr −1 mm −1 and showed an increasing trend with frequency. No significant differences in attenuation coefficient slope between the forearm dermis and fat were noted. Within the range of 14 to 34 MHz, the ratio of integrated (average) backscatter of dermis to that of fat ranged from 1.03 to 87.1 (median = 6.45), indicating significantly higher backscatter for dermis than for fat. Data were also recorded at the fingertip where the attenuation coefficient slope of the dermis was seen to be higher than that at the forearm. (E-mail: raju@mit.edu)

Vibrational fine structure in core level photoelectron lines of adsorbed molecules: System dependent effects

System dependent effects in resolving vibrational fine structure in the core-level lines of adsorbates are discussed. The example is carbon monoxide on transition metals. The importance of dynamic metallic screening is exemplified and the role of shake-up processes is discussed. The possible spin configurations and the magnetic state of the core-ionized adsorbate in the final state are investigated in terms of exchange splittings and the results extended within the equivalent core approximation to the ground state properties of adsorbed NO.

Tissue-characterization of the prostate using radio frequency ultrasonic signals

In this paper, we will present a complete method and system for the detection of prostatic carcinoma, providing color-coded images of the estimated probability of malignancy by processing radio-frequency ultrasonic echo signals. For this, a hardware setup based on a conventional diagnostic sonograph was realized. The image-processing software works on ultrasound images automatically segmented into regions of about 3x3.5 mm. System-dependent effects, as well as tissue attenuation, were measured and compensated for. Tissue-characterisation parameters, which have been used successfully by other authors, were calculated for each segment. To demonstrate the methods of selection of relevant parameters and comparison of different classifiers, a first clinical study using data of 33 patients with local prostatic carcinoma was performed. For these patients, location and extent of the carcinoma were known from histological findings after radical prostatectomy. Classifiers investigated during the study were: the linear and quadratic Bayes classifier, a nearest neighbor classifier, and several classifiers based on Kohonen-maps. The best classifier was used to calculate color-coded result images. Applying a threshold of 50% to the estimated probability of malignancy, produced the encouraging results of 82 and 88% for sensitivity and specificity, respectively.

Effects of Convective Solute and Impurity Transport in Protein Crystal Growth

High-resolution optical interferometry was used to investigate the effects of forced solution convection on the crystal growth kinetics of the model protein lysozyme. Most experiments were conducted with 99.99% pure protein solutions. To study impurity effects, ∼1% of lysozyme dimer (covalently bound) was added in some cases. We show that the unsteady kinetics, corresponding to bunching of growth steps, can be characterized by the Fourier components of time traces of the growth rate. Specific Fourier spectra are uniquely determined by the solution conditions (composition, temperature, and flow rate) and the growth layer source activity. We found that the average step velocity and growth rate increase by ∼10% with increasing flow rate, as a result of the enhanced solute supply to the interface. More importantly, faster convective transport results in lower fluctuation amplitudes. This observation supports our rationale for system-dependent effects of transport on the structural perfection of protein crystals. We also found that solution flow rates >500 μm/s result in stronger fluctuations while the average growth rate is decreased. This can lead to growth cessation at low supersaturations. With the intentionally contaminated solutions, these undesirable phenomena occurred at about half the flow rates required in pure solutions. Thus, we conclude that they are due to enhanced convective supply of impurities that are incorporated into the crystal during growth. Furthermore, we found that the impurity effects are reduced at higher crystal growth rates. Since the exposure time of terraces is inversely proportional to the growth rate, this observation suggests that the increased kinetics instability results from impurity adsorption on the interface. Finally, we provide evidence relating earlier observations of “slow protein crystal growth kinetics” to step bunch formation in response to nonsteady step generation.

Absolute backscatter coefficient over a wide range of frequencies in a tissue-mimicking phantom containing two populations of scatterers

The acquisition and interpretation of in vivo ultrasonic measurements in tissue encounter problems associated with limited access to the region of interest, intermixed scattering structures with different characteristic dimensions, and system-dependent effects. This work addresses these problems by adapting and testing a technique for measuring the absolute attenuation and the absolute backscatter coefficient (effective backscatter cross section per unit volume of material), as a function of frequency, in a single-transducer backscatter configuration. The frequency-dependent attenuation and backscatter coefficients of a tissue-mimicking gelatin phantom containing a random distribution of two populations of scatterers were measured, Three transducers with different center frequencies and focusing characteristics were used in order to verify that system-dependent effects were removed by the technique and to investigate the change in the measured parameters across a broad range of frequencies (2 to 60 MHz). A spherical autocorrelation model was applied to measurements of the backscatter coefficient in order to estimate the size of scatterers. Measurements demonstrate that the backscatter and attenuation properties of a mixture of two distinct intermixed scatterer-size populations change as a function of the frequency range across which the model is applied. Comparison of both the magnitude and the frequency dependence of the experimental results with the theoretical prediction of the backscatter coefficient showed good agreement.

Heavy-ion fusion below the Coulomb barrier: The systems 28,30Si + 58,62,64Ni and 32,34,36S + 58,64Ni

Fusion cross-sections for the 12 systems 28,30Si + 58,62,64Ni and 32,34,36S + 58,64Ni were measured at many energies from well below up to about 1.5 times the Coluomb barriers. The data show large sub-barrier fusion probabilities with strong isotopic dependences. The results of coupled-channel calculations involving the lowest 2 + and 3 − levels of both colliding nuclei and the 2-neutron transfer channel are compared with the measured excitation functions. Indications for the importance of the transfer channels are found. Signatures of system-dependent effects of the positive Q-value transfer channels are evidenced, also from a systematic intercomparison of the data.