Liver genomic responses to ciguatoxin: evidence for activation of Phase I and Phase II detoxification pathways following an acute hypothermic response in mice

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p ≤ 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (|fold change| ≥ 1.5 and p ≤ 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4°C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

Recent origin of a hominoid-specific splice form of neuropsin, a gene involved in learning and memory

Neuropsin is a secreted-type serine protease involved in learning and memory. The type II splice form of neuropsin is abundantly expressed in the human brain but not in the mouse brain. We sequenced the type II-spliced region of neuropsin gene in humans and representative nonhuman primate species. Our comparative sequence analysis showed that only the hominoid species (humans and apes) have the intact open reading frame of the type II splice form, indicating that the type II neuropsin originated recently in the primate lineage about 18 MYA. Expression analysis using RT-PCR detected abundant expression of the type II form in the frontal lobe of the adult human brain, but no expression was detected in the brains of lesser apes and Old World monkeys, indicating that the type II form of neuropsin only became functional in recent time, and it might contribute to the progressive change of cognitive abilities during primate evolution.

Adaptive evolution of MRGX2, a human sensory neuron specific gene involved in nociception

MRGX2, a G-protein-coupled receptor, is specifically expressed in the sensory neurons of the human peripheral nervous system and involved in nociception. Here, we studied DNA polymorphism patterns and evolution of the MRGX2 gene in world-wide human populations and the representative nonhuman primate species. Our results demonstrated that MRGX2 had undergone adaptive changes in the path of human evolution, which were likely caused by Darwinian positive selection. The patterns of DNA sequence polymorphisms in human populations showed an excess of derived substitutions, which against the expectation of neutral evolution, implying that the adaptive evolution of MRGX2 in humans was a relatively recent event. The reconstructed secondary structure of the human MRGX2 revealed that three of the four human-specific amino acid substitutions were located in the extra-cellular domains. Such critical substitutions may alter the interactions between MRGX2 protein and its ligand, thus, potentially led to adaptive changes of the pain-perception-related nervous system during human evolution. (c) 2005 Elsevier B.V. All rights reserved.

Effects of scopolamine on morphine-induced conditioned place preference in mice

It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies h

Deliberation in the motor system: reflex gains track evolving evidence leading to a decision.

Both decision making and sensorimotor control require real-time processing of noisy information streams. Historically these processes were thought to operate sequentially: cognitive processing leads to a decision, and the outcome is passed to the motor system to be converted into action. Recently, it has been suggested that the decision process may provide a continuous flow of information to the motor system, allowing it to prepare in a graded fashion for the probable outcome. Such continuous flow is supported by electrophysiology in nonhuman primates. Here we provide direct evidence for the continuous flow of an evolving decision variable to the motor system in humans. Subjects viewed a dynamic random dot display and were asked to indicate their decision about direction by moving a handle to one of two targets. We probed the state of the motor system by perturbing the arm at random times during decision formation. Reflex gains were modulated by the strength and duration of motion, reflecting the accumulated evidence in support of the evolving decision. The magnitude and variance of these gains tracked a decision variable that explained the subject's decision accuracy. The findings support a continuous process linking the evolving computations associated with decision making and sensorimotor control.

Comparing crowding in human and ideal observers.

A visual target is more difficult to recognize when it is surrounded by other, similar objects. This breakdown in object recognition is known as crowding. Despite a long history of experimental work, computational models of crowding are still sparse. Specifically, few studies have examined crowding using an ideal-observer approach. Here, we compare crowding in ideal observers with crowding in humans. We derived an ideal-observer model for target identification under conditions of position and identity uncertainty. Simulations showed that this model reproduces the hallmark of crowding, namely a critical spacing that scales with viewing eccentricity. To examine how well the model fits quantitatively to human data, we performed three experiments. In Experiments 1 and 2, we measured observers' perceptual uncertainty about stimulus positions and identities, respectively, for a target in isolation. In Experiment 3, observers identified a target that was flanked by two distractors. We found that about half of the errors in Experiment 3 could be accounted for by the perceptual uncertainty measured in Experiments 1 and 2. The remainder of the errors could be accounted for by assuming that uncertainty (i.e., the width of internal noise distribution) about stimulus positions and identities depends on flanker proximity. Our results provide a mathematical restatement of the crowding problem and support the hypothesis that crowding behavior is a sign of optimality rather than a perceptual defect.

Values and actions in aversion

Model-based and model-free controllers can, in principle, learn arbitrary actions to optimize their behavior, at least those actions that can be expressed and explored. Indeed, these are often referred to as instrumental controllers because their choices are learned to be instrumental for the delivery of desired outcomes. Although this flexibility is very powerful, it comes with an attendant cost of learning. Evolution appears to have endowed everything from the simplest organisms to us with powerful, pre-specified, but inflexible alternatives. These responses are termed Pavlovian, after the famous Russian physiologist and psychologist Pavlov. The responses of the Pavlovian controller are determined by evolutionary (phylogenetic) considerations rather than (ontogenetic) aspects of the contingent development or learning of an individual. These responses directly interact with instrumental choices arising from goal-directed and habitual controllers. This interaction has been studied in a wealth of animal paradigms, and can be helpful, neutral, or harmful, according to circumstance. Although there has been less careful or analytical study of it in humans, it can be interpreted as underpinning a wealth of behavioral aberrations. © 2009 Elsevier Inc. All rights reserved.

Body loadings and health risk assessment of polychlorinated dibenzo-p-dioxins and dibenzofurans at an intensive electronic waste recycling site in China

This study is one of the very few investigating the dioxin body burden of a group of child-bearing-aged women at an electronic waste (e-waste) recycling site (Taizhou, Zhejiang Province) (24 +/- 2.83 years of age, 40% were primiparae) and a reference site (Lin'an city, Zhejiang Province, about 245 km away from Taizhou) (24 +/- 2.35 years of age, 100% were primiparae) in China. Five sets of samples (each set consisted of human milk, placenta, and hair) were collected from each site. Body burdens of people from the e-waste processing site (human milk, 21.02 +/- 13.81 pg WHO-TEQ(1998/g) fat (World Health Organization toxic equivalency 1998); placenta, 31.15 +/- 15.67 pg WHO-TEQ(1998/g) fat; hair, 33.82 +/- 17.74 pg WHO-TEQ(1998/g) dry wt) showed significantly higher levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurnas (PCDD/Fs) than those from the reference site (human milk, 9.35 +/- 7.39 pg WHO-TEQ(1998/g) fat, placenta, 11.91 +/- 7.05 pg WHO-TEQ(1998/g) fat; hair, 5.59 +/- 4.36 pg WHO-TEQ(1998/g) dry wt) and were comparatively higher than other studies. The difference between the two sites was due to e-waste recycling operations, for example, open burning, which led to high background levels. Moreover, mothers from the e-waste recycling site consumed more foods of animal origin. The estimated daily intake of PCDD/Fs within 6 months by breast-fed infants from the e-waste processing site was 2 times higher than that from the reference site. Both values exceeded the WHO tolerable daily intake for adults by at least 25 and 11 times, respectively. Our results implicated that e-waste recycling operations cause prominent PCDD/F levels in the environment and in humans. The elevated body burden may have health implications for the next generation.

McArdle disease: a unique study model in sports medicine

McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities.

Automated cross-modal mapping in robotic eye/hand systems using plastic radial basis function networks

Q. Meng and M. H Lee, Automated cross-modal mapping in robotic eye/hand systems using plastic radial basis function networks, Connection Science, 19(1), pp 25-52, 2007.

Biologically inspired automatic construction of cross-modal mapping in robotic eye/hand systems

Q. Meng and M.H. Lee, 'Biologically inspired automatic construction of cross-modal mapping in robotic eye/hand systems', IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS 2006,) ,4742-49, Beijing, 2006.

Neural Control of Interlimb Coordination and Gait Timing in Bipeds and Quadrupeds

1) A large body of behavioral data conceming animal and human gaits and gait transitions is simulated as emergent properties of a central pattern generator (CPG) model. The CPG model incorporates neurons obeying Hodgkin-Huxley type dynamics that interact via an on-center off-surround anatomy whose excitatory signals operate on a faster time scale than their inhibitory signals. A descending cornmand or arousal signal called a GO signal activates the gaits and controL their transitions. The GO signal and the CPG model are compared with neural data from globus pallidus and spinal cord, among other brain structures. 2) Data from human bimanual finger coordination tasks are simulated in which anti-phase oscillations at low frequencies spontaneously switch to in-phase oscillations at high frequencies, in-phase oscillations can be performed both at low and high frequencies, phase fluctuations occur at the anti-phase in-phase transition, and a "seagull effect" of larger errors occurs at intermediate phases. When driven by environmental patterns with intermediate phase relationships, the model's output exhibits a tendency to slip toward purely in-phase and anti-phase relationships as observed in humans subjects. 3) Quadruped vertebrate gaits, including the amble, the walk, all three pairwise gaits (trot, pace, and gallop) and the pronk are simulated. Rapid gait transitions are simulated in the order--walk, trot, pace, and gallop--that occurs in the cat, along with the observed increase in oscillation frequency. 4) Precise control of quadruped gait switching is achieved in the model by using GO-dependent modulation of the model's inhibitory interactions. This generates a different functional connectivity in a single CPG at different arousal levels. Such task-specific modulation of functional connectivity in neural pattern generators has been experimentally reported in invertebrates. Phase-dependent modulation of reflex gain has been observed in cats. A role for state-dependent modulation is herein predicted to occur in vertebrates for precise control of phase transitions from one gait to another. 5) The primary human gaits (the walk and the run) and elephant gaits (the amble and the walk) are sirnulated. Although these two gaits are qualitatively different, they both have the same limb order and may exhibit oscillation frequencies that overlap. The CPG model simulates the walk and the run by generating oscillations which exhibit the same phase relationships. but qualitatively different waveform shapes, at different GO signal levels. The fraction of each cycle that activity is above threshold quantitatively distinguishes the two gaits, much as the duty cycles of the feet are longer in the walk than in the run. 6) A key model properly concerns the ability of a single model CPG, that obeys a fixed set of opponent processing equations to generate both in-phase and anti-phase oscillations at different arousal levels. Phase transitions from either in-phase to anti-phase oscillations, or from anti-phase to in-phase oscillations, can occur in different parameter ranges, as the GO signal increases.

Identification of RNA editing in the human exome and development of DARNED DatabaseSF

RNA editing is a biological phenomena that alters nascent RNA transcripts by insertion, deletion and/or substitution of one or a few nucleotides. It is ubiquitous in all kingdoms of life and in viruses. The predominant editing event in organisms with a developed central nervous system is Adenosine to Inosine deamination. Inosine is recognized as Guanosine by the translational machinery and reverse-transcriptase. In primates, RNA editing occurs frequently in transcripts from repetitive regions of the genome. In humans, more than 500,000 editing instances have been identified, by applying computational pipelines on available ESTs and high-throughput sequencing data, and by using chemical methods. However, the functions of only a small number of cases have been studied thoroughly. RNA editing instances have been found to have roles in peptide variants synthesis by non-synonymous codon substitutions, transcript variants by alterations in splicing sites and gene silencing by miRNAs sequence modifications. We established the Database of RNA EDiting (DARNED) to accommo-date the reference genomic coordinates of substitution editing in human, mouse and fly transcripts from published literatures, with additional information on edited genomic coordinates collected from various databases e.g. UCSC, NCBI. DARNED contains mostly Adenosine to Inosine editing and allows searches based on genomic region, gene ID, and user provided sequence. The Database is accessible at http://darned.ucc.ie RNA editing instances in coding region are likely to result in recoding in protein synthesis. This encouraged me to focus my research on the occurrences of RNA editing specific CDS and non-Alu exonic regions. By applying various filters on discrepancies between available ESTs and their corresponding reference genomic sequences, putative RNA editing candidates were identified. High-throughput sequencing was used to validate these candidates. All predicted coordinates appeared to be either SNPs or unedited.

Relationships between polybrominated diphenyl ether concentrations in house dust and serum.

Polybrominated diphenyl ethers (PBDEs) have been measured in the home environment and in humans, but studies linking environmental levels to body burdens are limited. This study examines the relationship between PBDE concentrations in house dust and serum from adults residing in these homes. We measured PBDE concentrations in house dust from 50 homes and in serum of male-female couples from 12 of the homes. Detection rates, dust-serum, and within-matrix correlations varied by PBDE congener. There was a strong correlation (r = 0.65-0.89, p < 0.05) between dust and serum concentrations of several predominant PBDE congeners (BDE 47, 99, and 100). Dust and serum levels of BDE 153 were not correlated (r < 0.01). The correlation of dust and serum levels of BDE 209 could not be evaluated due to low detection rates of BDE 209 in serum. Serum concentrations of the sum of BDE 47, 99, and 100 were also strongly correlated within couples (r = 0.85, p = 0.0005). This study provides evidence that house dust is a primary exposure pathway of PBDEs and supports the use of dust PBDE concentrations as a marker for exposure to PBDE congeners other than BDE 153.

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes.

Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extra-chromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.