Structure-based characterization of canine-human chimeric uricases and its evolutionary implications

Uricase was lost in hominoids during primate evolution, but the inactivation mechanism remains controversial. To investigate the inactivation process of hominoid uricase, chimeric constructions between canine and human uricase were employed to screen the target regions that may contain labile or inactivated mutations in deduced human uricase. Four chimeric uricases were constructed and showed different enzymatic characteristics. Homology modeling, rational site-directed mutagenesis and DNA alignment were used to analyze the changes. Arg119 is conserved in functional mammalian uricases and its side-chains are crucial in maintaining the stability of the β-barrel core. A single CGT (Arg) to CAT (His) mutation at codon 119 that is shared by the human and great ape clade greatly reduces this stability and could cause the loss of uricase activity. We speculate that this missense mutation occurred first and inactivated the uricase protein in humans and great apes and that later the known nonsense mutation at codon 33 occurred and silenced the uricase gene. A single GTC (Val) to GCC (Ala) mutation at codon 296 in canine uricase is regarded as deleterious structural mutation, but such kinds of deleterious mutations have been widely accumulated in extant mammalian uricases. We speculate that a reduction in uricase activity has been an evolutionary tendency in mammals. Moreover, from structure-activity analysis of helix 2 in ancestral primate uricase, we suggest that before the inactivation of hominoid uricase, deleterious structural evolutionary changes had occurred in ancestral primates. The loss of hominoid uricase should be caused by progressive multistep mutations rather than a single mutation event.     

Physiological and pathological oscillatory networks in the human motor system.

Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.     

Neural Mechanisms Underlying Stop-and-Restart Difficulties: Involvement of the Motor and Perceptual Systems

The ability to suddenly stop a planned movement or a movement being performed and restart it after a short interval is an important mechanism that allows appropriate behavior in response to contextual or environmental changes. However, performing such stop-and-restart movements smoothly is difficult at times. We investigated performance (response time) of stop-and-restart movements using a go/stop/re-go task and found consistent stop-and-restart difficulties after short (∼100 ms) stop-to-restart intervals (SRSI), and an increased probability of difficulties after longer (>200 ms) SRSIs, suggesting that two different mechanisms underlie stop-and-restart difficulties. Next, we investigated motor evoked potentials (MEPs) in a moving muscle induced by transcranial magnetic stimulation during a go/stop/re-go task. In re-go trials with a short SRSI (100 ms), the MEP amplitude continued to decrease after the re-go-signal onset, indicating that stop-and-restart difficulties with short SRSIs might be associated with a neural mechanism in the human motor system, namely, stop-related suppression of corticomotor (CM) excitability. Finally, we recorded electroencephalogram (EEG) activity during a go/stop/re-go task and performed a single-trial-based EEG power and phase time-frequency analysis. Alpha-band EEG phase locking to re-go-signal, which was only observed in re-go trials with long SRSI (250 ms), weakened in the delayed re-go response trials. These EEG phase dynamics indicate an association between stop-and-restart difficulties with long SRSIs and a neural mechanism in the human perception system, namely, decreased probability of EEG phase locking to visual stimuli. In contrast, smooth stop-and-restart human movement can be achieved in re-go trials with sufficient SRSI (150–200 ms), because release of stop-related suppression and simultaneous counter-activation of CM excitability may occur as a single task without second re-go-signal perception. These results suggest that skilled motor behavior is subject to various constraints in not only motor, but also perceptual (and attentional), systems.     

Internal models and intermittency: A theoretical account of human tracking behavior

This paper concerns the use of tracking studies to test a theoretical account of the information processing performed by the human CNS during control of movement. The theory provides a bridge between studies of reaction time and continuous tracking. It is proposed that the human CNS includes neuronal circuitry to compute inverse internal models of the multiple input, multiple output, dynamic, nonlinear relationships between outgoing motor commands and their resulting perceptual consequences. The inverse internal models are employed during movement execution to transform preplanned trajectories of desired perceptual consequences into appropriate outgoing motor commands to achieve them. A finite interval of time is required by the CNS to preplan the desired perceptual consequences of a movement and it does not commence planning a new movement until planning of the old one has been completed. This behavior introduces intermittency into the planning of movements. In this paper we show that the gain and phase frequency response characteristics of the human operator in a visual pursuit tracking task can be derived theoretically from these assumptions. By incorporating the effects of internal model inaccuracy and of speed-accuracy trade-off in performance, it is shown that various aspects of experimentally measured tracking behavior can be accounted for.     

Puncture marks on early African anthropoids

Field studies of living primates have shown that primate predation is a rare event. This must also have been true for past primate communities. In the Fayum Oligocene of Egypt, specimens of all four species of Upper Fossil Wood Zone primates show evidence of tooth puncture marks. Of the four potential groups of primate predators--the snakes, the raptors, the crocodiles, and the primitive carnivores or creodonts--only the crocodiles and the creodonts could have made these puncture marks. When one compares the feeding habits of living crocodiles and mammalian carnivores with the evidence from the Fayum, it appears that the Fayum primates were preyed upon and/or scavenged by mammalian carnivore-like animals. The dismemberment of the Fayum primates by Oligocene predators indicates, in part, why the Fayum fossil material is rarely articulated. Bone damage by predators may well set limits on what bone associations can be discovered in the Fayum even before the bones are scattered and buried by depositional processes.     

Cortical Components of Reaction-Time during Perceptual Decisions in Humans

The mechanisms of perceptual decision-making are frequently studied through measurements of reaction time (RT). Classical sequential-sampling models (SSMs) of decision-making posit RT as the sum of non-overlapping sensory, evidence accumulation, and motor delays. In contrast, recent empirical evidence hints at a continuous-flow paradigm in which multiple motor plans evolve concurrently with the accumulation of sensory evidence. Here we employ a trial-to-trial reliability-based component analysis of encephalographic data acquired during a random-dot motion task to directly image continuous flow in the human brain. We identify three topographically distinct neural sources whose dynamics exhibit contemporaneous ramping to time-of-response, with the rate and duration of ramping discriminating fast and slow responses. Only one of these sources, a parietal component, exhibits dependence on strength-of-evidence. The remaining two components possess topographies consistent with origins in the motor system, and their covariation with RT overlaps in time with the evidence accumulation process. After fitting the behavioral data to a popular SSM, we find that the model decision variable is more closely matched to the combined activity of the three components than to their individual activity. Our results emphasize the role of motor variability in shaping RT distributions on perceptual decision tasks, suggesting that physiologically plausible computational accounts of perceptual decision-making must model the concurrent nature of evidence accumulation and motor planning.     

Linking Perception,Cognition, and Action: Psychophysical Observations and Neural Network Modelling

It has been argued that perception, decision making, and movement planning are in reality tightly interwoven brain processes. However, how they are implemented in neural circuits is still a matter of debate. We tested human subjects in a temporal categorization task in which intervals had to be categorized as short or long. Subjects communicated their decision by moving a cursor into one of two possible targets, which appeared separated by different angles from trial to trial. Even though there was a 1 second-long delay between interval presentation and decision communication, categorization difficulty affected subjects’ performance, reaction (RT) and movement time (MT). In addition, reaction and movement times were also influenced by the distance between the targets. This implies that not only perceptual, but also movement-related considerations were incorporated into the decision process. Therefore, we searched for a model that could use categorization difficulty and target separation to describe subjects’ performance, RT, and MT. We developed a network consisting of two mutually inhibiting neural populations, each tuned to one of the possible categories and composed of an accumulation and a memory node. This network sequentially acquired interval information, maintained it in working memory and was then attracted to one of two possible states, corresponding to a categorical decision. It faithfully replicated subjects’ RT and MT as a function of categorization difficulty and target distance; it also replicated performance as a function of categorization difficulty. Furthermore, this model was used to make new predictions about the effect of untested durations, target distances and delay durations. To our knowledge, this is the first biologically plausible model that has been proposed to account for decision making and communication by integrating both sensory and motor planning information.     

Sleep-Dependent Reactivation of Ensembles in Motor Cortex Promotes Skill Consolidation

Despite many prior studies demonstrating offline behavioral gains in motor skills after sleep, the underlying neural mechanisms remain poorly understood. To investigate the neurophysiological basis for offline gains, we performed single-unit recordings in motor cortex as rats learned a skilled upper-limb task. We found that sleep improved movement speed with preservation of accuracy. These offline improvements were linked to both replay of task-related ensembles during non-rapid eye movement (NREM) sleep and temporal shifts that more tightly bound motor cortical ensembles to movements; such offline gains and temporal shifts were not evident with sleep restriction. Interestingly, replay was linked to the coincidence of slow-wave events and bursts of spindle activity. Neurons that experienced the most consistent replay also underwent the most significant temporal shift and binding to the motor task. Significantly, replay and the associated performance gains after sleep only occurred when animals first learned the skill; continued practice during later stages of learning (i.e., after motor kinematics had stabilized) did not show evidence of replay. Our results highlight how replay of synchronous neural activity during sleep mediates large-scale neural plasticity and stabilizes kinematics during early motor learning.     

The primate psi beta 1 gene. An ancient beta-globin pseudogene

The human beta-globin gene cluster contains five functional genes plus a single pseudogene termed psi beta 1. Hybridization and comparative sequence analysis show that this pseudogene is not the product of a recent gene duplication, but is ancient and has been maintained in all major primate groups ranging from prosimians to anthropoids, at the same position as in man, between gamma- and delta-globin genes. In the lemur, a prosimian, the central exons of the psi beta 1 and delta-globin genes have undergone an unequal exchange, which has resulted in a contraction of the beta-globin gene cluster and the formation of a Lepore-type psi beta 1-delta globin pseudogene. Comparisons of defects shared by prosimian, New World monkey and human psi beta 1 sequences suggest that the ancestral primate gene was probably a pseudogene with an abnormal initiation codon but few if any additional defects, and that most contemporary pseudogene defects were accumulated relatively recently by slow neutral drift. We suggest that psi beta 1 arose early in primate evolution by silencing of a pre-existing discrete functional gene, and show that psi beta 1-related sequences are also present in other mammalian orders. In view of the antiquity of psi beta 1-related sequences, we propose that this gene be renamed the eta-globin gene.     

Saccadic eye movements minimize the consequences of motor noise

The durations and trajectories of our saccadic eye movements are remarkably stereotyped. We have no voluntary control over these properties but they are determined by the movement amplitude and, to a smaller extent, also by the movement direction and initial eye orientation. Here we show that the stereotyped durations and trajectories are optimal for minimizing the variability in saccade endpoints that is caused by motor noise. The optimal duration can be understood from the nature of the motor noise, which is a combination of signal-dependent noise favoring long durations, and constant noise, which prefers short durations. The different durations of horizontal vs. vertical and of centripetal vs. centrifugal saccades, and the somewhat surprising properties of saccades in oblique directions are also accurately predicted by the principle of minimizing movement variability. The simple and sensible principle of minimizing the consequences of motor noise thus explains the full stereotypy of saccadic eye movements. This suggests that saccades are so stereotyped because that is the best strategy to minimize movement errors for an open-loop motor system.     

Time Adaptation Shows Duration Selectivity in the Human Parietal Cortex

Although psychological and computational models of time estimation have postulated the existence of neural representations tuned for specific durations, empirical evidence of this notion has been lacking. Here, using a functional magnetic resonance imaging (fMRI) adaptation paradigm, we show that the inferior parietal lobule (IPL) (corresponding to the supramarginal gyrus) exhibited reduction in neural activity due to adaptation when a visual stimulus of the same duration was repeatedly presented. Adaptation was strongest when stimuli of identical durations were repeated, and it gradually decreased as the difference between the reference and test durations increased. This tuning property generalized across a broad range of durations, indicating the presence of general time-representation mechanisms in the IPL. Furthermore, adaptation was observed irrespective of the subject’s attention to time. Repetition of a nontemporal aspect of the stimulus (i.e., shape) did not produce neural adaptation in the IPL. These results provide neural evidence for duration-tuned representations in the human brain.     

The Importance of Lateral Connections in the Parietal Cortex for Generating Motor Plans

Substantial evidence has highlighted the significant role of associative brain areas, such as the posterior parietal cortex (PPC) in transforming multimodal sensory information into motor plans. However, little is known about how different sensory information, which can have different delays or be absent, combines to produce a motor plan, such as executing a reaching movement. To address these issues, we constructed four biologically plausible network architectures to simulate PPC: 1) feedforward from sensory input to the PPC to a motor output area, 2) feedforward with the addition of an efference copy from the motor area, 3) feedforward with the addition of lateral or recurrent connectivity across PPC neurons, and 4) feedforward plus efference copy, and lateral connections. Using an evolutionary strategy, the connectivity of these network architectures was evolved to execute visually guided movements, where the target stimulus provided visual input for the entirety of each trial. The models were then tested on a memory guided motor task, where the visual target disappeared after a short duration. Sensory input to the neural networks had sensory delays consistent with results from monkey studies. We found that lateral connections within the PPC resulted in smoother movements and were necessary for accurate movements in the absence of visual input. The addition of lateral connections resulted in velocity profiles consistent with those observed in human and non-human primate visually guided studies of reaching, and allowed for smooth, rapid, and accurate movements under all conditions. In contrast, Feedforward or Feedback architectures were insufficient to overcome these challenges. Our results suggest that intrinsic lateral connections are critical for executing accurate, smooth motor plans.     

运动对时距知觉的影响及其神经机制

在运动过程中,时距知觉的能力非常重要,能帮助个体对时长进行判断及对事件的发生做出预测和准备.近年来,越来越多的研究发现运动本身会直接影响个体的时距知觉.本文分别从运动参数、运动阶段、视觉运动刺激和运动有关的个体因素四个方面梳理了运动对时距知觉产生影响的行为学证据.目前已经有大量研究从不同角度证明,大脑运动系统组成了支持主观时间知觉的神经网络,并且编码和参与了人类的时距知觉.运动作用于时距知觉的理论机制可以基于内部时钟模型的理论框架并进而从感觉运动信息的交互、运动对唤醒状态的改变及具身认知理论三个角度予以解释.未来研究需要关注运动对不同单位级别时距知觉的影响,测评运动状态下时距知觉的研究范式及技术手段等多个方面进行思考和推进,从而更好地揭示运动如何调节时距知觉过程及其作用机制.还应该结合竞技运动项目特点,为减少运动中时距知觉误差和提高运动员时距知觉能力提供帮助与指导.     

Vanishing GC-rich isochores in mammalian genomes

To understand the origin and evolution of isochores-the peculiar spatial distribution of GC content within mammalian genomes-we analyzed the synonymous substitution pattern in coding sequences from closely related species in different mammalian orders. In primate and cetartiodactyls, GC-rich genes are undergoing a large excess of GC --> AT substitutions over AT --> GC substitutions: GC-rich isochores are slowly disappearing from the genome of these two mammalian orders. In rodents, our analyses suggest both a decrease in GC content of GC-rich isochores and an increase in GC-poor isochores, but more data will be necessary to assess the significance of this pattern. These observations question the conclusions of previous works that assumed that base composition was at equilibrium. Analysis of allele frequency in human polymorphism data, however, confirmed that in the GC-rich parts of the genome, GC alleles have a higher probability of fixation than AT alleles. This fixation bias appears not strong enough to overcome the large excess of GC --> AT mutations. Thus, whatever the evolutionary force (neutral or selective) at the origin of GC-rich isochores, this force is no longer effective in mammals. We propose a model based on the biased gene conversion hypothesis that accounts for the origin of GC-rich isochores in the ancestral amniote genome and for their decline in present-day mammals.     

Attending to the possibilities of action

Actions taking place in the environment are critical for our survival. We review evidence on attention to action, drawing on sets of converging evidence from neuropsychological patients through to studies of the time course and neural locus of action-based cueing of attention in normal observers. We show that the presence of action relations between stimuli helps reduce visual extinction in patients with limited attention to the contralesional side of space, while the first saccades made by normal observers and early perceptual and attentional responses measured using electroencephalography/event-related potentials are modulated by preparation of action and by seeing objects being grasped correctly or incorrectly for action. With both normal observers and patients, there is evidence for two components to these effects based on both visual perceptual and motor-based responses. While the perceptual responses reflect factors such as the visual familiarity of the action-related information, the motor response component is determined by factors such as the alignment of the objects with the observer''s effectors and not by the visual familiarity of the stimuli. In addition to this, we suggest that action relations between stimuli can be coded pre-attentively, in the absence of attention to the stimulus, and action relations cue perceptual and motor responses rapidly and automatically. At present, formal theories of visual attention are not set up to account for these action-related effects; we suggest ways that theories could be expected to enable action effects to be incorporated.     

Causal role of dorsolateral prefrontal cortex in human perceptual decision making

The way that we interpret and interact with the world entails making decisions on the basis of available sensory evidence. Recent primate neurophysiology [1-6], human neuroimaging [7-13], and modeling experiments [14-19] have demonstrated that perceptual decisions are based on an integrative process in which sensory evidence accumulates over time until an internal decision bound is reached. Here we used repetitive transcranial magnetic stimulation (rTMS) to provide causal support for the role of the dorsolateral prefrontal cortex (DLPFC) in this integrative process. Specifically, we used a speeded perceptual categorization task designed to induce a time-dependent accumulation of sensory evidence through rapidly updating dynamic stimuli and found that disruption of the left DLPFC with low-frequency rTMS reduced accuracy and increased response times relative to a sham condition. Importantly, using the drift-diffusion model, we show that these behavioral effects correspond to a decrease in drift rate, a parameter describing the rate and thereby the efficiency of the sensory evidence integration in the decision process. These results provide causal evidence linking the DLPFC to the mechanism of evidence accumulation during perceptual decision making.     

The autonomy of the visual systems and the modularity of conscious vision.

Anatomical and physiological evidence shows that the primate visual brain consists of many distributed processing systems, acting in parallel. Psychophysical studies show that the activity in each of the parallel systems reaches its perceptual end-point at a different time, thus leading to a perceptual asynchrony in vision. This, together with clinical and human imaging evidence, suggests strongly that the processing systems are also perceptual systems and that the different processing-perceptual systems can act more or less autonomously. Moreover, activity in each can have a conscious correlate without necessarily involving activity in other visual systems. This leads us to conclude not only that visual consciousness is itself modular, reflecting the basic modular organization of the visual brain, but that the binding of cellular activity in the processing-perceptual systems is more properly thought of as a binding of the consciousnesses generated by each of them. It is this binding that gives us our integrated image of the visual world.     

Chromosome painting of the pygmy tree shrew shows that no derived cytogenetic traits link primates and scandentia

We hybridized human chromosome paints on metaphases of the pygmy tree shrew (Tupaia minor, Scandentia). The lack of the ancestral mammalian 4/8 association in both Primates and Scandentia was long considered a cytogenetic landmark that phylogenetically linked these mammalian orders. However, our results show that the association 4/8 is present in Tupaia along with not previously reported associations for 1/18 and 7/10. Altogether there are 11 syntenic associations of human chromosome segments in the pygmy tree shrew karyotype: 1/18, 2/21, 3/21, 4/8, 7/10, 7/16, 11/20, 12/22 (twice), 14/15 and 16/19. Our data remove any cytogenetic evidence that Scandentia has a preferential phylogenetic relationship with Primates.     

The uniquely human capacity to throw evolved from a non-throwing primate: an evolutionary dissociation between action and perception

Humans are uniquely endowed with the ability to engage in accurate, high-momentum throwing. Underlying this ability is a unique morphological adaptation that enables the characteristic rotation of the arm and pelvis. What is unknown is whether the psychological mechanisms that accompany the act of throwing are also uniquely human. Here we explore this problem by asking whether free-ranging rhesus monkeys (Macaca mulatta), which lack both the morphological and neural structures to throw, nonetheless recognize the functional properties of throwing. Rhesus not only understand that human throwing represents a threat, but that some aspects of a throwing event are more relevant than others; specifically, rhesus are sensitive to the kinematics, direction and speed of the rotating arm, the direction of the thrower's eye gaze and the object thrown. These results suggest that the capacity to throw did not coevolve with psychological mechanisms that accompany throwing; rather, this capacity may have built upon pre-existing perceptual processes. These results are consistent with a growing body of work showing that non-human animals often exhibit perceptual competencies that do not show up in their motor responses, suggesting evolutionary dissociations between the systems of perception that provide understanding of the world and those that mediate action on the world.     

Motor Cost Influences Perceptual Decisions

Perceptual decision making has been widely studied using tasks in which subjects are asked to discriminate a visual stimulus and instructed to report their decision with a movement. In these studies, performance is measured by assessing the accuracy of the participants’ choices as a function of the ambiguity of the visual stimulus. Typically, the reporting movement is considered as a mere means of reporting the decision with no influence on the decision-making process. However, recent studies have shown that even subtle differences of biomechanical costs between movements may influence how we select between them. Here we investigated whether this purely motor cost could also influence decisions in a perceptual discrimination task in detriment of accuracy. In other words, are perceptual decisions only dependent on the visual stimulus and entirely orthogonal to motor costs? Here we show the results of a psychophysical experiment in which human subjects were presented with a random dot motion discrimination task and asked to report the perceived motion direction using movements of different biomechanical cost. We found that the pattern of decisions exhibited a significant bias towards the movement of lower cost, even when this bias reduced performance accuracy. This strongly suggests that motor costs influence decision making in visual discrimination tasks for which its contribution is neither instructed nor beneficial.