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PubMed2006

PepDist: a new framework for protein-peptide binding prediction based on learning peptide distance functions.

BACKGROUND: Many different aspects of cellular signalling, trafficking and targeting mechanisms are mediated by interactions between proteins and peptides. Representative examples are MHC-peptide complexes in the immune system. Developing computational methods for protein-peptide binding prediction is therefore an important task with applications to vaccine and drug design. METHODS: Previous learning approaches address the binding prediction problem using traditional margin based binary classifiers. In this paper we propose PepDist: a novel approach for predicting binding affinity. Our approach is based on learning peptide-peptide distance functions. Moreover, we suggest to learn a single peptide-peptide distance function over an entire family of proteins (e.g. MHC class I). This distance function can be used to compute the affinity of a novel peptide to any of the proteins in the given family. In order to learn these peptide-peptide distance functions, we formalize the problem as a semi-supervised learning problem with partial information in the form of equivalence constraints. Specifically, we propose to use DistBoost, which is a semi-supervised distance learning algorithm. RESULTS: We compare our method to various state-of-the-art binding prediction algorithms on MHC class I and MHC class II datasets. In almost all cases, our method outperforms all of its competitors. One of the major advantages of our novel approach is that it can also learn an affinity function over proteins for which only small amounts of labeled peptides exist. In these cases, our method's performance gain, when compared to other computational methods, is even more pronounced. We have recently uploaded the PepDist webserver which provides binding prediction of peptides to 35 different MHC class I alleles. The webserver which can be found at http://www.pepdist.cs.huji.ac.il is powered by a prediction engine which was trained using the framework presented in this paper. CONCLUSION: The results obtained suggest that learning a single distance function over an entire family of proteins achieves higher prediction accuracy than learning a set of binary classifiers for each of the proteins separately. We also show the importance of obtaining information on experimentally determined non-binders. Learning with real non-binders generalizes better than learning with randomly generated peptides that are assumed to be non-binders. This suggests that information about non-binding peptides should also be published and made publicly available.

Algorithms↗

PubMedDate not supplied

Relationship between learning characteristics and the properties of visual objects in rhesus macaques with bilateral removal of parietal cortex field 7.

Behavioral experiments were used in rhesus macaques with bilateral excision of field 7 of the lower parietal cortex to study the relationship between visual differentiation learning processes and a variety of stimulus properties. All animals showed significant differences associated with stimulus properties, which produced different types of learning curves. For each monkey, visual stimuli were divided into compact groups in terms of the "similarity" of their learning characteristics. Removal of field 7 had no effect on the process of learning visual image discrimination when this was based on properties such as color and geometrical shape, but worsened the learning characteristics when visual differentiation was based on spatial information, when the learning process became unstable, with increases in the numbers of peaks and troughs on the learning curve and a significant increase in the duration of the learning period. The time to a stable motor response also became significantly greater than for visual images distinguished by shape and color. It is suggested that during the process of learning visual discrimination, processing and extraction of image signs by the visual system for objects characterized by spatial relationships is accompanied by the formation of spatial distinguishing signs, this process involving neuronal structures in field 7 of the lower parietal cortex, which appears to be the main area determining visual-vestibular interactions. Increases in oscillations and in the difficulty of the learning process for differentiation on the basis of spatial information after removal of field 7 might be due to a transfer from one strategy to another, resulting from disruption of the mechanisms which evaluate body image and egocentric orientation on the basis of visual-vestibular interactions.

Animals↗

PubMed1991

Rhesus monkey (Macaca mulatta) complex learning skills reassessed.

Results from three experiments on basic learning and transfer in rhesus monkeys (Macaca mulatta) are reported in which fully automated testing paradigms, afforded by the Language Research Center's Computerized Test System (LRC-CTS), were employed. Performance levels for discrimination learning set, transfer index, and mediational-learning testing were uniformly higher than was predicted from the literature, in contrast to previous reports of compromised learning under similar conditions (automated apparatus, planimetric stimuli, spatial discontiguity between stimuli and response loci). Analyses reveal relatively advanced learning set performance, transfer-index ratios, and positive transfer of learning even at stringent criterion levels. Moreover, the data suggest that rhesus monkeys tested in these experiments exhibit mediational instead of associative learning strategies, as do great apes and in contrast to previous reports of rhesus learning. We argue that the LRC-CTS enhances learning by nonhuman primate subjects, obviating those factors, reported in the literature from experiments in which manual or other automated systems were employed, that compromise learning.

Animals↗

PubMed2006

[E-learning in the education and training of physicians. Methods, results, evaluation].

E-learning has been established in the education and training of physicians in various types: linear sequential and hyper-textual forms of multimedia presentations and texts, tutorial systems and simulations. Case-based e-learning systems are of special importance in medicine because they allow for mediation of process and practical knowledge by presentation of authentic medical cases in a simulated environment. The integration into the medical education and advanced professional training is crucial for the long-term success of e-learning; in case-based systems this can be accomplished by blended learning approaches which combine elements of traditional teaching with e-learning. Learning management systems (LMS) support integration of traditional teaching and e-learning by serving as an organizational platform for content of teaching. Further, they provide means of communication for trainers and trainees, authoring tools, interactive components, course management and role-based sharing concept. The dissemination of e-learning can be fostered by attention to requirements and user analysis, early adoption to organizational structures, curricular integration and continuous cooperation with students. Summarized, didactic and organizational aspects determine the success of our own e-learning offers as well as they influence the general further development of e-learning more than technical features.

Computer-Assisted Instruction↗

PubMed1996

Limbic thalamic, cingulate cortical and hippocampal neuronal correlates of discriminative approach learning in rabbits.

Previous research employing lesions and recording of neuronal activity has implicated cingulothalamic and hippocampal circuitry in the mediation of discriminative instrumental avoidance learning in rabbits. This study was directed at the question of whether the cingulothalamic circuitry is specialized for avoidance learning, or whether it is also involved in appetitively motivated learning. Multi-unit neuronal recordings in the aforementioned areas were obtained as adult New-Zealand white rabbits learned to approach and orally contact a drinking spout for water reward after a tone conditional stimulus (CS+), and to ignore the spout after a different, non-predictive tone conditional stimulus (CS-). As during avoidance learning, excitatory and discriminative training-induced neuronal activity (TIA) developed during the course of approach learning. Discriminative TIA refers to development of greater neuronal firing response to the CS+ than to the CS-. Excitatory TIA refers to increased neuronal discharge magnitude during training compared to the activity elicited before training, when CS presentations were unpaired with foot-shock presentations. As during avoidance learning, TIA in anterior cingulate cortical and interconnected mediodorsal (MD) thalamic neuronal records preceded TIA in posterior cingulate cortical and interconnected anterior ventral thalamic records. Delayed changes also occurred in area CA1 of the hippocampus in parallel with changes in the posterior cingulate cortex and the anterior thalamic nuclei. In contrast to the avoidance-related activity, the changes in the thalamic areas preceded or occurred concurrently with changes in the related cingulate cortical areas. This difference is hypothesized to be due to a reduced or absent contribution of amygdaloid efferents to the approach learning-related TIA. The overall magnitude of the elicited training-induced neuronal responses was reduced, relative to the discharges during avoidance conditioning. The discharge magnitude differences suggested a greater recruitment of limbic circuit functions during avoidance learning, possibly due to the aversiveness and high arousal associated with the avoidance task. In general, the results indicate that the circuitry formed by interconnected cingulate cortical, limbic thalamic and hippocampal neurons has fundamentally similar functions in both approach and avoidance learning.

Animals↗

PubMedDate not supplied

Do neuroleptics impair learning in schizophrenic patients?

Dopamine (DA) has been shown to be involved in reward-related (incentive) learning but not stimulus-stimulus (s-s) associative learning. Schizophrenic individuals receive neuroleptics (DA receptor blockers) for therapy and therefore may have impaired incentive learning. To test this hypothesis, in experiment 1, schizophrenic outpatients receiving haloperidol or flupenthixol and matched controls were tested on tasks involving incentive or s-s learning. Patients were also given the Brief Psychiatric Rating Scale (BPRS). Results showed the patients to be significantly impaired in every task. However, only impairments of s-s learning were correlated with psychiatric state. Thus, deficits on the tasks involving incentive learning were interpreted as resulting from neuroleptic drugs rather than psychiatric state. Experiment 2 tested 26 schizophrenic inpatients receiving a variety of neuroleptics (converted to chloropromazine equivalency (CPZEQ)) on the same tasks. A blood sample was collected from the patients and from age-matched controls and prolactin levels were found to be significantly higher in the patients. Multiple regression analysis was used on patient data to determine whether prolactin level or CPZEQ were related to performance. It was found that incentive learning but not s-s associative learning was significantly predicted by one of these two indexes of neuroleptic drug dose. The results of these experiments provide some support for the hypothesis that neuroleptics might impair incentive but not s-s associative learning in schizophrenics. The observation that neuroleptics affect human incentive learning might lead to more efficient use of behavior modification programs in the treatment of schizophrenia.

Adult↗

PubMed2006

Spatial learning in Long-Evans Hooded rats and C57BL/6J mice: different strategies for different performance.

Spatial learning abilities of rodents have been extensively used to explore the management of a wide range of cognitive and emotional processes such as learning, memory, attention and anxiety. Knowledge about the organization and processing of spatial learning has mainly been obtained in rats. Due to increasing generation of genetically modified mice, cognitive abilities of mice are now extensively tested. The present paper aimed at comparing spatial representation, learning and strategies in C57BL/6J mice and Long-Evans Hooded rats when subjected to the same spatial learning paradigm, i.e. learning a food location in a crossmaze. We also analyzed the influence of environmental richness on learning modalities in both species. Our results showed that rats and mice could exhibit similar spatial learning abilities in some circumstances. However, Long-Evans rats and C57BL/6J mice may set up different strategies depending on the availability of visual information within the environment. Rats' learning strategies mainly relied on distant visual cues and seemed more efficient than those used by mice as they needed less time than mice to solve the task. We emphasize that the strategies of mice are less robust and flexible than the ones set up by rats. Finally, the richness of the environment was shown to affect speed and quality of spatial learning in both species.

Analysis of Variance↗

PubMed2005

Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain.

Intellectual function is impaired in patients with hyperammonemia and hepatic encephalopathy. Chronic hyperammonemia with or without liver failure impairs the glutamate-nitric oxide-cGMP pathway function in brain in vivo and reduces extracellular cGMP in brain as well as the ability of rats to learn a Y maze conditional discrimination task. We hypothesized that the decrease in extracellular cGMP may be responsible for the impairment in learning ability and intellectual function and that pharmacological modulation of the levels of cGMP may restore learning ability. The aim of this work was to try to reverse the impairment in learning ability of hyperammonemic rats by pharmacologically increasing extracellular cGMP in brain. We assessed whether learning ability may be restored by increasing extracellular cGMP in brain by continuous intracerebral administration of: (1) zaprinast, an inhibitor of the phosphodiesterase that degrades cGMP or (2) cGMP. We carried out tests of conditional discrimination learning in a Y maze with control and hyperammonemic rats treated or not with zaprinast or cGMP. Learning ability was reduced in hyperammonemic rats, which needed more trials than control rats to learn the task. Continuous intracerebral administration of zaprinast or cGMP restored the ability of hyperammonemic rats to learn this task. Pharmacological modulation of extracellular cGMP levels in brain may be a useful therapeutic approach to improve learning and memory performance in individuals in whom cognitive abilities are impaired by different reasons, for example in patients with liver disease who present hyperammonemia and decreased intellectual function.

Animals↗

PubMed2006

Can design principles of traditional learning theories be fulfilled by computer-based training systems in medicine: the example of CAMPUS.

PURPOSE: Computer-based training (CBT) systems offer the potential to efficiently support modern teaching and learning. However, it is still unknown if a similar efficient learning experience built on sound learning theories and corresponding design principles can be created in the complex health care environment. The purpose of this paper is to analyse to what extent learning theories and corresponding design principles are relevant and can successfully be applied in computer-based training in medicine. METHODS: We use the case-based CBT system CAMPUS as an example for a CBT system currently used to enhance the medical teaching and learning experience. We apply two well-accepted learning theories (Bloom's taxonomy and practice fields) and related design principles to determine to what extent they are relevant and fulfilled in the context of CAMPUS. RESULTS: We demonstrate that in principle these learning theories and design principles can be implemented using computer-based training. However, not all design principles can be fulfilled by the system alone; rather the integration of the system into adequate -- traditional or virtual -- teaching and learning environments is essential. CONCLUSIONS: Traditional learning theories and design principles are a valuable means in designing adequate CBT systems in medicine. They can be successfully implemented in CBT systems for medical education if the system itself is adequately integrated into teaching and learning environments.

Computer-Assisted Instruction↗

PubMed2006

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus.

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Animals↗

PubMed2002

Intact artificial grammar learning in patients with cerebellar degeneration and advanced Parkinson's disease.

In an artificial grammar learning task, subjects were asked to memorise short lists of letter strings formed according to complex rules for letter order. After an interval they were unexpectedly asked to discriminate new grammatical strings from strings which used the same letters but violated the sequential constraints of the grammar. Artificial grammar learning can be mastered successfully by amnesic patients and is considered to be an implicit learning task independent of declarative learning and memory mechanisms. In this study, 10 patients with cerebellar degeneration (CD), 21 Parkinson's disease (PD) and 15 control subjects were tested on artificial grammar learning. Additionally PD patients with advanced disease were examined under adequate medication and dopaminergic withdrawal. All patient groups showed intact artificial grammar learning. Neither cerebellar damage nor basal ganglia dysfunction nor dopaminergic medication impairs or affects artificial grammar learning. Although the patients showed significant executive dysfunction, implicit learning remains intact. The conclusion is that cerebellar and basal ganglia circuits play no essential part in this kind of implicit learning. The results suggest that artificial grammar learning is a cortically mediated function comparable to the mechanism of visual priming.

Aged↗

PubMed1998

Systemic harmaline blocks associative and motor learning by the actions of the inferior olive.

Is there a role for the inferior olive in learning? Novel paradigms of conditioning involving tongue protrusion were developed using the rat to test whether: (a) the indole alkaloid harmaline blocks associative learning via actions within the inferior olive, and (b) the inferior olive is required for associative and motor learning. Harmaline blocked associative learning as measured by the absence of conditioned responses to a tone over six daily sessions of conditioning and the absence of retention without harmaline. Harmaline's effect on associative learning was completely blocked by prior removal of the inferior olive with 3-acetylpyridine. Rats whose inferior olives were chronically lesioned showed normal associative learning, normal associative memory, and could learn to modify tongue protrusion via a motor learning paradigm involving response shaping. Removal of the inferior olive degraded the performance of the licking motor system by increasing the latency of conditioned tongue protrusions and by increasing the temporal variability of rhythmic licking elicited by intraoral water. The experiments raise doubt as to whether the inferior olive encodes memory in the cerebellum but demonstrate that the inferior olive is essential for the temporal precision of movement. The results indicate that harmaline's antilearning action is produced by its ability to exaggerate the normal propensity of olivary neurons to fire rhythmically, a process that must be constrained under physiological conditions for normal learning to occur. It is concluded that there may be an important role for the rhythmic activity of inferior olivary neurons in the temporal processes that underlie both motor control and learning.

Animals↗

PubMed2006

Learning in the absence of experience-dependent regulation of NMDAR composition.

Olfactory discrimination (OD) learning consists of two phases: an initial N-methyl-D-aspartate (NMDA) receptor-sensitive rule-learning phase, followed by an NMDA receptor (NMDAR)-insensitive pair-learning phase. The rule-learning phase is accompanied by changes in the composition and function of NMDARs at synapses in the piriform cortex, resulting in a high level of the NR2a subunit relative to NR2b. Here we show that the learning-induced changes in NMDAR composition in the adult piriform cortex are due to a decrease in the level of the NR2b subunit protein, rather than an increase in the level of NR2a. Chronic administration of an NMDAR open channel blocker during training delays OD learning and blocks learning-induced changes in NMDAR subunit composition. However, the animals still learn the OD task. Our data demonstrate that learning can occur in the absence of activity-dependent regulation of NMDAR composition, suggesting differences in the mechanism for long-term maintenance of NMDAR-dependent and NMDAR-independent learning.

Analysis of Variance↗

PubMed2004

Learned fear of "unseen" faces after Pavlovian, observational, and instructed fear.

This study compared fear learning acquired through direct experience (Pavlovian conditioning) and fear learning acquired without direct experience via either observation or verbal instruction. We examined whether these three types of learning yielded differential responses to conditioned stimuli (CS+) that were presented unmasked (available to explicit awareness) or masked (not available to explicit awareness). In the Pavlovian group, the CS+ was paired with a mild shock, whereas the observational-learning group learned through observing the emotional expression of a confederate receiving shocks paired with the CS+. The instructed-learning group was told that the CS+ predicted a shock. The three groups demonstrated similar levels of learning as measured by the skin conductance response to unmasked stimuli. As in previous studies, participants also displayed a significant learning response to masked stimuli following Pavlovian conditioning. However, whereas the observational-learning group also showed this effect, the instructed-learning group did not.

Analysis of Variance↗

PubMed1992

Correlations of memory and learning with vision in aged patients before and after a cataract operation.

The connection between memory and learning with vision was investigated by studying 100 cataract operation patients, aged 71 to 76 years, 25 of them being men and 75 women. The cataract operation restored sufficient acuity of vision for reading (minimum E-test value 0.40) to 79% of the subjects. Short-term memory was studied with series of numbers, homogenic and heterogenic inhibition, and long sentences. Learning was tested with paired-associate learning and word learning. Psychological symptoms were measured on the Brief Psychiatric Rating Scale and personality on the Mini-Mult MMPI. Memory and learning improved significantly when vision was normalized after the cataract operation. Poor memory and learning scores correlated with monocular vision before the operation and with defects in the field of vision, due to glaucoma and exceeding 20%, postsurgery. Monocular vision and defects in the visual field caused a continuous sense of abnormalness, which impaired old people's ability to concentrate on tasks of memory and learning. Cerebrovascular disturbances, beginning dementia, and moderate psychological symptoms obstructed memory and learning on both test rounds. Depression was the most important psychological symptom contributing to poor memory and learning scores after the cataract operation. The memory and learning defects mainly reflected disturbances in memorizing.

Aged↗

PubMed2006

Dual-task interference in perceptual category learning.

The effect of a working-memory-demanding dual task on perceptual category learning was investigated. In Experiment 1, participants learned unidimensional rule-based or information integration category structures. In Experiment 2, participants learned a conjunctive rule-based category structure. In Experiment 1, unidimensional rule-based category learning was disrupted more by the dual working memory task than was information integration category learning. In addition, rule-based category learning differed qualitatively from information integration category learning in yielding a bimodal, rather than a normal, distribution of scores. Experiment 2 showed that rule-based learning can be disrupted by a dual working memory task even when both dimensions are relevant for optimal categorization. The results support the notion of at least two systems of category learning a hypothesis-testing system that seeks verbalizable rules and relies on working memory and selective attention, and an implicit system that is procedural-learning based and is essentially automatic.

Association Learning↗

PubMed1997

Bird song learning as an adaptive strategy.

Parallels are often drawn between bird song learning and human language learning. The analogies include an early sensitive period for learning, separation of sensory and motor phases of learning, 'innate knowledge' of language or song, and specialized neural systems. Nevertheless, in distinction to human language learning, song learning is usually viewed as a purely auditory process. This view is implied in the typical experimental paradigm for studying song learning, in which the bird is isolated in a sound-proof chamber and exposed only to tape-recorded song. This paradigm remains the major method of studying song learning despite recent demonstrations of the importance of social variables, and it contains the implicit assumption that non-auditory variables, especially social and ecological variables, play only a minor role in this process. I will argue here that understanding the functions of song learning requires that we investigate it in the field, where social and ecological variables have full play. We have done just this for the song sparrow, and when viewed in this perspective song learning in the song sparrow takes on the clear outlines of an adaptive strategy.

Adaptation, Psychological↗

PubMed1993

An examination of the relations between hippocampal long-term potentiation, kindling, afterdischarge, and place learning in the water maze.

Two approaches were used to study the relations between the acquisition of place learning in the Morris water maze and long-term potentiation (LTP), kindling, and afterdischarge (AD). In the first, the possibility of behavioral LTP in the dentate gyrus field potential evoked by stimulation of the perforant path was evaluated in rats that showed robust place learning in the water maze. There was no effect of place learning on the field potential, and field potential measures did not correlate with place learning acquisition measures. In the second approach, the effect of bilateral saturation of LTP on subsequent place learning in the water maze task, begun within 5 minutes of the last LTP session, was evaluated. The effect of kindled seizures evoked bilaterally from the perforant path, or of a single unilateral AD, on acquisition of the water maze task (begun within 10 minutes) were also evaluated. Bilateral LTP saturation did not affect place learning, and the bilateral LTP group learned as readily as controls. In contrast, the kindled and AD groups were severely impaired in their performance of the place learning task. A second day of training in the water maze without any further electrical stimulation indicated that these groups had acquired considerable information on the first day of maze training and were not distinguishable from controls on the second day of training. This indicated that the deficit in these groups on the first day of training was temporary and likely resulted from a temporary perturbation of normal brain function due to the seizures. The results indicate that bilateral saturation of LTP in the dentate gyrus does not affect place learning in the water maze. They also indicate that recent hippocampal seizures, but not kindling, disrupt place learning in this task.

Animals↗