897 resultados para Domain-specific visual language


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Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.

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Lisbon, October 27, 2014, Dr. Jose Luis Cardoso director of the Institute of Social Sciences (ICS) at the University of Lisbon, has suspended the publication of the number 212 of the prestigious journal Análise Social. The reason: the number contains a visual essay produced by Ricardo Campos that is qualified to use a 'strong language'. While the online edition of the magazine was available (not try to find it at the site of the ICS) the printed edition was in printing machines. Now, the hard copies will be destroyed.

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Across Latin America 420 indigenous languages are spoken. Spanish is considered a second language in indigenous communities and is progressively introduced in education. However, most of the tools to support teaching processes of a second language have been developed for the most common languages such as English, French, German, Italian, etc. As a result, only a small amount of learning objects and authoring tools have been developed for indigenous people considering the specific needs of their population. This paper introduces Multilingual–Tiny as a web authoring tool to support the virtual experience of indigenous students and teachers when they are creating learning objects in indigenous languages or in Spanish language, in particular, when they have to deal with the grammatical structures of Spanish. Multilingual–Tiny has a module based on the Case-based Reasoning technique to provide recommendations in real time when teachers and students write texts in Spanish. An experiment was performed in order to compare some local similarity functions to retrieve cases from the case library taking into account the grammatical structures. As a result we found the similarity function with the best performance

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The research assesses the skills of upper comprehensive school pupils in history. The focus is on locating personal motives, assessing wider reasons hidden in historical sources and evaluating source reliability. The research also questions how a wide use of multiple sources affects pupils’ holistic understanding of historical phenomena. The participants were a multicultural group of pupils. The origins of their cultures can be traced to the Balkan, the Middle East, Asia and Europe. The number of native Finnish speakers and pupils speaking Finnish as their second language was almost equal. The multicultural composition provides opportunities to assess how culturally responsive learning history from sources is. The intercultural approach to learning in a multicultural setting emphasizes equality as a precondition for learning. In order to set assignments at least to some extent match with all participants only those answers were taken into account which were produced by pupils who had studied history for a similar period of time in the Finnish comprehensive school system. Due to the small number of participants (41), the study avoids wide generalizations. Nevertheless, possible cultural blueprints in pupils’ way of thinking are noted. The first test examined the skills of pupils to find motives for emigration. The results showed that for 7th graders finding reasons is not a problematic task. However, the number of reasons noticed and justifications varied. In addition, the way the pupils explained their choices was a distinguishing factor. Some pupils interpreted source material making use of previous knowledge on the issue, while other pupils based their analysis solely on the text handed and did not try to add their own knowledge. Answers were divided into three categories: historical, explanatory and stating. Historical answers combined smoothly previously learned historical knowledge to one’s own source analysis; explanatory answers often ignored a wider frame, although they were effective when explaining e.g. historical concepts. The stating answers only noticed motives from the sources and made no attempts to explain them historically. Was the first test culturally responsive? All pupils representing different cultures tackled the first source exam successfully, but there were some signs of how historical concepts are understood in a slightly different way if the pupil’s personal history has no linkage to the concepts under scrutiny. The second test focused on the history of Native Americans. The test first required pupils to recognize whether short source extracts (5) were written by Indians or Caucasians. Based on what they had already learned from North American history, the pupils did not find it hard to distinguish between the sources. The analysis of multiphase causes and consequences of the disputes between Native Americans and white Americans caused dispersion among pupils. Using two historical sources and combining historical knowledge from both of them simultaneously was cumbersome for many. The explanations of consequences can be divided into two groups: the ones emphasizing short term consequences and those placing emphasis on long term consequences. The short term approach was mainly followed by boys in every group. The girls mainly paid attention to long term consequences. The result suggests that historical knowledge in sources is at least to some extent read through role and gender lenses. The third test required pupils to explain in their own words how the three sources given differed in their account of living conditions in Nazi Germany, which turned out to be demanding for many pupils. The pupils’ stronghold was rather the assessment of source reliability and accounts why the sources approached the same events differently. All participants wrote critical and justified comments on reliability and aspects that might have affected the content of the sources. The pupils felt that the main reasons that affected source reliability were the authors’ ethnic background, nationality and profession. The assessment showed that pupils were well aware that position in a historical situation has an impact on historical accounts, but in certain cases the victim’s account was seen as a historical truth. The account of events by a historian was chosen most often as the most reliable source, but it was often justified leniently with an indication to professionalism rather than with clear ideas of how historians conduct accounts based on sources. In brief, the last source test demonstrates that pupils have a strong idea that the ethnicity or nationalism determines how people explained events of the past. It is also an implication that pupils understand how historical knowledge is interpretative. The results also imply that history can be analyzed from a neutral perspective. One’s own membership in an ethnical or religious group does not automatically mean that a person’s cultural identity excludes historical explanations if something in them contradicts with his or her identity. The second method of extracting knowledge of pupils’ historical thinking was an essay analysis. The analysis shows that an analytical account of complicated political issues, which often include a great number of complicated political concepts, leads more likely to an inconsistent structure in the written work of pupils. The material also demonstrates that pupils have a strong tendency to take a critical stance when assessing history. Historical empathy in particular is shown if history somehow has a linkage to young people, children or minorities. Some topics can also awake strong feelings, especially among pupils with emigrant background, if there is a linkage between one’s own personal history and that of the school; and occasionally a student’s historical experience or thoughts replaced school history. Using sources during history lessons at school seems to have many advantages. It enhances the reasoning skills of pupils and their skills to assess the nature of historical knowledge. Thus one of the main aims and a great benefit of source work is to encourage pupils to express their own ideas and opinions. To conclude, when assessing the skills of adolescents in history - their work with sources, comments on history, historical knowledge and finally their historical thinking - one should be cautious and avoid cut off score evaluations. One purpose of pursuing history with sources is to encourage pupils to think independently, which is a useful tool for further identity construction. The idea that pupils have the right to conduct their own interpretations of history can be partially understood as part of a wider learning process, justification to study history comes from extrinsic reasons. The intrinsic reason is history itself; in order to understand history one should have a basic understanding of history as a specific domain of knowledge. Using sources does not mean that knowing history is of secondary importance. Only a balance between knowing the contextual history, understanding basic key concepts and working with sources is a solid base to improve pupils’ historical understanding.

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A variety of language disturbances including aphasia have been described after subcortical stroke but less is known about the factors that influence the long-term recovery of stroke-induced language dysfunction. We prospectively examined the role of the affected hemisphere and the lesion site in the occurrence and recovery of language deficits in nonthalamic subcortical stroke. Forty patients with unilateral basal gangliastroke underwent language assessment within 1 week, 3 months and 1 year after stroke. Disturbances in at least one language domain were observed in 35 patients during the first week post stroke including aphasia diagnosed in 11 patients. Importantly, the appearance of deficits after stroke onset and the improvement of language function were not determined by the site of subcortical lesion, but instead were critically influenced by the affected hemisphere. In fact, the language impairments following left and right basal ganglia stroke mirrored the language dysfunction observed after cortical lesions in the same hemisphere. A significant overall language improvement was observed at 3 months after stroke, although residual deficits in languageexecutive function were the most commonly observed impairment at 1 year follow-up. Although a substantial improvement of language function can be expected after nonthalamic subcortical stroke, our findings suggest that language recovery may not be fully achieved at 1 year post

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During the past decades testing has matured from ad-hoc activity into being an integral part of the development process. The benefits of testing are obvious for modern communication systems, which operate in heterogeneous environments amongst devices from various manufacturers. The increased demand for testing also creates demand for tools and technologies that support and automate testing activities. This thesis discusses applicability of visualization techniques in the result analysis part of the testing process. Particularly, the primary focus of this work is visualization of test execution logs produced by a TTCN-3 test system. TTCN-3 is an internationally standardized test specification and implementation language. The TTCN-3 standard suite includes specification of a test logging interface and a graphical presentation format, but no immediate relationship between them. This thesis presents a technique for mapping the log events to the graphical presentation format along with a concrete implementation, which is integrated with the Eclipse Platform and the OpenTTCN Tester toolchain. Results of this work indicate that for majority of the log events, a visual representation may be derived from the TTCN-3 standard suite. The remaining events were analysed and three categories relevant in either log analysis or implementation of the visualization tool were identified: events indicating insertion of something into the incoming queue of a port, events indicating a mismatch and events describing the control flow during the execution. Applicability of the results is limited into the domain of TTCN-3, but the developed mapping and the implementation may be utilized with any TTCN-3 tool that is able to produce the execution log in the standardized XML format.

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The human language-learning ability persists throughout life, indicating considerable flexibility at the cognitive and neural level. This ability spans from expanding the vocabulary in the mother tongue to acquisition of a new language with its lexicon and grammar. The present thesis consists of five studies that tap both of these aspects of adult language learning by using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) during language processing and language learning tasks. The thesis shows that learning novel phonological word forms, either in the native tongue or when exposed to a foreign phonology, activates the brain in similar ways. The results also show that novel native words readily become integrated in the mental lexicon. Several studies in the thesis highlight the left temporal cortex as an important brain region in learning and accessing phonological forms. Incidental learning of foreign phonological word forms was reflected in functionally distinct temporal lobe areas that, respectively, reflected short-term memory processes and more stable learning that persisted to the next day. In a study where explicitly trained items were tracked for ten months, it was found that enhanced naming-related temporal and frontal activation one week after learning was predictive of good long-term memory. The results suggest that memory maintenance is an active process that depends on mechanisms of reconsolidation, and that these process vary considerably between individuals. The thesis put special emphasis on studying language learning in the context of language production. The neural foundation of language production has been studied considerably less than that of perceptive language, especially on the sentence level. A well-known paradigm in language production studies is picture naming, also used as a clinical tool in neuropsychology. This thesis shows that accessing the meaning and phonological form of a depicted object are subserved by different neural implementations. Moreover, a comparison between action and object naming from identical images indicated that the grammatical class of the retrieved word (verb, noun) is less important than the visual content of the image. In the present thesis, the picture naming was further modified into a novel paradigm in order to probe sentence-level speech production in a newly learned miniature language. Neural activity related to grammatical processing did not differ between the novel language and the mother tongue, but stronger neural activation for the novel language was observed during the planning of the upcoming output, likely related to more demanding lexical retrieval and short-term memory. In sum, the thesis aimed at examining language learning by combining different linguistic domains, such as phonology, semantics, and grammar, in a dynamic description of language processing in the human brain.

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Many cognitive deficits after TBI (traumatic brain injury) are well known, such as memory and concentration problems, as well as reduced information-processing speed. What happens to patients and cognitive functioning after immediate recovery is poorly known. Cognitive functioning is flexible and may be influenced by genetic, psychological and environmental factors decades after TBI. The general aim of this thesis was to describe the long-term cognitive course after TBI, to find variables that may contribute to it, and how the cognitive functions after TBI are associated with specific medical factors and reduced survival. The original study group consisted of 192 patients with TBI who were originally assessed with the Mild Deterioration Battery (MDB) on average two years after the injury, during the years 1966 – 1972. During a 30-year follow-up, we studied the risks for reduced survival, and the mortality of the patients was compared with the general population using the Standardized Mortality Ratio (SMR). Sixty-one patients were re-assessed during 1998-2000. These patients were evaluated with the MDB, computerized testing, and with various other neuropsychological methods for attention and executive functions. Apolipoprotein-E (ApoE) genotyping and magnetic resonance imaging (MRI) based on volumetric analysis of the hippocampus and lateral ventricles were performed. Depressive symptoms were evaluated with the short form of the Beck depression inventory. The cognitive performance at follow-up was compared with a control group that was similar to the study group in regard to age and education. The cognitive outcome of the patients with TBI varied after three decades. The majority of the patients showed a decline in their cognitive level, the rest either improved or stayed at the same level. Male gender and higher age at injury were significant risk factors for the decline. Whereas most cognitive domains declined during the follow-up, semantic memory behaved in the opposite way, showing recovery after TBI. In the follow-up assessment, the memory decline and impairments in the set-shifting domain of executive functions were associated with MRI-volumetric measures, whereas reduction in information-processing speed was not associated with the MRI measures. The presence of local contusions was only weakly associated with cognitive functions. Only few cognitive methods for attention were capable of discriminating TBI patients with and without depressive symptoms. On the other hand, most complex attentional tests were sensitive enough to discriminate TBI patients (non-depressive) from controls. This means that complex attention functions, mediated by the frontal lobes, are relatively independent of depressive symptoms post-TBI. The presence of ApoE4 was associated with different kinds of memory processes including verbal and visual episodic memory, semantic memory and verbal working memory, depending on the length of time since TBI. Many other cognitive processes were not affected by the presence of ApoE4. Age at injury and poor vocational outcome were independent risk factors for reduced survival in the multivariate analysis. Late mortality was higher among younger subjects (age < 40 years at death) compared with the general population which should be borne in mind when assessing the need for rehabilitation services and long-term follow-up after TBI.

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This dissertation examined skill development in music reading by focusing on the visual processing of music notation in different music-reading tasks. Each of the three experiments of this dissertation addressed one of the three types of music reading: (i) sight-reading, i.e. reading and performing completely unknown music, (ii) rehearsed reading, during which the performer is already familiar with the music being played, and (iii) silent reading with no performance requirements. The use of the eye-tracking methodology allowed the recording of the readers’ eye movements from the time of music reading with extreme precision. Due to the lack of coherence in the smallish amount of prior studies on eye movements in music reading, the dissertation also had a heavy methodological emphasis. The present dissertation thus aimed to promote two major issues: (1) it investigated the eye-movement indicators of skill and skill development in sight-reading, rehearsed reading and silent reading, and (2) developed and tested suitable methods that can be used by future studies on the topic. Experiment I focused on the eye-movement behaviour of adults during their first steps of learning to read music notation. The longitudinal experiment spanned a nine-month long music-training period, during which 49 participants (university students taking part in a compulsory music course) sight-read and performed a series of simple melodies in three measurement sessions. Participants with no musical background were entitled as “novices”, whereas “amateurs” had had musical training prior to the experiment. The main issue of interest was the changes in the novices’ eye movements and performances across the measurements while the amateurs offered a point of reference for the assessment of the novices’ development. The experiment showed that the novices tended to sight-read in a more stepwise fashion than the amateurs, the latter group manifesting more back-and-forth eye movements. The novices’ skill development was reflected by the faster identification of note symbols involved in larger melodic intervals. Across the measurements, the novices also began to show sensitivity to the melodies’ metrical structure, which the amateurs demonstrated from the very beginning. The stimulus melodies consisted of quarter notes, making the effects of meter and larger melodic intervals distinguishable from effects caused by, say, different rhythmic patterns. Experiment II explored the eye movements of 40 experienced musicians (music education students and music performance students) during temporally controlled rehearsed reading. This cross-sectional experiment focused on the eye-movement effects of one-bar-long melodic alterations placed within a familiar melody. The synchronizing of the performance and eye-movement recordings enabled the investigation of the eye-hand span, i.e., the temporal gap between a performed note and the point of gaze. The eye-hand span was typically found to remain around one second. Music performance students demonstrated increased professing efficiency by their shorter average fixation durations as well as in the two examined eye-hand span measures: these participants used larger eye-hand spans more frequently and inspected more of the musical score during the performance of one metrical beat than students of music education. Although all participants produced performances almost indistinguishable in terms of their auditory characteristics, the altered bars indeed affected the reading of the score: the general effects of expertise in terms of the two eye- hand span measures, demonstrated by the music performance students, disappeared in the face of the melodic alterations. Experiment III was a longitudinal experiment designed to examine the differences between adult novice and amateur musicians’ silent reading of music notation, as well as the changes the 49 participants manifested during a nine-month long music course. From a methodological perspective, an opening to research on eye movements in music reading was the inclusion of a verbal protocol in the research design: after viewing the musical image, the readers were asked to describe what they had seen. A two-way categorization for verbal descriptions was developed in order to assess the quality of extracted musical information. More extensive musical background was related to shorter average fixation duration, more linear scanning of the musical image, and more sophisticated verbal descriptions of the music in question. No apparent effects of skill development were observed for the novice music readers alone, but all participants improved their verbal descriptions towards the last measurement. Apart from the background-related differences between groups of participants, combining verbal and eye-movement data in a cluster analysis identified three styles of silent reading. The finding demonstrated individual differences in how the freely defined silent-reading task was approached. This dissertation is among the first presentations of a series of experiments systematically addressing the visual processing of music notation in various types of music-reading tasks and focusing especially on the eye-movement indicators of developing music-reading skill. Overall, the experiments demonstrate that the music-reading processes are affected not only by “top-down” factors, such as musical background, but also by the “bottom-up” effects of specific features of music notation, such as pitch heights, metrical division, rhythmic patterns and unexpected melodic events. From a methodological perspective, the experiments emphasize the importance of systematic stimulus design, temporal control during performance tasks, and the development of complementary methods, for easing the interpretation of the eye-movement data. To conclude, this dissertation suggests that advances in comprehending the cognitive aspects of music reading, the nature of expertise in this musical task, and the development of educational tools can be attained through the systematic application of the eye-tracking methodology also in this specific domain.

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Several glutamate receptor (GluR) subunits have been characterized during the past few years. In the present study, subunit-specific antisera were used to determine the distribution of the AMPA-type glutamate receptor subunits GluR1-4 in retinorecipient areas of the chick brain. Six white leghorn chicks (Gallus gallus, 7-15 days old, unknown sex) were deeply anesthetized and perfused with 4% buffered paraformaldehyde and brain sections were stained using immunoperoxidase techniques. The AMPA-type glutamate receptor subunits GluR1, GluR2/3 and GluR4 were present in several retinorecipient areas, with varying degrees of colocalization. For example, perikarya in layers 2, 3, and 5 of the optic tectum contained GluR1, whereas GluR2/3 subunits appeared mainly in neurons of layer 13. The GluR4 subunit was only detected in a few cells of the tectal layer 13. GluR1 and GluR2/3 were observed in neurons of the nucleus geniculatus lateralis ventralis, whereas GluR4 was only present in its neuropil. Somata in the accessory optic nucleus appeared to contain GluR2/3 and GluR4, whereas GluR1 was the dominant subunit in the neuropil of this nucleus. These results suggest that different subpopulations of visual neurons might express different combinations of AMPA-type GluR subunits, which in turn might generate different synaptic responses to glutamate derived from retinal ganglion cell axons

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The main objective of the present study was to assess the specificity and sensitivity of a modified assay using short synthetic peptides of the V3 region of HIV-1 gp120, which is the main target for neutralizing antibodies. Results from an enzyme immunoassay (EIA) employing a panel of synthetic peptides of HIV-1 subtypes and using urea washes to detect high avidity antibodies (AAV3) were compared with those obtained by the heteroduplex mobility assay and DNA sequencing. The EIA correctly typed 100% of subtype B (sensitivity = 1.0; specificity = 0.95), 100% of HIV-1 E samples (sensitivity = 1.0; specificity = 1.0), and 95% of subtype C specimens (sensitivity = 0.95; specificity = 0.94). In contrast, only 50% of subtype A (sensitivity = 0.5; specificity = 0.95), 60% of subtype D (sensitivity = 0.6; specificity = 1.0), and 28% of subtype F samples (sensitivity = 0.28; specificity = 0.95) were correctly identified. This approach was also able to discriminate in a few samples antibodies from patients infected with B variants circulating in Brazil and Thailand that reacted specifically. The assays described in this study are relatively rapid and simple to perform compared to molecular approaches and can be used to screen large numbers of serum or plasma samples. Moreover, the classification in subtypes (genotypes) may overestimate HIV-1 diversity and a classification into serotypes, based on antigenic V3 diversity or another principal neutralization domain, may be more helpful for vaccine development and identification of variants.

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The syndecans, heparan sulfate proteoglycans, are abundant molecules associated with the cell surface and extracellular matrix and consist of a protein core to which heparan sulfate chains are covalently attached. Each of the syndecan core proteins has a short cytoplasmic domain that binds cytosolic regulatory factors. The syndecans also contain highly conserved transmembrane domains and extracellular domains for which important activities are becoming known. These protein domains locate the syndecan on cell surface sites during development and tumor formation where they interact with other receptors to regulate signaling and cytoskeletal organization. The functions of cell surface heparan sulfate proteoglycan have been centered on the role of heparan sulfate chains, located on the outer side of the cell surface, in the binding of a wide array of ligands, including extracellular matrix proteins and soluble growth factors. More recently, the core proteins of the syndecan family transmembrane proteoglycans have also been shown to be involved in cell signaling through interaction with integrins and tyrosine kinase receptors.

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The importance of package design as a marketing tool is growing as the competition in retail environment increases. However, there is a lack of studies on how each element of package design affects consumer decisions in different countries. The objective of this thesis is to study the role of package design to Japanese consumers. The research was conducted through an experiment with a sample of 37 Japanese female participants. They were divided into two groups and were given different tasks: one group had to choose a chocolate for themselves, and the other for a group of friends. The participants were presented with 15 different Finnish chocolate boxes to choose from. The qualitative data was gathered through observation and semi-structured interviews. In addition, data from questionnaires was quantified and all the data was triangulated. The empirical results suggest that visual elements strongly affect the decision making of Japanese consumers. Image was the most important element which acted as both, a visual and an informational aspect in the experiment. Informational elements on the other hand have little effect, especially when the context is written in a foreign language. However, informational elements affected participants who were choosing chocolates for a group of friends. A unique finding was the importance of kawaii (cuteness) to Japanese consumers.

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Previous assessment of verticality by means of rod and rod and frame tests indicated that human subjects can be more (field dependent) or less (field independent) influenced by a frame placed around a tilted rod. In the present study we propose a new approach to these tests. The judgment of visual verticality (rod test) was evaluated in 50 young subjects (28 males, ranging in age from 20 to 27 years) by randomly projecting a luminous rod tilted between -18 and +18° (negative values indicating left tilts) onto a tangent screen. In the rod and frame test the rod was displayed within a luminous fixed frame tilted at +18 or -18°. Subjects were instructed to verbally indicate the rod’s inclination direction (forced choice). Visual dependency was estimated by means of a Visual Index calculated from rod and rod and frame test values. Based on this index, volunteers were classified as field dependent, intermediate and field independent. A fourth category was created within the field-independent subjects for whom the amount of correct guesses in the rod and frame test exceeded that of the rod test, thus indicating improved performance when a surrounding frame was present. In conclusion, the combined use of subjective visual vertical and the rod and frame test provides a specific and reliable form of evaluation of verticality in healthy subjects and might be of use to probe changes in brain function after central or peripheral lesions.

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The purpose of the present study was to measure contrast sensitivity to equiluminant gratings using steady-state visual evoked cortical potential (ssVECP) and psychophysics. Six healthy volunteers were evaluated with ssVECPs and psychophysics. The visual stimuli were red-green or blue-yellow horizontal sinusoidal gratings, 5° × 5°, 34.3 cd/m2 mean luminance, presented at 6 Hz. Eight spatial frequencies from 0.2 to 8 cpd were used, each presented at 8 contrast levels. Contrast threshold was obtained by extrapolating second harmonic amplitude values to zero. Psychophysical contrast thresholds were measured using stimuli at 6 Hz and static presentation. Contrast sensitivity was calculated as the inverse function of the pooled cone contrast threshold. ssVECP and both psychophysical contrast sensitivity functions (CSFs) were low-pass functions for red-green gratings. For electrophysiology, the highest contrast sensitivity values were found at 0.4 cpd (1.95 ± 0.15). ssVECP CSF was similar to dynamic psychophysical CSF, while static CSF had higher values ranging from 0.4 to 6 cpd (P < 0.05, ANOVA). Blue-yellow chromatic functions showed no specific tuning shape; however, at high spatial frequencies the evoked potentials showed higher contrast sensitivity than the psychophysical methods (P < 0.05, ANOVA). Evoked potentials can be used reliably to evaluate chromatic red-green CSFs in agreement with psychophysical thresholds, mainly if the same temporal properties are applied to the stimulus. For blue-yellow CSF, correlation between electrophysiology and psychophysics was poor at high spatial frequency, possibly due to a greater effect of chromatic aberration on this kind of stimulus.