Towards a resolution of conflicting models of illusory contour processing in humans.

Despite myriad studies, neurophysiologic mechanisms mediating illusory contour (IC) sensitivity remain controversial. Among the competing models one favors feed-forward effects within lower-tier cortices (V1/V2). Another situates IC sensitivity first within higher-tier cortices, principally lateral-occipital cortices (LOC), with later feedback effects in V1/V2. Still others postulate that LOC are sensitive to salient regions demarcated by the inducing stimuli, whereas V1/V2 effects specifically support IC sensitivity. We resolved these discordances by using misaligned line gratings, oriented either horizontally or vertically, to induce ICs. Line orientation provides an established assay of V1/V2 modulations independently of IC presence, and gratings lack salient regions. Electrical neuroimaging analyses of visual evoked potentials (VEPs) disambiguated the relative timing and localization of IC sensitivity with respect to that for grating orientation. Millisecond-by-millisecond analyses of VEPs and distributed source estimations revealed a main effect of grating orientation beginning at 65 ms post-stimulus onset within the calcarine sulcus that was followed by a main effect of IC presence beginning at 85 ms post-stimulus onset within the LOC. There was no evidence for differential processing of ICs as a function of the orientation of the grating. These results support models wherein IC sensitivity occurs first within the LOC.

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease.

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

In the eye of the listener: pupil dilation elucidates discourse processing.

The current study investigated cognitive resource allocation in discourse processing by means of pupil dilation and behavioral measures. Short question-answer dialogs were presented to listeners. Either the context question queried a new information focus in the successive answer, or else the context query was corrected in the answer sentence (correction information). The information foci contained in the answer sentences were either adequately highlighted by prosodic means or not. Participants had to judge the adequacy of the focus prosody with respect to the preceding context question. Prosodic judgment accuracy was higher in the conditions bearing adequate focus prosody than in the conditions with inadequate focus prosody. Latency to peak pupil dilation was longer when new information foci were perceived compared to correction foci. Moreover, for the peak dilation, an interaction of focus type and prosody was found. Post hoc statistical tests revealed that prosodically adequate correction focus positions were processed with smaller peak dilation in comparison to all other dialog conditions. Thus, pupil dilation and results of a principal component analysis suggest an interaction of focus type and focus prosody in discourse processing.

In vivo brain macromolecule signals in healthy and glioblastoma mouse models: (1) H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T.

In (1) H magnetic resonance spectroscopy, macromolecule signals underlay metabolite signals, and knowing their contribution is necessary for reliable metabolite quantification. When macromolecule signals are measured using an inversion-recovery pulse sequence, special care needs to be taken to correctly remove residual metabolite signals to obtain a pure macromolecule spectrum. Furthermore, since a single spectrum is commonly used for quantification in multiple experiments, the impact of potential macromolecule signal variability, because of regional differences or pathologies, on metabolite quantification has to be assessed. In this study, we introduced a novel method to post-process measured macromolecule signals that offers a flexible and robust way of removing residual metabolite signals. This method was applied to investigate regional differences in the mouse brain macromolecule signals that may affect metabolite quantification when not taken into account. However, since no significant differences in metabolite quantification were detected, it was concluded that a single macromolecule spectrum can be generally used for the quantification of healthy mouse brain spectra. Alternatively, the study of a mouse model of human glioma showed several alterations of the macromolecule spectrum, including, but not limited to, increased mobile lipid signals, which had to be taken into account to avoid significant metabolite quantification errors.

Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major.

Metacaspases are cysteine peptidases that could play a role similar to caspases in the cell death programme of plants, fungi and protozoa. The human protozoan parasite Leishmania major expresses a single metacaspase (LmjMCA) harbouring a central domain with the catalytic dyad histidine and cysteine as found in caspases. In this study, we investigated the processing sites important for the maturation of LmjMCA catalytic domain, the cellular localization of LmjMCA polypeptides, and the functional role of the catalytic domain in the cell death pathway of Leishmania parasites. Although LmjMCA polypeptide precursor form harbours a functional mitochondrial localization signal (MLS), we determined that LmjMCA polypeptides are mainly localized in the cytoplasm. In stress conditions, LmjMCA precursor forms were extensively processed into soluble forms containing the catalytic domain. This domain was sufficient to enhance sensitivity of parasites to hydrogen peroxide by impairing the mitochondrion. These data provide experimental evidences of the importance of LmjMCA processing into an active catalytic domain and of its role in disrupting mitochondria, which could be relevant in the design of new drugs to fight leishmaniasis and likely other protozoan parasitic diseases.

Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease.

A crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein (GP) that is essential for virus-host cell attachment and entry. The maturation of the arenavirus GP precursor (GPC) critically depends on proteolytic processing by the cellular proprotein convertase (PC) subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Here we undertook a molecular characterization of the SKI-1/S1P processing of the GPCs of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and the pathogenic Lassa virus (LASV). Previous studies showed that the GPC of LASV undergoes processing in the endoplasmic reticulum (ER)/cis-Golgi compartment, whereas the LCMV GPC is cleaved in a late Golgi compartment. Herein we confirm these findings and provide evidence that the SKI-1/S1P recognition site RRLL, present in the SKI-1/S1P prodomain and LASV GPC, but not in the LCMV GPC, is crucial for the processing of the LASV GPC in the ER/cis-Golgi compartment. Our structure-function analysis revealed that the cleavage of arenavirus GPCs, but not cellular substrates, critically depends on the autoprocessing of SKI-1/S1P, suggesting differences in the processing of cellular and viral substrates. Deletion mutagenesis showed that the transmembrane and intracellular domains of SKI-1/S1P are dispensable for arenavirus GPC processing. The expression of a soluble form of the protease in SKI-I/S1P-deficient cells resulted in the efficient processing of arenavirus GPCs and rescued productive virus infection. However, exogenous soluble SKI-1/S1P was unable to process LCMV and LASV GPCs displayed at the surface of SKI-I/S1P-deficient cells, indicating that GPC processing occurs in an intracellular compartment. In sum, our study reveals important differences in the SKI-1/S1P processing of viral and cellular substrates.

Normative Topographic ERP Analyses of Speed of Speech Processing and Grammar Before and After Grammatical Treatment.

Typically developing (TD) preschoolers and age-matched preschoolers with specific language impairment (SLI) received event-related potentials (ERPs) to four monosyllabic speech sounds prior to treatment and, in the SLI group, after 6 months of grammatical treatment. Before treatment, the TD group processed speech sounds faster than the SLI group. The SLI group increased the speed of their speech processing after treatment. Posttreatment speed of speech processing predicted later impairment in comprehending phrase elaboration in the SLI group. During the treatment phase, change in speed of speech processing predicted growth rate of grammar in the SLI group.

Occupational exposure to diisononyl phthalate (DiNP) in polyvinyl chloride processing operations

PURPOSE: Diisononyl phthalate (DiNP) is primarily used as a plasticizer in polyvinyl chloride (PVC) materials. While information is available on general population exposure to DiNP, occupational exposure data are lacking. We present DiNP metabolite urinary concentrations in PVC processing workers, estimate DiNP daily intake for these workers, and compare worker estimates to other populations. METHODS: We assessed DiNP exposure in participants from two companies that manufactured PVC materials, a PVC film manufacturer (n = 25) and a PVC custom compounder (n = 12). A mid-shift and end-shift urine sample was collected from each participant and analyzed for the DiNP metabolite mono(carboxy-isooctyl) phthalate (MCiOP). Mixed models were used to assess the effect on MCiOP concentrations of a worker being assigned to (1) a task using DiNP and (2) a shift where DiNP was used. A simple pharmacokinetic model was used to estimate DiNP daily intake from the MCiOP concentrations. RESULTS: Creatinine-adjusted MCiOP urinary concentrations ranged from 0.42-80 μg/g in PVC film and from 1.11-13.4 μg/g in PVC compounding. PVC film participants who worked on a task using DiNP (n = 7) had the highest MCiOP geometric mean (GM) end-shift concentration (25.2 μg/g), followed by participants who worked on a shift where DiNP was used (n = 11) (17.7 μg/g) as compared to participants with no task (2.92 μg/g) or shift (2.08 μg/g) exposure to DiNP. The GM end-shift MCiOP concentration in PVC compounding participants (4.80 μg/g) was comparable to PVC film participants with no task or shift exposure to DiNP. Because no PVC compounding participants were assigned to tasks using DINP on the day sampled, DiNP exposure in this company may be underestimated. The highest DiNP intake estimate was 26 μg/kg/day. CONCLUSION: Occupational exposure to DiNP associated with PVC film manufacturing tasks were substantially higher (sixfold to tenfold) than adult general population exposures; however, all daily intake estimates were less than 25% of current United States or European acceptable or tolerable daily intake estimates. Further characterization of DiNP occupational exposures in other industries is recommended.

Altered processing of contextual information during fear extinction in PTSD: an fMRI study.

Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

Targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel antiviral strategy against arenaviruses.

A crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (GP) responsible for virus attachment and entry. Processing of the GP precursor (GPC) by the cellular proprotein convertase site 1 protease (S1P), also known as subtilisin-kexin-isozyme 1 (SKI-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. Here, we sought to evaluate arenavirus GPC processing by S1P as a target for antiviral therapy using a recently developed peptide-based S1P inhibitor, decanoyl (dec)-RRLL-chloromethylketone (CMK), and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). To control for off-target effects of dec-RRLL-CMK, we employed arenavirus reverse genetics to introduce a furin recognition site into the GPC of LCMV. The rescued mutant virus grew to normal titers, and the processing of its GPC critically depended on cellular furin, but not S1P. Treatment with the S1P inhibitor dec-RRLL-CMK resulted in specific blocking of viral spread and virus production of LCMV. Combination of the protease inhibitor with ribavirin, currently used clinically for treatment of human arenavirus infections, resulted in additive drug effects. In cells deficient in S1P, the furin-dependent LCMV variant established persistent infection, whereas wild-type LCMV underwent extinction without the emergence of S1P-independent escape variants. Together, the potent antiviral activity of an inhibitor of S1P-dependent GPC cleavage, the additive antiviral effect with ribavirin, and the low probability of emergence of S1P-independent viral escape variants make S1P-mediated GPC processing by peptide-derived inhibitors a promising strategy for the development of novel antiarenaviral drugs.

Multiple sclerosis decreases explicit counterfactual processing and risk taking in decision making.

INTRODUCTION: Deficits in decision making (DM) are commonly associated with prefrontal cortical damage, but may occur with multiple sclerosis (MS). There are no data concerning the impact of MS on tasks evaluating DM under explicit risk, where different emotional and cognitive components can be distinguished. METHODS: We assessed 72 relapsing-remitting MS (RRMS) patients with mild to moderate disease and 38 healthy controls in two DM tasks involving risk with explicit rules: (1) The Wheel of Fortune (WOF), which probes the anticipated affects of decisions outcomes on future choices; and (2) The Cambridge Gamble Task (CGT) which measures risk taking. Participants also underwent a neuropsychological and emotional assessment, and skin conductance responses (SCRs) were recorded. RESULTS: In the WOF, RRMS patients showed deficits in integrating positive counterfactual information (p<0.005) and greater risk aversion (p<0.001). They reported less negative affect than controls (disappointment: p = 0.007; regret: p = 0.01), although their implicit emotional reactions as measured by post-choice SCRs did not differ. In the CGT, RRMS patients differed from controls in quality of DM (p = 0.01) and deliberation time (p = 0.0002), the latter difference being correlated with attention scores. Such changes did not result in overall decreases in performance (total gains). CONCLUSIONS: The quality of DM under risk was modified by MS in both tasks. The reduction in the expression of disappointment coexisted with an increased risk aversion in the WOF and alexithymia features. These concomitant emotional alterations may have implications for better understanding the components of explicit DM and for the clinical support of MS patients.

Working memory load improves early stages of independent visual processing.

Increasing evidence suggests that working memory and perceptual processes are dynamically interrelated due to modulating activity in overlapping brain networks. However, the direct influence of working memory on the spatio-temporal brain dynamics of behaviorally relevant intervening information remains unclear. To investigate this issue, subjects performed a visual proximity grid perception task under three different visual-spatial working memory (VSWM) load conditions. VSWM load was manipulated by asking subjects to memorize the spatial locations of 6 or 3 disks. The grid was always presented between the encoding and recognition of the disk pattern. As a baseline condition, grid stimuli were presented without a VSWM context. VSWM load altered both perceptual performance and neural networks active during intervening grid encoding. Participants performed faster and more accurately on a challenging perceptual task under high VSWM load as compared to the low load and the baseline condition. Visual evoked potential (VEP) analyses identified changes in the configuration of the underlying sources in one particular period occurring 160-190 ms post-stimulus onset. Source analyses further showed an occipito-parietal down-regulation concurrent to the increased involvement of temporal and frontal resources in the high VSWM context. Together, these data suggest that cognitive control mechanisms supporting working memory may selectively enhance concurrent visual processing related to an independent goal. More broadly, our findings are in line with theoretical models implicating the engagement of frontal regions in synchronizing and optimizing mnemonic and perceptual resources towards multiple goals.

Respiratory health effects of fifteen years of improved collective protection in a wheat-processing worker population.

INTRODUCTION: Occupational exposure to grain dust causes respiratory symptoms and pathologies. To decrease these effects, major changes have occurred in the grain processing industry in the last twenty years. However, there are no data on the effects of these changes on workers' respiratory health. OBJECTIVES: The aim of this study was to evaluate the respiratory health of grain workers and farmers involved in different steps of the processing industry of wheat, the most frequently used cereal in Europe, fifteen years after major improvements in collective protective equipment due to mechanisation. MATERIALS AND METHOD: Information on estimated personal exposure to wheat dust was collected from 87 workers exposed to wheat dust and from 62 controls. Lung function (FEV1, FVC, and PEF), exhaled nitrogen monoxide (FENO) and respiratory symptoms were assessed after the period of highest exposure to wheat during the year. Linear regression models were used to explore the associations between exposure indices and respiratory effects. RESULTS: Acute symptoms - cough, sneezing, runny nose, scratchy throat - were significantly more frequent in exposed workers than in controls. Increased mean exposure level, increased cumulative exposure and chronic exposure to more than 6 mg.m (-3) of inhaled wheat dust were significantly associated with decreased spirometric parameters, including FEV1 and PEF (40 ml and 123 ml.s (-1) ), FEV1 and FVC (0.4 ml and 0.5 ml per 100 h.mg.m (-3) ), FEV1 and FVC (20 ml and 20 ml per 100 h at >6 mg.m (-3) ). However, no increase in FENO was associated with increased exposure indices. CONCLUSIONS: The lung functions of wheat-related workers are still affected by their cumulative exposure to wheat dust, despite improvements in the use of collective protective equipment.

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

BACKGROUND: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. RESULTS: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. CONCLUSIONS: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.

Predictors of academic achievement and social competence in adolescence : facilitation, inhibition and general cognitive processing /

The relevance of attentional measures to cognitive and social adaptive behaviour was examined in an adolescent sample. Unlike previous research, the influence of both inhibitory and facilitory aspects of attention were studied. In addition, contributions made by these attentional processes were compared with traditional psychometric measures of cognitive functioning. Data were gathered from 36 grade 10 and 1 1 high school students (20 male and 16 female students) with a variety of learning and attentional difficulties. Data collection was conducted in the course of two testing sessions. In the first session, students completed questionnaires regarding their medical history, and everyday behaviours (the Brock Adaptive Functioning Questionnaire), along with non-verbal problem solving tasks and motor speed tasks. In the second session, students performed working memory measures and computer-administered tasks assessing inhibitory and facilitory aspects of attention. Grades and teacher-rated measures of cognitive and social impulsivity were also gathered. Results indicate that attentional control has both cognitive and social/emotional implications. Performance on negative priming and facilitation trials from the Flanker task predicted grades in core courses, social functioning measures, and cognitive and social impulsivity ratings. However, beneficial effects for academic and social functioning associated with inhibition were less prevalent in those demonstrating a greater ability to respond to facilitory cues. There was also some evidence that high levels of facilitation were less beneficial to academic performance, and female students were more likely to exceed optimal levels of facilitory processing. Furthermore, lower negative priming was ''S'K 'i\':y-: -'*' - r " j«v ; ''*.' iij^y Inhibition, Facilitation and Social Competence 3 associated with classroom-rated distraction and hyperactivity, but the relationship between inhibition and social aspects of impulsivity was stronger for adolescents with learning or reading problems, and the relationship between inhibition and cognitive impulsivity was stronger for male students. In most cases, attentional measures were predictive of performance outcomes independent of traditional psychometric measures of cognitive functioning. >,, These findings provide support for neuropsychological models linking inhibition to control of interference and arousal, and emphasize the fundamental role of attention in everyday adolescent activities. The findings also warrant further investigation into the ways which inhibitory and facilitory attentional processes interact, and the contextdependent nature of attentional control.associated with classroom-rated distraction and hyperactivity, but the relationship between inhibition and social aspects of impulsivity was stronger for adolescents with learning or reading problems, and the relationship between inhibition and cognitive impulsivity was stronger for male students. In most cases, attentional measures were predictive of performance outcomes independent of traditional psychometric measures of cognitive functioning. >,, These findings provide support for neuropsychological models linking inhibition to control of interference and arousal, and emphasize the fundamental role of attention in everyday adolescent activities. The findings also warrant further investigation into the ways which inhibitory and facilitory attentional processes interact, and the contextdependent nature of attentional control.