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A principal components analysis was performed on a set (10) of acoustic, aerodynamic, perceptual and laryngoscopic data obtained from 87 dysphonic patients. Two principal components were clearly identified: the first represents in some way the glottal air leakage, resulting in turbulent noise, particularly obvious in higher spectral frequencies, and giving the perceptual impression of breathiness; the second accounts rather for the degree of aperiodicity in vocal fold oscillation, reflected in jitter measurements and with a perceptual correlate of harshness or roughness. Morphological changes of vocal folds correlate more closely with this second principal component. Among acoustic parameters, harmonics-to-noise ratio in the formant zone and magnitude of the dominant cepstrum peak seem to integrate to some extent the effects of both principal components.

The present study aimed at testing, by means of a response-effect compatibility paradigm, whether finger-numeral representations derived from finger counting may underlie simple arithmetic problem solving in adults. Participants were asked to provide a verbal response to simple additions, which triggered the presentation of the correct (Experiment 1) or an incorrect (Experiment 2) response, displayed either as a configuration of fingers or as a series of rods. Answers were faster with finger configurations than with rods, and only when the finger configuration showed the correct result. These findings support the idea that, even in adults, simple arithmetic operations are still unconsciously underlain by finger-numeral representations.

Prosopagnosia is an impairment at individualizing faces that classically follows brain damage. Several studies have reported observations supporting an impairment of holistic/configural face processing in acquired prosopagnosia. However, this issue may require more compelling evidence as the cases reported were generally patients suffering from integrative visual agnosia, and the sensitivity of the paradigms used to measure holistic/configural face processing in normal individuals remains unclear. Here we tested a well-characterized case of acquired prosopagnosia (PS) with no object recognition impairment, in five behavioral experiments (whole/part and composite face paradigms with unfamiliar faces). In all experiments, for normal observers we found that processing of a given facial feature was affected by the location and identity of the other features in a whole face configuration. In contrast, the patient's results over these experiments indicate that she encodes local facial information independently of the other features embedded in the whole facial context. These observations and a survey of the literature indicate that abnormal holistic processing of the individual face may be a characteristic hallmark of prosopagnosia following brain damage, perhaps with various degrees of severity.

Models of face processing suggest that facial familiarity and expression processes involve independent visual systems. But under some conditions, the two processes interact, as when selective attention is solicited, and/or when a link is established between consecutive stimuli. To assess these assumptions during perceptual face processing, event-related potentials (ERPs) were used while subjects discriminated either familiarity or expression in a task-switching paradigm. Switched trials were designed with competitor priming, the unattended dimension being previously attended. The results indicate interactions appearing in the right hemisphere during the perceptual encoding stage (N170) when subjects processed either familiarity or expression during switched trials. These interactions gain both hemispheres during memory retrieval (P2) and in terms of accuracy. Altogether, these results confirm the critical role of the right hemisphere in perceiving faces and their expressions. Moreover, they suggest that familiarity and expression can interact in both directions. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Glucose-induced insulin secretion is classically attributed to the cooperation of a KATP channel-dependent Ca(2+) influx with subsequent rise of the cytosolic free Ca(2+) concentration ([Ca(2+)]c) (triggering pathway) and a KATP channel-independent augmentation of secretion without further increase of [Ca(2+)]c (amplifying pathway). Here we characterized the effects of glucose in beta-cells lacking KATP channels because of a knockout of the pore-forming subunit Kir6.2. Islets from 1-year and 2-week-old Kir6.2KO mice were used freshly after isolation and after 18h culture to measure glucose effects on [Ca(2+)]c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca(2+)]c and insulin secretion were marginally elevated, and high glucose increased [Ca(2+)]c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30mM KCl). Culture in 10mM glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of a rise in [Ca(2+)]c with modulation of [Ca(2+)]c oscillations. Similar results were obtained in 2-week-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca(2+)]c and insulin secretion, by inducing KATP channel-independent depolarization and Ca(2+) influx via voltage-dependent Ca(2+) channels. In conclusion, Kir6.2KO beta-cells down-regulate insulin secretion by maintaining low [Ca(2+)]c but culture reveals a glucose-responsive phenotype mainly by increasing [Ca(2+)]c. The results support models implicating a KATP channel-independent amplifying pathway in glucose-induced insulin secretion, and show that KATP channels are not the only possible transducers of metabolic effects on the triggering Ca(2+) signal.

The CB(1) cannabinoid receptor shows complex interactions with intracellular signalling partners, and responses to cannabinoid ligands are likely to be influenced by concomitant inputs modifying the overall tone of signalling cascades. This appears even more relevant as we previously evidenced opposite regulations of tyrosine hydroxylase (TH) expression by the two common cannabinoid agonists HU 210 and CP 55,940. Therefore, we studied the consequences of manipulating adenylyl cyclase activity with forskolin on the regulation of TH gene transcription in neuroblastoma cells (N1E-115). Reporter gene experiments performed with the luciferase sequence cloned under the control of modified fragments of the TH gene promoter revealed that the AP-1 consensus sequence is essential for cannabinoid-mediated regulation of TH expression. Consistently, inhibition of PKC totally blocked the responses mediated by both HU 210 and CP 55,940. In addition, forskolin which boosts adenylyl cyclase activity remarkably modified the responses to the cannabinoid agonists. Thus, in these conditions, both agonists efficiently reduced TH gene promoter activity, a response requiring functional PKA/CRE-dependent signallings. Finally, the modulations of the promoter were inhibited in pertussis toxin treated cells, suggesting that responses to both agonists are mediated through G(i/o)-dependent mechanisms. Emphasising on the importance of functional selectivity at GPCRs, these data demonstrate that the concomitant activation of adenylyl cyclase by forskolin strongly influences the biochemical responses triggered by distinct cannabinoid agonists. Together our results suggest that the physiological modulation of TH expression by cannabinoid agonists in dopaminergic neurons would be influenced by additional endogenous inputs.

BACKGROUND/AIMS: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonist drugs, like pioglitazone (PGZ), are proposed as treatments for steatohepatitis. Their mechanisms of action remain ill-clarified. METHODS: To test the hypothesis that PGZ improves steatohepatitis through adiponectin-dependent stimulation of AMPK and/or PPARalpha, mice lacking adiponectin (Adipo(-/-)) or the AMPKalpha1 catalytic subunit (AMPKalpha1(-/-)) or wild-type (Wt) mice were fed the methionine and choline deficient (MCD) diet, supplemented or not with PGZ. RESULTS: In Wt mice, PGZ increased circulating levels of adiponectin and reduced the severity of MCD-induced steatohepatitis but there was no evidence of activation of AMPK or PPARalpha and their downstream targets. By contrast, PGZ completely repressed nuclear translocation of SREBP-1c, a key transcription factor for de novo lipogenesis. This effect was lacking in Adipo(-/-) mice in which PGZ failed to prevent steatohepatitis. Surprisingly, AMPKalpha1(-/-) mice were resistant to MCD-induced steatohepatitis, a status also associated with repression of SREBP-1c. CONCLUSIONS: The preventive effect of PGZ on MCD-induced steatohepatitis depends on adiponectin upregulation but apparently does not involve AMPK or PPARalpha activation. The inhibition of SREBP-1c and dependent repression of lipogenesis are likely to participate in this effect. The mechanisms by which PGZ and adiponectin control SREBP-1c and inflammation remain to be elucidated.

When damaged perinatally, as in congenital hemiplegia (CH), the corticospinal tract usually undergoes an extensive reorganization, such as the stabilization of normally transient projections to the ipsilateral spinal cord. Whether the reorganization of the corticospinal projections occurring in CH patients is also accompanied by a topographical rearrangement of the hand representations in the primary motor cortex (M1) remains unclear. To address this issue, we mapped, for both hands, the representation of the first dorsal interosseous muscle (1DI) in 12 CH patients by using transcranial magnetic stimulation co-registered onto individual three-dimensional magnetic resonance imaging; these maps were compared with those gathered in age-matched controls (n = 11). In the damaged hemisphere of CH patients, the representation of the paretic 1DI was either found in the hand knob of M1 (n = 5), shifted caudally (n = 5), or missing (n = 2). In the intact hemisphere of six CH patients, an additional, ipsilateral, representation of the paretic 1DI was found in the hand knob, where it overlapped exactly the representation of the non-paretic 1DI. In the other six CH patients, the ipsilateral representation of the paretic 1DI was either shifted caudally (n = 2) or was lacking (n = 4). Surprisingly, in these two subgroups of patients, the representation of the contralateral non-paretic 1DI was found in a more medio-dorsal position than in controls. The present study demonstrates that, besides the well-known reorganization of the corticospinal projections, early brain injuries may also lead to a topographical rearrangement of the representations of both the paretic and non-paretic hands in M1.

AIMS/HYPOTHESIS: Survival and function of insulin-secreting pancreatic beta cells are markedly altered by changes in nutrient availability. In vitro, culture in 10 rather than 2 mmol/l glucose improves rodent beta cell survival and function, whereas glucose concentrations above 10 mmol/l are deleterious. METHODS: To identify the mechanisms of such beta cell plasticity, we tested the effects of 18 h culture at 2, 5, 10 and 30 mmol/l glucose on the transcriptome of rat islets pre-cultured for 1 week at 10 mmol/l glucose using Affymetrix Rat 230 2.0 arrays. RESULTS: Culture in either 2-5 or 30 mmol/l instead of 10 mmol/l glucose markedly impaired beta cell function, while little affecting cell survival. Of about 16,000 probe-sets reliably detected in islets, some 5,000 were significantly up- or downregulated at least 1.4-fold by glucose. Analysis of these probe-sets with GeneCluster software identified ten mRNA profiles with unidirectional up- or downregulation between 2 and 10, 2 and 30, 5 and 10, 5 and 30 or 10 and 30 mmol/l glucose. It also identified eight complex V-shaped or inverse V-shaped profiles with a nadir or peak level of expression in 5 or 10 mmol/l glucose. Analysis of genes belonging to these various clusters using Onto-express and GenMAPP software revealed several signalling and metabolic pathways that may contribute to induction of beta cell dysfunction and apoptosis after culture in low- or high- vs intermediate-glucose concentration. CONCLUSIONS/INTERPRETATION: We have identified 18 distinct mRNA profiles of glucose-induced changes in islet gene mRNA levels that should help understand the mechanisms by which glucose affects beta cell survival and function under states of chronic hypo- or hyperglycaemia.

Context: In obesity, adipocyte hypertrophy and macrophage infiltration lead to overproduction of proinflammatory adipokines, which play a crucial role in the metabolic syndrome. The molecular mechanisms underlying this overproduction are still unsettled. The role of TNF-alpha also remains controversial in human obesity. Objective: We revisited the contribution of TNF-alpha to adipokine dysregulation in central obesity. We more particularly assessed the involvement of TNF-alpha vs. other stromal-vascular cell (SVC)-secreted factors and searched for potential differential responses to TNF-alpha between adipocytes of lean and obese individuals. Design and participants: Primary cultures of omental adipocytes from obese and non-obese age- and sex-matched subjects were used. For some experiments, we generated media previously conditioned by SVC, which mimic adipocyte microenvironment. Results: Adipocytes of obese subjects mainly overexpressed adipokines, in comparison to those of lean ones, when cultured SVC-conditioned media. This was abrogated by immunoneutralization of TNF-alpha, indicating that among the numerous factors secreted by SVC, TNF-alpha is a crucial contributor to adipokine dysregulation. Accordingly, adipocytes of obese subjects overproduced adipokines in response to direct exposure of TNF-alpha. This hyper-responsiveness was mediated by TNF-alpha-receptor-1 and hyper-activation of the NF-kappaB pathway. Correspondingly, NF-kappaB activity was increased in adipocytes of obese subjects and correlated with adipocyte size, adipokine expression and in vivo insulin resistance. Eventually, adipokine overexpression in adipocytes of obese subjects was prevented by NF-kappaB inhibitors. Conclusions: In obesity, TNF-alpha that is, over other SVC-secreted factors, a crucial determinant of adipokine dysregulation acts on enlarged adipocytes, which are hyper-responsive to this triggering signal. This ultimately exacerbates adipokine production, inflammation and the met

Because motor imagery (MI) and visual imagery (VI) are influenced differently by factors such as biomechanical constraints or stimulus size, it is conceivable that they rely on separate processes, possibly involving distinct cortical networks, a view corroborated by neuroimaging and neuropsychological studies. In the posterior parietal cortex, it has been suggested that the superior parietal lobule (SPL) underlies VI, whereas MI relies on the supramarginalis gyrus (SMG). However, because several brain imaging studies have also shown an overlap of activations in SPL and SMG during VI or MI, the question arises as to which extent these 2 subregions really contribute to distinct imagery processes. To address this issue, we used repetitive transcranial magnetic stimulation to induce virtual lesions of either SMG or SPL in subjects performing a MI (hand drawing rotation) or a VI (letter rotation) task. Whatever hemisphere was stimulated, SMG lesions selectively altered MI, whereas SPL lesions only affected VI, demonstrating a double dissociation between MI and VI. Because these deficits were not influenced by the angular distance of the stimuli, we suggest that SMG and SPL are involved in the reenactment of the motor and visual representations, respectively, and not in mental rotation processes per se.

Adult mesenchymal stem cells (MSCs) exhibit neuroprotective properties when introduced into the degenerating central nervous system through different putative mechanisms including secretion of growth factors and transdifferentiation. In the present study, we injected MSCs into the cerebrospinal fluid of symptomatic hSOD1(G93A) rats, a transgenic animal model of familial amyotrophic lateral sclerosis (ALS) expressing a mutated form of the human superoxide dismutase. MSCs were found to infiltrate the nervous parenchyma and migrate substantially into the ventral gray matter, where motor neurons degenerate. Even though overall astrogliosis was not modified, MSCs differentiated massively into astrocytes at the site of degeneration. The intrathecal delivery of MSCs and the subsequent generation of healthy astrocytes at symptomatic stage decreased motor neuron loss in the lumbar spinal cord, preserving motor functions and extending the survival of hSOD1(G93A) rats. This neuroprotection was correlated with decreased inflammation, as shown by the lower proliferation of microglial cells and the reduced expressiontion of COX-2 and NOX-2. Together, these data highlight the protective capacity of adult MSC-derived astrocytes when grafted into the central nervous system and illustrate an attractive strategy to target excessive inflammation in ALS. (c) 2009 Wiley-Liss, Inc.

BACKGROUND AND PURPOSE: Recent work demonstrated that application of peripheral nerve and cortical stimulation independently can induce modest improvements in motor performance in patients with stroke. The purpose of this study was to test the hypothesis that combining peripheral nerve stimulation (PNS) to the paretic hand with anodal direct current stimulation (tDCS) to the ipsilesional primary motor cortex (M1) would facilitate beneficial effects of motor training more than each intervention alone or sham (tDCSSham and PNSSham). METHODS: Nine chronic stroke patients completed a blinded crossover designed study. In separate sessions, we investigated the effects of single applications of PNS+tDCS, PNS+tDCSSham, tDCS+PNSSham, and PNSSham+tDCSSham before motor training on the ability to perform finger motor sequences with the paretic hand. RESULTS: PNS+tDCS resulted in a 41.3% improvement in the number of correct key presses relative to PNSSham+tDCSSham, 15.4% relative to PNS+tDCSSham, and 22.7% relative to tDCS+PNSSham. These performance differences were maintained 1 and 6 days after the end of the training. CONCLUSIONS: These results indicate that combining PNS with tDCS can facilitate the beneficial effects of training on motor performance beyond levels reached with each intervention alone, a finding of relevance for the neurorehabilitation of motor impairments after stroke.

While the astrocytic control of extracellular glutamate concentration at synaptic contacts is well characterized, little is known regarding the clearance of glutamate along axon tracts, even though local excitotoxic damage has been reported. Therefore, we have compared glutamate handling in astrocyte cultures derived from white matter (corpus callosum) and grey matter tissues (cortical structures). These populations of astrocytes showed clearly distinct phenotypes, adopting stellate or protoplasmic morphologies respectively. In addition, white matter astrocytes showed high densities of the intermediate filament proteins glial fibrillary acidic protein, vimentin and nestin. The glutamate-aspartate transporter and glutamate transporter-1, as well as glutamine synthetase, were found to be expressed at higher levels in white matter compared with grey matter astrocytes. Consistent with this aspartate uptake capacity was three to fourfold higher in white matter cells, and the use of specific inhibitors revealed a substantial activity of glutamate transporter-1, contrasting with grey matter cells where this transporter appeared poorly functional. In addition, expression of type 5 metabotropic glutamate receptors was considerably higher in white matter astrocytes where the agonist (S)-3,5-dihydroxyphenylglycine triggered a large release of intracellular calcium. Differences in these astrocyte cultures were also observed when exposed to experimental conditions that trigger glial activation. This study highlights typical features of cultured astrocytes derived from white matter tissues, which appear constitutively adapted to handle excitotoxic insults. Moreover, the expression and activity of the astroglial components involved in the control of glutamatergic transmission are reinforced when these cells are maintained under conditions mimicking a gliotic environment.

OBJECTIVE: We studied how glucose and ATP-sensitive K(+) (K(ATP)) channel modulators affect alpha-cell [Ca(2+)](c). RESEARCH DESIGN AND METHODS: GYY mice (expressing enhanced yellow fluorescent protein in alpha-cells) and NMRI mice were used. [Ca(2+)](c), the K(ATP) current (I(KATP), perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single alpha-cells and, for comparison, in single beta-cells. RESULTS: In 0.5 mmol/l glucose, [Ca(2+)](c) oscillated in some alpha-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca(2+)](c) by approximately 30% in oscillating cells and was ineffective in the others. alpha-Cell I(KATP) was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in beta-cells. Tolbutamide increased alpha-cell [Ca(2+)](c), whereas diazoxide and azide abolished [Ca(2+)](c) oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change I(KATP) and NAD(P)H fluorescence in alpha-cells in contrast to beta-cells. The use of nimodipine showed that L-type Ca(2+) channels are the main conduits for Ca(2+) influx in alpha-cells. gamma-Aminobutyric acid and zinc did not decrease alpha-cell [Ca(2+)](c), and insulin, although lowering [Ca(2+)](c) very modestly, did not affect glucagon secretion. CONCLUSIONS: alpha-Cells display similarities with beta-cells: K(ATP) channels control Ca(2+) influx mainly through L-type Ca(2+) channels. However, alpha-cells have distinct features from beta-cells: Most K(ATP) channels are already closed at low glucose, glucose does not affect cell metabolism and I(KATP), and it slightly decreases [Ca(2+)](c). Hence, glucose and K(ATP) channel modulators exert distinct effects on alpha-cell [Ca(2+)](c). The direct small glucose-induced drop in alpha-cell [Ca(2+)](c) contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets.

BACKGROUND & AIMS: A number of diseases are characterized by defective formation of the intrahepatic bile ducts. In the embryo, hepatoblasts differentiate to cholangiocytes, which give rise to the intrahepatic bile ducts. Here, we investigated how these ducts develop in mouse liver and characterized the role of the transcription factor SRY-related HMG box transcription factor 9 (SOX9). METHODS: We identified SOX9 as a new biliary marker and used it with other cell markers in immunostaining experiments to characterize the process of bile duct morphogenesis. The expression of growth factors was determined by in situ hybridization and immunostaining, and their role was studied on cultured embryonic hepatoblasts. SOX9 function was investigated by phenotyping mice with a liver-specific inactivation of Sox9. RESULTS: Biliary tubulogenesis started with formation of asymmetrical ductal structures, lined on the portal side by cholangiocytes and on the parenchymal side by hepatoblasts. When the ducts grew from the hilum to the periphery, the hepatoblasts lining the asymmetrical structures differentiated to cholangiocytes, thereby allowing formation of symmetrical ducts lined only by cholangiocytes. We also provide evidence that transforming growth factor-? promotes differentiation of the hepatoblasts lining the asymmetrical structures. In the absence of SOX9, the maturation of asymmetrical structures into symmetrical ducts was delayed. This was associated with abnormal expression of CCAAT/Enhancer Binding Protein ? and Homolog of Hairy/Enhancer of Split-1, as well as of the transforming growth factor-? receptor type II, which are regulators of biliary development. CONCLUSIONS: Our results suggest that biliary development proceeds according to a new mode of tubulogenesis characterized by transient asymmetry and whose timing is controlled by SOX9.

The human brain recognizes faces by means of two main diagnostic sources of information: three-dimensional (3D) shape and two-dimensional (2D) surface reflectance. Here we used event-related potentials (ERPs) in a face adaptation paradigm to examine the time-course of processing for these two types of information. With a 3D morphable model, we generated pairs of faces that were either identical, varied in 3D shape only, in 2D surface reflectance only, or in both. Sixteen human observers discriminated individual faces in these 4 types of pairs, in which a first (adapting) face was followed shortly by a second (test) face. Behaviorally, observers were as accurate and as fast for discriminating individual faces based on either 3D shape or 2D surface reflectance alone, but were faster when both sources of information were present. As early as the face-sensitive N170 component (~160 ms following the test face), there was larger amplitude for changes in 3D shape relative to the repetition of the same face, especially over the right occipito-temporal electrodes. However, changes in 2D reflectance between the adapter and target face did not increase the N170 amplitude. At about 250 ms, both 3D shape and 2D reflectance contributed equally, and the largest difference in amplitude compared to the repetition of the same face was found when both 3D shape and 2D reflectance were combined, in line with observers' behavior. These observations indicate that evidence to recognize individual faces accumulate faster in the right hemisphere human visual cortex from diagnostic 3D shape information than from 2D surface reflectance information.

Interactions between the ventral premotor (PMv) and the primary motor cortex (M1) are crucial for transforming an object's geometrical properties, such as its size and shape, into a motor command suitable for grasp of the object. Recently, we showed that PMv interacts with M1 in a specific fashion, depending on the hand posture. However, the functional connectivity between PMv and M1 during the preparation of an actual grasp is still unknown. To address this issue, PMv-M1 interactions were tested while subjects were preparing to grasp different visible objects requiring either a precision grip or a whole hand grasp. A conditioning-test transcranial magnetic stimulation (TMS) paradigm was used: a test stimulus was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. Motor evoked potentials (MEPs) were recorded in the first dorsal interosseus and abductor digiti minimi muscles, which show highly differentiated activity according to grasp. While subjects prepared to grasp, delivering a conditioning PMv pulse 6 or 8msec before a test pulse over M1 strikingly facilitated MEPs in the specific muscles that were used in the upcoming grasp. This degree of facilitation correlated with the amount of muscle activity used later in the trial to grasp the objects. The present results demonstrate that, during grasp preparation, the PMv-M1 interactions are muscle-specific. PMv appears to process the object geometrical properties relevant for the upcoming grasp, and transmits this information to M1, which in turn generates a motor command appropriate for the grasp. We also reveal that the grasp-specific facilitation resulting from PMv-M1 interactions is differently related to the upcoming grasp muscle activity than is that from paired-pulse stimulation over M1, suggesting that these two TMS paradigms assess the excitability of cortico-cortical pathways devoted to the control of grasp at two different levels.

RATIONALE: N-butyldeoxynojyrimicin (NB-DNJ, miglustat, Zavesca) an approved drug for treating Gaucher disease, was reported to be able to correct the defective trafficking of the F508del-CFTR protein. OBJECTIVES: To evaluate the efficacy of in vivo airway delivery of miglustat for restoring ion transport in CF. METHODS: We used nasal transepithelial potential difference (NPD) as a measure of sodium and chloride transport. The effect of nasal instillation of a single dose of miglustat was investigated in F508del, cftr knockout and normal homozygous mice. The galactose iminosugar analogue N-butyldeoxygalactonojirimycin (NB-DGJ) was used as a placebo. MEASUREMENTS AND MAIN RESULTS: In F508del mice, sodium conductance, evaluated by basal hyperpolarization, and chloride conductance, evaluated by perfusing the nasal mucosa with chloride-free solution in the presence of amiloride and forskolin, were normalized 1 h after up to an intranasal dose of 50 picomoles of miglustat. Chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of alternative chloride channels, was much higher after miglustat than after placebo. In cftr knockout mice, a normalizing effect was observed on sodium but not on chloride conductance. CONCLUSIONS: Our results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-dependent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF.

In this experiment, we investigated whether the Central Nervous System uses internal forward models of inertial loads to maintain the stability of a precision grip when manipulating objects in the absence of gravity. The micro-gravity condition causes profound changes in the profile of tangential constraints at the finger-object interface. In order to assess the ability to predict the micro-gravity-specific variation of inertial loads, we analyzed the grip force adjustments that occurred when naïve subjects held an object in a precision grip and performed point-to-point movements under the weightless condition induced by parabolic flight. Such movements typically presented static and dynamic phases, which permitted distinction between a static component of the grip force (measured before the movement) and a dynamic component of the grip force (measured during the movement). The static component tended to gradually decrease across the parabolas, whereas the dynamic component was rapidly modulated with the micro-gravity-specific inertial loads. In addition, the amplitude of the modulation significantly correlated with the amplitude of the tangential constraints for the dynamic component. These results strongly support the hypothesis that the internal representation of arm and object dynamics adapts to new gravitational contexts. In addition, the difference in timescales of adaptation of static and dynamic components suggests that they can be processed independently. The prediction of self-induced variation of inertial loads permits fine modulation of grip force, which ensures a stable grip during manipulation of an object in a new environment.

In contrast with type 1 diabetes that is caused by autoimmune destruction of pancreatic b-cells, type 2 diabetes (T2D) results from the combination of insulin resistance and defective insulin secretion due to reduced b-cell mass and function. Although the initial cause of such ß-cell dysfunction is not known, it is well established that even moderate hyperglycaemia further alters b-cell function and survival. This process of glucotoxicity contributes thus to the progressive worsening of glucose intolerance in these patients. Therefore, elucidating the molecular mechanisms of b-cell glucotoxicity may provide important insights into the pathophysiology of T2D. Methods: Islets were isolated from male Wistar rats and pre-cultured for one week in the presence of 10 mM glucose. Cell survival, function and gene expression were then measured after further culture for 1 to 7 days in the presence of low, intermediate and high glucose concentrations (2, 5, 10 or 30 mM) plus various test substances. First study: The alterations of ß-cell gene expression by high glucose are similar to those caused by IL-1b, a pro-inflammatory cytokine which triggers ß-cell apoptosis in T1D following the activation of the transcription factor NFB. This suggested that the effects of high glucose may result from the activation of NFkB, likely as a result of oxidative stress. To test this hypothesis, I compared the effects of IL-1ß, high glucose and hydrogen peroxide with or without the antioxidant N-Acetyl-L-cystein (NAC) on NFkB activation and target gene mRNA levels in cultured islets. As expected, exogenous IL-1b rapidly activated NFkB and increased the expression of its target genes c-Myc, Hmox1, iNOS, Fas and IkBa. In contrast, culture in the presence of 30mM glucose (G30) or 50µM hydrogen peroxide stimulated the expression of c-Myc, Hmox1 and Fas without activating NFkB or increasing the expression of its target genes iNOS and IBa. These effects were nevertheless inhibited by NAC and by inhib, Contrairement au diabète de type 1 qui fait suite à la destruction des cellules b du pancréas endocrine par un processus auto-immunitaire, le diabète de type 2 (DT2) résulte de la combinaison d'une insulino-résistance et d'un défaut de sécrétion d'insuline par réduction de la masse et de la fonction des cellules b. Si la cause initiale de ce défaut de sécrétion n'est pas connue, il est par contre bien établi que l'hyperglycémie une fois présente contribue aux altérations de fonction et survie des cellules b. Ce processus de glucotoxicité contribue ainsi à l'aggravation progressive de l'intolérance glucidique chez ces patients. L'étude des mécanismes moléculaires de la glucotoxicité dans les cellules b est donc indispensable à une meilleure compréhension de la physiopathologie du DT2. Méthodes: Des îlots isolés de rats mâles Wistar ont été précultivés une semaine en présence de 10 mM glucose. La survie, la fonction et l'expression des gènes ont ensuite été mesurés dans ces îlots cultivés pendant 1 à 7 jours en présence de concentrations de glucose faibles, intermédiaires ou élevées (2, 5, 10 ou 30 mM) et de divers agents pharmacologiques. Première étude: Les altérations d'expression des gènes des cellules b par les concentrations élevées de glucose sont semblables à celles provoquées par l'IL-1b, une cytokine pro-inflammatoire qui déclenche l'apoptose des cellules ß dans le DT1 en activant le facteur de transcription NF B. Ceci suggère que l'hyperglycémie active NFkB, peut-être suite à un stress oxydatif. Pour tester cette hypothèse, j'ai comparé les effets de l'IL-1ß, de concentrations élevées de glucose et du peroxyde d'hydrogène, en présence ou non de l'anti-oxydant N-Acetyl-L-cystéine (NAC), sur l'activation de NFkB et l'expression de ses gènes cibles (ARNm) dans les îlots en culture. J'ai confirmé que l'IL-1b exogène active rapidement NFkB et l'expression de ses gènes cibles c-Myc, Hmox1, iNOS, Fas et IkBa. Par contre, la culture en présence de 30mM de glucose (, (SBIM 3) -- UCL, 2009

A recent study published in this journal has shown an abnormal performance at discriminating differences with respect to the eyes of unfamiliar faces in two acquired prosopagnosic patients, but preserved processing of the mouth region. Here we extend these findings by showing a similar lack of sensitivity to the eyes in the very same face matching experiment for the prosopagnosic patient PS, who also showed normal performance for detecting differences in the mouth region. These results complement previously published evidence that the patient PS presents a lack of sensitivity to diagnostic information located on the eyes of familiar faces during individual face recognition tasks. More generally, they indicate that the impaired processing of the eyes of faces is a fundamental aspect of acquired prosopagnosia that can arise following damage to different brain localizations.

TOPIC: Olfactory dysfunction may be assessed in the clinic with psychophysical testing and electrophysiological recording. Chemosensory event-related potentials (CSERPs) constitute an objective method to assess chemosensory function. Olfactory and trigeminal stimuli activate chemoreceptors from the olfactory neuroepithelium and from the nasal mucosa to evoke an electrophysiological response respectively called olfactory (OERPs) and trigeminal ERPs (TERPs). The purpose of this study is to assess the usefulness and feasibility of these diagnostic tools in the rhinology clinic and to correlate these results to the olfactory disorder aetiology. MATERIALS AND METHODS: This study encompasses a cohort of 229 patients with a complaint of olfactory dysfunction from different origins. Orthonasal (Sniffing stick test with the treshold-discrimination-identification score: maximal score 48) and retronasal olfactory (maximal score 20) testing as well as CSERPs both after olfactory and trigeminal stimuli have been routinely performed. Olfactory dysfunction aetiologies were as follows: congenital (Cong.), chronic rhinosinusitis (CRS), idiopathic (Idiop.), post-medication (PM), neurologic (Neuro.), post-traumatic (PT) and post-infection (PI). RESULTS: Mean orthonasal and retronasal scores were respectively: 11.8 and 10.1 for Cong., 18.5 and 13.1 for CRS, 15.6 and 10.4 for Idiop., 15.3 and 10.2 for PM, 17 and 10.6 for Neuro., 15 and 9.9 for PT and 18.3 and 12 for PI. Correlations between orthonasal and retronasal scores were present for all subgroups except congenital and chronic rhinosinusitis subgroups. Orthonasal and retronasal scores were different (p < 0.05) when comparing CRS vs Cong., CRS vs PT and PT vs PI. Technical problems (olfactometer or olfactory stimulation, EEG amplifier,...) and patients discomfort (anxiety, stress,...) did not allow to draw any conclusion in 2 patients. Three patients after olfactory stimulus and 6 patients after trigeminal stimulus demonstrated too

High grade gliomas are known to release excitotoxic concentrations of glutamate, a process thought to contribute to their malignant phenotype through enhanced autocrine stimulation of their proliferation and destruction of the surrounding nervous tissue. A model of C6 glioma cells in which expression of the high affinity glutamate transporter GLT-1 can be manipulated both in vivo and in vitro was used in order to investigate the consequences of increasing glutamate clearance on tumour progression. These cells were grafted in the striatum of Wistar rats and doxycycline was administered after validation of tumour development by magnetic resonance imaging. Both GLT-1 expression examined by immunohistochemistry and glutamate transport activity measured on synaptosomes appeared robustly increased in samples from doxycycline-treated animals. Moreover, these rats showed extended survival times as compared to vehicle-treated animals, an effect that was consistent with volumetric data revealing delayed tumour growth. As constitutive deficiency in glutamate clearance at the vicinity of brain tumours is well established, these data illustrate the potential benefit that could be obtained by enhancing glutamate transport by glioma cells in order to reduce their invasive behaviour.

The aim of this study was to investigate the role of Kupffer cell in glucose metabolism and hepatic insulin sensitivity in mice. Both phagocytic activity and secretory capacity of Kupffer cells were blunted 24h after GdCl(3) administration. Glucose tolerance - evaluated following an oral glucose tolerance test (OGTT) - was higher in GdCl(3)-treated mice whereas fasting insulinemia and HOMA-IR index decreased. The improvement of glucose tolerance and hepatic insulin signalling pathway after inhibition of Kupffer cells was supported by a lower hepatic gluconeogenic enzyme expression and a higher phosphorylation of Akt upon insulin challenge. Moreover, fasting hyperglycemia, insulin resistance and impaired glucose tolerance - induced by high fat (HF) diet - were improved through chronic administration of GdCl(3). Interestingly, the inhibition of Kupffer cell exerted antiobesity effects in HF-fed mice, and lowered hepatic steatosis. Therefore, strategies targeting Kupffer cell functions could be a promising approach to counteract obesity and related metabolic disorders.

Impaired glutamate uptake associated with accumulation of extracellular glutamate is a well-documented feature of amyotrophic lateral sclerosis (ALS) and related excitotoxicity is frequently proposed to participate in the progression of the disease. We herein characterised the expression and activity of the glutamate transporter glutamate transporter 1 (GLT-1) in cultured cortical astrocytes derived from a transgenic rat strain expressing an ALS-related mutated form of human superoxide dismutase 1 (hSOD1(G93A)). Measurements of d-[(3)H]-aspartate uptake velocity in the presence of selective glutamate transporter blockers demonstrated that astrocytes from the transgenic rats showed an impaired GLT-1 activity as compared to cells from wild-type animals. In addition, the density of GLT-1a mRNA in cells from hSOD1(G93A) animals appeared nearly 2-fold lower while the density of GLT-1b mRNA was nearly 2-fold higher. Besides, we observed that exposing the astrocytes from hSOD1(G93A) rats to the neuroprotective transmitter Peptide Histidine Isoleucine (PHI) for 24h caused a 4.5-fold increase in the GLT-1b mRNA level without influencing the expression of the other key isoform GLT-1a. This selective upregulation of GLT-1b by the neuropeptide was correlated with a significant increase in d-[(3)H]-aspartate uptake activity. The possibility to specifically regulate a single isoform of the high-affinity transporter GLT-1 is an unprecedented observation which sheds light on new perspectives for the pharmacological manipulation of glutamate transmission in diseases such as ALS.

Impaired glial glutamate uptake is commonly involved in neuronal damages observed in acute and chronic nervous disorders. As nervous insults are frequently associated with local inflammation involving microglia, this study aims at exploring the link between activated microglia and altered glutamate uptake in astrocytes. The regulation of the expression and activity of type 1 glutamate transporter (GLT-1) was examined after exposing cultures of rat astrocytes to conditioned medium from lipopolysaccharide-activated microglia cultures. Significant increases in GLT-1 mRNA expression and dihydrokainate sensitive uptake of aspartate were observed after 72h of treatment. These effects were reproduced by direct exposure of the astrocyte cultures to tumor necrosis factor alpha, a major cytokine released by activated microglia. The regulation of GLT-1 activity in response to inflammatory stimuli was also evidenced in cells exposed to dibutyryl cAMP, recognised as a model of reactive astrocytes in which the expression of this glutamate transporter is constitutively enhanced. Taken together, these results suggest that the GLT-1-dependent control of glutamate neurotransmission by either naive or chemically activated astrocytes is influenced by microglia-mediated inflammation.

Recent data reported that chitosan reduces high-fat (HF) diet-induced obesity in mice without describing the metabolic consequences of such an effect. The aim of this study was to investigate the capacity of chitosan derived from edible mushrooms to modify adipocytokine levels and to assess the relevance of this effect on the development of fat mass, and on glucose and lipid metabolism in obese mice. Mice were fed a HF diet or a HF diet supplemented with 5% fungal chitosan for ten weeks. HF-induced hypertriglyceridaemia, fasting hyperinsulinaemia and fat accumulation in liver, muscle and white adipose tissue (WAT) were reduced after chitosan treatment. The higher lipid content in the caecum following treatment with chitosan suggested that this dietary fiber reduced lipid absorption. We postulated that the lower triglyceridaemia observed upon chitosan treatment could also be the result of the lower FIAF (fasting-induced adipose factor) expression observed in visceral adipose tissue. IL-6, resistin and leptin levels decreased in the serum after chitosan supplementation. We conclude that fungal chitosan counteracts some inflammatory disorders and metabolic alterations occurring in diet-induced obese mice since it decreases feed efficiency, fat mass, adipocytokine secretion and ectopic fat deposition in the liver and the muscle.

Tumor cells fuel their metabolism with glucose and glutamine to meet the bioenergetic and biosynthetic demands of proliferation. Hypoxia and oncogenic mutations drive glycolysis, with the pyruvate to lactate conversion being promoted by increased expression of lactate dehydrogenase A and inactivation of pyruvate dehydrogenase. The NAD(+) pool is consecutively regenerated and supports the high glycolytic flux required to produce anabolic intermediates. Glutaminolysis provides metabolic intermediates such as alpha-ketoglutarate to feed and thereby maintain the tricarboxylic acid cycle as a biosynthetic hub. Glycolysis and glutaminolysis share the capacity to generate NADPH, from the pentose phosphate pathway and through the malate conversion into pyruvate, respectively. Both pathways ultimately lead to the secretion of lactate. More than a waste product, lactate was recently identified as a major energy fuel in tumors. Lactate produced by hypoxic tumor cells may indeed diffuse and be taken up by oxygenated tumor cells. Preferential utilization of lactate for oxidative metabolism spares glucose which may in turn reach hypoxic tumor cells. Monocarboxylate transporter 1 regulates the entry of lactate into oxidative tumor cells. Its inhibition favors the switch from lactate-fuelled respiration to glycolysis and consecutively kills hypoxic tumor cells from glucose starvation. Combination with radiotherapy renders remaining cells more sensitive to irradiation, emphasizing how interference with tumor cell metabolism may complement current anticancer modalities.

BACKGROUND: Metabolic compatibility between donor and recipient species is an important matter for pig islet xenotransplantation. Glucagon is a key hormone for the function of pig islets as well as control of hypoglycemia in the recipients of the islets. Because a discrepancy exists in the composition of glucagon cells of pig and human/primate islets, the present study was designed to determine the role of native recipient glucagon cells in the treatment of diabetes by islet transplantation in a "pig-to-primate" model. METHODS: Streptozotocin-treated (50 mg/kg) monkeys (n = 12, follow-up of 6 to 231 days) were compared with non-diabetic animals (n = 5; follow-up, 180 days). Metabolic [fasting and intravenous glucose tolerance tests (IVGTTs) for serum levels of glucose, insulin, glucagon] and morphologic (endocrine volume density and cell mass for insulin and glucagon) were compared between non-diabetic and diabetic animals. Six additional diabetic primates were given transplants of 15 000 adult pig islet equivalents without immunosuppression to monitor glucose, glucagon, insulin, and porcine C-peptide levels until 48 h after transplantation. RESULTS: Elevated fasting blood glucose, pathologic IVGTT, destruction of 95% of beta-cell mass, and glycosylated hemoglobin (>13%) were assessed in diabetic monkeys. The serum glucagon levels and glucagon cell mass correlated significantly with diabetes time course of diabetes (R = 0.940, p = 0.005; R = 0.663, p = 0.019, respectively). A mean increase of 89% in glucagon cell mass was observed for primates suffering from diabetes >53 days. No response of glucagon secretion was observed for diabetic animals during IVGTT, because no increase of serum insulin levels followed glucose loading. Blood glucose levels dropped after pig islet xenografts in diabetic primates. This reduction was maintained by an insulin level >20 microU/ml over the period of time of xenograft function (porcine C-peptide >0.1 ng/ml). A total restoration of n

Processing of amyloid precursor protein (APP) by gamma-secretase is the last step in the formation of the Abeta peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamembrane (JM) domains of APP that facilitate proteolysis. Using peptides corresponding to the APP TM and JM regions (residues 618-660), we show that the TM domain forms an alpha-helical homodimer mediated by consecutive GxxxG motifs. We find that the APP TM helix is disrupted at the intracellular membrane boundary near the epsilon-cleavage site. This helix-to-coil transition is required for gamma-secretase processing; mutations that extend the TM alpha-helix inhibit epsilon cleavage, leading to a low production of Abeta peptides and an accumulation of the alpha- and beta-C-terminal fragments. Our data support a progressive cleavage mechanism for APP proteolysis that depends on the helix-to-coil transition at the TM-JM boundary and unraveling of the TM alpha-helix.

Polychlorinated biphenyls (PCBs) are widespread persistent environmental contaminants that display a complex spectrum of toxicological properties, including hepatotoxicity. Although Aroclor 1254 is ubiquitous in the environment, its potential cytotoxic effect on rat hepatocytes and the mechanism underlines its cytotoxicity are not fully investigated. Therefore, the present study was conducted to investigate: (1) the potential cytotoxicity of Aroclor 1254 in rat hepatocytes, and (2) characterization of the molecular mechanisms involved in the Aroclor 1254-induced hepatotoxicity, particularly the role of mitochondria, possibly a primary target in such event, could greatly explain the cytotoxic effect of Aroclor 1254 in rat hepatocytes. Hepatocytes were isolated from adult male albino rats and incubated for 24h in a fresh media containing 0, 20, 30, 40, 50 or 60muM of Aroclor 1254. At the end of incubation, hepatocytes and hepatocyte mitochondria were used for the assay. Our results showed cytotoxicity of Aroclor 1254 in rat hepatocytes starting at a concentration of 30muM as manifested by increased lactate dehydrogenase (LDH) leakage, decreased cell viability (MTT assay) and increased lipid peroxidation. As mitochondria are known to be one possible site of the cell damage, the effects of Aroclor 1254 on hepatocyte mitochondria was investigated. Aroclor 1254 induced reactive oxygen species (ROS) generation in hepatocyte mitochondria, inhibited mitochondrial respiratory chain complexes I and III and beta-oxidation of free fatty acids, depletion of mitochondrial antioxidant enzymes GPx and GR and the non-enzymatic antioxidant reduced glutathione, inhibited mitochondrial membrane potential (Deltapsi(m)), decreased mitochondrial aconitase and cardiolipin content, and elevated levels of cytochrome P450 subfamily, CYP1A and CYP2B activities as indicated by ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-deethylase (PROD). Therefore, we can conclude that Aroclor 12

Faces are recognized by means of both shape and surface reflectance information. However, it is unclear how these two types of diagnostic information are represented in the human brain. To clarify this issue, we tested 14 participants in an event-related functional magnetic resonance adaptation paradigm, with 4 conditions created by using a 3D morphable model: (1) repetition of the same adapting face; (2) variation in shape only; (3) variation in surface reflectance only; (4) variation in both shape and surface reflectance. Change in face shape alone was the dominant driving force of the adaptation release in functionally defined face-sensitive areas in the right hemisphere (FFA, OFA). In contrast, homologous areas of the left hemisphere showed comparable adaptation release to changes in face shape and surface reflectance. When both changes in shape and reflectance were combined, there was no further increased release from adaptation in face-sensitive areas. Overall, these observations indicate that the two main sources of information in individual faces, shape and reflectance, contribute to individual face sensitivity found in the cortical face network. Moreover, the sensitivity to shape cues is more dominant in the right hemisphere, possibly reflecting a privileged mode of global (holistic) face processing.

PURPOSE OF REVIEW: Allogeneic islet transplantation faces difficulties because organ shortage is recurrent; several pancreas donors are often needed to treat one diabetic recipient; and the intrahepatic site of islet implantation may not be the most appropriate one. Another source of insulin-producing cells, therefore, would be of major interest, and pigs represent a possible and serious source for obtaining such cells. RECENT FINDINGS: Pig islet grafts may appear difficult because of the species barrier, but recent studies demonstrate that pig islets may function in diabetic primates for at least 6 months. SUMMARY: Pig islet xenotransplantation, however, must still overcome the selection of a suitable pig donor to translate preclinical findings into clinical applications. This review summarizes the actual acquired knowledge of pig islet transplantation in primates to select the 'ideal' pig donor.

BACKGROUND: We have previously shown that gut microbial fermentation of prebiotics promotes satiety and lowers hunger and energy intake in humans. In rodents, these effects are associated with an increase in plasma gut peptide concentrations, which are involved in appetite regulation and glucose homeostasis. OBJECTIVE: Our aim was to examine the effects of prebiotic supplementation on satiety and related hormones during a test meal for human volunteers by using a noninvasive micromethod for blood sampling to measure plasma gut peptide concentrations. DESIGN: This study was a randomized, double-blind, parallel, placebo-controlled trial. A total of 10 healthy adults (5 men and 5 women) were randomly assigned to groups that received either 16 g prebiotics/d or 16 g dextrin maltose/d for 2 wk. Meal tolerance tests were performed in the morning to measure the following: hydrogen breath test, satiety, glucose homeostasis, and related hormone response. RESULTS: We show that the prebiotic treatment increased breath-hydrogen excretion (a marker of gut microbiota fermentation) by approximately 3-fold and lowered hunger rates. Prebiotics increased plasma glucagon-like peptide 1 and peptide YY concentrations, whereas postprandial plasma glucose responses decreased after the standardized meal. The areas under the curve for plasma glucagon-like peptide 1 and breath-hydrogen excretion measured after the meal (0-60 min) were significantly correlated (r = 0.85, P = 0.007). The glucose response was inversely correlated with the breath-hydrogen excretion areas under the curve (0-180 min; r = -0.73, P = 0.02). CONCLUSION: Prebiotic supplementation was associated with an increase in plasma gut peptide concentrations (glucagon-like peptide 1 and peptide YY), which may contribute in part to changes in appetite sensation and glucose excursion responses after a meal in healthy subjects.

The exact contribution of Broca's area to motor cognition is still controversial. Here we used repetitive transcranial magnetic stimulation (5 Hz, five pulses) to interfere transiently with the function of left BA44 in 13 healthy individuals; the task consisted of reordering human actions or nonbiological events based on three pictures presented on a computer screen and extracted from a video showing the entire sequence beforehand. We found that a virtual lesion of left BA44 impairs individual performance only for biological actions, and more specifically for object-oriented syntactic actions. Our finding provides evidence that Broca's area plays a crucial role in encoding complex human movements, a process which may be crucial for understanding and/or programming actions.

Pancreatic beta-cells exposed to high glucose concentrations display altered gene expression, function, survival and growth that may contribute to the slow deterioration of the functional beta-cell mass in type 2 diabetes. These glucotoxic alterations may result from various types of stress imposed by the hyperglycaemic environment, including oxidative stress, endoplasmic reticulum stress, cytokine-induced apoptosis and hypoxia. The glucose regulation of oxidative stress-response and integrated stress-response genes in cultured rat islets follows an asymmetric V-shaped profile parallel to that of beta-cell apoptosis, with a large increase at low glucose and a moderate increase at high vs. intermediate glucose concentrations. These observations suggest that both types of stress could play a role in the alteration of the functional beta-cell mass under states of prolonged hypoglycaemia and hyperglycaemia. In addition, beta-cell demise under glucotoxic conditions may also result from beta-cell hypoxia and, in vivo, from their exposure to inflammatory cytokines released locally by non-endocrine islet cells. A better understanding of the relative contribution of each type of stress to beta-cell glucotoxicity and of their pathophysiological cause in vivo may lead to new therapeutic strategies to prevent the slow deterioration of the functional beta-cell mass in glucose intolerant and type 2 diabetic patients.

Identifying a facial feature (e.g. the eyes) is influenced by the position and identity of other features (e.g. the mouth) of the face, supporting the view that an individual face is represented as a whole in the human brain. To clarify how early in the time-course of face processing this holistic individual representation is accessed we recorded event-related potentials during an adaptation paradigm of the composite face illusion (CFI). Observers performed a matching task on top halves of two faces presented sequentially. For each face pair, top and bottom face halves could be both identical, both different, or only the bottom half differed. The signal was larger over the right occipito-temporal cortex at about 160 ms (N170) when the attended top half differed between the two faces than when identical top halves were repeated. Crucially, a larger N170 was also found when the top halves of the two faces were the same, yet the observers had the illusion that they differed (CFI). This effect was not found when the two face halves were spatially misaligned. These observations indicate that the earliest perceptual representation of an individual face in the human brain is holistic rather than based on independent face parts.

I published a critical review of the face inversion effect (Rossion, 2008) that triggered a few reactions and commentaries by colleagues in the field (Riesenhuber & Wolff, 2009; Yovel, in press). Here, I summarize my original paper and attempt to identify the source of both the agreements and disagreements with my colleagues, as well as other authors, regarding the nature of the face inversion effect. My view is that the major cause of the detrimental effect of inversion on an observer's performance at individual face recognition is the disruption of a perceptual process. This perceptual process is makes and observer see the multiple features of a whole individual upright face at once. It also makes the percept of a given facial feature highly dependent on the location and identity of the other features in the whole face. The perceptual process is holistic because it is driven by a holistic face representation, derived from visual experience. Hence, an inverted face cannot be perceived holistically: the perceptual field of the observer is constricted for inverted faces, each facial feature having to be processed sequentially, independently, i.e. over a smaller spatial window than the whole face. Consequently, it is particularly difficult to perceive diagnostic cues that involve several elements over a wide space on an inverted face, such as long-range relative distances between features (e.g., relative distance between eyes and mouth), or diagnostic cues that are located far away from usual gaze fixation (e.g., mouth-nose distance or mouth shape when fixating between the eyes). These difficulties are mere consequences of face inversion--the cause being a loss of holistic perception--, and it does not follow that relative distances between internal features are necessarily particularly important to recognize faces, that they should be labeled "configural", or should be given a specific status at the representational level. I argue that distinguishing the cause and co

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that induces hepatic and extrahepatic oxidative stress and the mechanisms of TCDD-induced reactive oxygen species are not fully investigated. Moreover, the potential toxicity of TCDD in isolated rat hepatocytes is not fully explored. The aim of the current study was to explore the possible cytotoxic effect of TCDD on primary rat hepatocytes and to explore the impact of mitochondria in TCDD-induced toxicity. Hepatocytes were isolated from adult rat liver and incubated with 0, 5, 10 or 15nM of TCDD for 24, 48 and 72h. Cell viability, lactate dehydrogenase (LDH) leakage into media along with reactive oxygen species (ROS) generation and hydrogen peroxide (H(2)O(2)) production, mitochondrial membrane potential (Deltapsi(m)), superoxide dismutase (SOD), catalse (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), total thiol contents, hepatic aryl hydrocarbon hydroxylase (AHH), and ethoxyresorufin O-deethylase (EROD) were performed in hepatocytes. In addition, superoxide anion generation, lipid peroxidation (LPO), mitochondrial protein carbonyl content and respiratory chain complexes II and IV were assayed in hepatocyte mitochondria. Cell viability was significantly decreased while LDH leakage into media was significantly increased in a dose and time related manner. ROS generation and H(2)O(2) production along with EROD and AHH activities were significantly increased in hepatocytes in the same pattern. The antioxidant enzymes SOD, CAT, GPx and GR and the non-enzymatic protein thiols, in addition to Deltapsi(m) were significantly decreased in hepatocytes in a concentration and time dependent pattern. On the other side, mitochondrial superoxide anion along with LPO and mitochondrial protein carbonyl content were significantly increased while the respiratory chain complexes II and IV activities were significantly decreased in hepatocyte mitochondria. This effect may lead to disruption in t

The impact of inversion on the extraction of relational and featural face information was investigated in two fMRI experiments. Unlike previous studies, the contribution of horizontal and vertical spatial relations were considered separately since they have been shown to be differentially vulnerable to face inversion (Goffaux & Rossion, 2007). Hence, inversion largely affects the perception of vertical relations (e.g. eye or mouth height) while the processing of features (e.g. eye shape and surface) and of horizontal relations (e.g. inter-ocular distance) is affected to a far lesser extent. Participants viewed pairs of faces that differed either at the level of one local feature (i.e. the eyes) or of the spatial relations of this feature with adjacent features. Changes of spatial relations were divided into two conditions, depending on the vertical or horizontal axis of the modifications. These stimulus conditions were presented in separate blocks in the first (block) experiment while they were presented in a random order in the second event-related (ER) experiment. Face-preferring voxels located in the right-lateralized middle fusiform gyrus (rMFG) largely decreased their activity with inversion. Inversion-related decreases were more moderate in left-lateralized middle fusiform gyrus (lMFG). ER experiment revealed that inversion affected rMFG and lMFG activity in distinct stimulus conditions. Whereas inversion affected lMFG processing only in featural condition, inversion selectively affected the processing of vertical relations in rMFG. Correlation analyses further indicated that the inversion effect (IE) observed in rMFG and right inferior occipital gyrus (rIOG) reliably predicted the large behavioural IE observed for the processing of vertical relations. In contrast, lMFG IE correlated with the weak behavioural IE observed for the processing of horizontal relations. Our findings suggest that face configuration is mostly encoded in rMFG, whereas more local aspect

We report a functional magnetic resonance imaging (fMRI) adaptation study of two well-described patients, DF and PS, who present face identity recognition impairments (prosopagnosia) following brain-damage. Comparing faces to non-face objects elicited activation in all visual areas of the cortical face processing network that were spared subsequent to brain damage. The common brain lesion in the two patients was in the right inferior occipital cortex, in the territory of the right "occipital face area" ('OFA'), which strengthens the critical role of this region in processing faces. Despite the lesion to the right 'OFA', there was normal range of sensitivity to faces in the right "fusiform face area" ('FFA') in both patients, supporting a non-hierarchical model of face processing at the cortical level. At the same time, however, sensitivity to individual face representations, as indicated by release from adaptation to identity, was abnormal in the right 'FFA' of both patients. This suggests that the right 'OFA' is necessary to individualize faces, perhaps through reentrant interactions with other cortical face sensitive areas. The lateral occipital area (LO) is damaged bilaterally in patient DF, who also shows visual object agnosia. However, in patient PS, in whom LO was spared, sensitivity to individual representations of non-face objects was still found in this region, as in the normal brain, consistent with her preserved object recognition abilities. Taken together, these observations, which fruitfully combine functional imaging and neuropsychology, place strong constraints on the possible functional organization of the cortical areas mediating face processing in the human brain.

Congenital blindness is one of the rare human models to explore the role of experience-driven cross-modal compensation after early sensory deprivation. We re-examined spatial attention abilities in congenitally blind participants and sighted controls using a paradigm comparable to the one of our previous study (Collignon, Renier, Bruyer, Tranduy, & Veraart, 2006), except that this time the auditory and tactile stimuli were now presented in sequence. Although both groups performed the task with similar accuracy, we observed that blind participants had shorter reaction times than sighted controls for the detection of spatial targets in both sensory modalities. Moreover, this finding held true for both the selective and divided attention conditions. These results not only confirm previous reports on the superiority of the blind during auditory and tactile attention tasks, but also broaden our knowledge of the mechanisms underlying cross-modal compensation.

The time needed to search for an object in a complex environment increases with the number of distracting stimuli, a phenomenon known as the "set-size effect." This observation has led to the view that, during visual search, several attentional shifts are performed, suggesting that visual information is processed serially. In an attempt to find direct evidence for such attentional shifts, we implemented several dual tasks combining a covert visual search (CVS) task or a cued target detection task with a character reporting task which allowed us to determine, a posteriori, the attentional allocation. We found that, in the cueing task, subjects preferentially reported characters displayed at different locations, demonstrating that the attention spotlight actually shifted in this condition. In contrast, in both feature and conjunction CVS, subjects predominantly reported several characters. ashed at the same location, whatever the delay between their presentations, indicating that, despite a clear "set-size effect," attention remained static. These results demonstrate that CVS can be performed without shifting attention and that the "set-size effect" does not necessarily attest that visual information is processed serially. The present study therefore supports the hypothesis that parallel mechanisms are involved in visual information processing during visual search, in agreement with previous theoretical studies.

Objective: Training to perform a serial reaction-time task (procedural motor learning) with one hand results in performance improvements in the untrained as well as in the trained hand, a phenomenon referred to as intermanual transfer. The aim of this study was to investigate the neurophysiological changes associated with intermanual transfer associated with learning to perform an eminently different task involving fine force control within the primary motor cortex (M1). We hypothesized that intermanual transfer of learning Such a task would reveal intracortical changes within M1. Methods: Speed (time to complete each sequence) and accuracy (% of accuracy errors) of motor performance were measured in both hands before and after right (dominant) hand practice. Transcranial magnetic stimulation (TMS) was used to characterize recruitment curves (RC), short intracortical inhibition (SICI), intracortical facilitation (ICF) and interhemispheric inhibition (IHI) from the left to the right M1. Results: Practice resulted in significant improvements in both speed and accuracy in the right trained hand and in the left untrained hand. RC increased in the left M1, SICI decreased in both M1s, and IHI from the left to the right M1 decreased. No changes were identified in ICF nor in RC in the right M1. Conclusions: Our results suggest that some neurophysiological mechanisms operating in the M1 controlling performance of an untrained hand may contribute to optimize the procedure for selecting and implementing correct pinch force levels. Significance: These results raise the hypothesis of a contribution of modulation of SICI and IHI, or an interaction between both to intermanual transfer after learning a sequential pinch force task. (C) 2009 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ZnT8 using ZnT8-knockout (ZnT8(-/-)) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8(-/-) beta cells and were replaced by immature, pale insulin "progranules,'' which were larger than in ZnT8(+/+) islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8(-/-) mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8(-/-) genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations.

The segregation between cortical pathways for the identification and localization of objects is thought of as a general organizational principle in the brain. Yet, little is known about the unimodal versus multimodal nature of these processing streams. The main purpose of the present study was to test whether the auditory and tactile dual pathways converged into specialized multisensory brain areas. We used functional magnetic resonance imaging (fMRI) to compare directly in the same subjects the brain activation related to localization and identification of comparable auditory and vibrotactile stimuli. Results indicate that the right inferior frontal gyrus (IFG) and both left and right insula were more activated during identification conditions than during localization in both touch and audition. The reverse dissociation was found for the left and right inferior parietal lobules (IPL), the left superior parietal lobule (SPL) and the right precuneus-SPL, which were all more activated during localization conditions in the two modalities. We propose that specialized areas in the right IFG and the left and right insula are multisensory operators for the processing of stimulus identity whereas parts of the left and right IPL and SPL are specialized for the processing of spatial attributes independently of sensory modality.