A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes.

The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

Inhibition of the Kit Ligand/c-Kit Axis Attenuates Metastasis in a Mouse Model Mimicking Local Breast Cancer Relapse after Radiotherapy.

PURPOSE: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis. EXPERIMENTAL DESIGN: 4T1 cells were injected in 20 Gy preirradiated mammary tissue to mimic postradiation relapses, or in nonirradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histologic analyses, adoptive cell transfer, genetic, and pharmacologic interventions were carried out. RESULTS: Tumors growing in preirradiated mammary tissue had reduced angiogenesis and were more hypoxic, invasive, and metastatic to lung and lymph nodes compared with control tumors. Increased metastasis involved the mobilization of CD11b(+)c-Kit(+)Ly6G(high)Ly6C(low)(Gr1(+)) myeloid cells through the HIF1-dependent expression of Kit ligand (KitL) by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and premetastatic lungs, to give rise to CD11b(+)c-Kit(-) cells. Pharmacologic inhibition of HIF1, silencing of KitL expression in tumor cells, and inhibition of c-Kit with an anti-c-Kit-blocking antibody or with a tyrosine kinase inhibitor prevented the mobilization of CD11b(+)c-Kit(+) cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b(+)c-Kit(+) cells and inhibiting lung metastasis after irradiation of established tumors. CONCLUSIONS: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in preirradiated mammary tissue. Pharmacologic inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy. Clin Cancer Res; 18(16); 4365-74. ©2012 AACR.

High b-value Diffusion-weighted Imaging: A Sensitive Method to Reveal White Matter Changes in Schizophrenia

Background: b-value is the parameter characterizing the intensity of the diffusion weighting during image acquisition. Data acquisition is usually performed with low b value (b~1000 s/mm2). Evidence shows that high b-values (b>2000 s/mm2) are more sensitive to the slow diffusion compartment (SDC) and maybe more sensitive in detecting white matter (WM) anomalies in schizophrenia.Methods: 12 male patients with schizophrenia (mean age 35 +/-3 years) and 16 healthy male controls matched for age were scanned with a low b-value (1000 s/mm2) and a high b-value (4000 s/mm2) protocol. Apparent diffusion coefficient (ADC) is a measure of the average diffusion distance of water molecules per time unit (mm2/s). ADC maps were generated for all individuals. 8 region of interests (frontal and parietal region bilaterally, centrum semi-ovale bilaterally and anterior and posterior corpus callosum) were manually traced blind to diagnosis.Results: ADC measures acquired with high b-value imaging were more sensitive in detecting differences between schizophrenia patients and healthy controls than low b-value imaging with a gain in significance by a factor of 20- 100 times despite the lower image Signal-to-noise ratio (SNR). Increased ADC was identified in patient's WM (p=0.00015) with major contributions from left and right centrum semi-ovale and to a lesser extent right parietal region.Conclusions: Our results may be related to the sensitivity of high b-value imaging to the SDC believed to reflect mainly the intra-axonal and myelin bound water pool. High b-value imaging might be more sensitive and specific to WM anomalies in schizophrenia than low b-value imaging

Flujos de detritos recientes en la cordillera frontal de Mendoza: Un ejemplo de riesgo natural en la ruta 7 = Recent debris flows in the Frontal Cordillera of Mendoza: An example of natural risk on the Road 7

In this paper is presented a study dealing with the debris flows that reached the national road 7 in January 2005, in the km 1,118.5, Mendoza province. The area is located in the Frontal Cordillera near the limit of the Precordillera. A detailed geomorphologic map has been realized for this study using a Quickbird satellite imagery of the year 2006. Various calculations of volumes, velocities and peak discharges have been performed with the field data and using a geographic information system (GIS). The geomorphologic survey has permitted to propose three propagation scenarios in case of a new event. These allowed creating a map of debris flows susceptibility for the stretch of the road that has been studied. Finally, it has been proposed protection and mitigation measures, based on the results of the study, to protect the road from a new event.

Age-related differences on event-related potentials and brain rhythm oscillations during working memory activation.

Previous functional imaging studies have pointed to the compensatory recruitment of cortical circuits in old age in order to counterbalance the loss of neural efficiency and preserve cognitive performance. Recent electroencephalographic (EEG) analyses reported age-related deficits in the amplitude of an early positive-negative working memory (PN(wm)) component as well as changes in working memory (WM)-load related brain oscillations during the successful performance of the n-back task. To explore the age-related differences of EEG activation in the face of increasing WM demands, we assessed the PN(wm) component area, parietal alpha event-related synchronization (ERS) as well as frontal theta ERS in 32 young and 32 elderly healthy individuals who successfully performed a highly WM demanding 3-back task. PN(wm) area increased with higher memory loads (3- and 2-back > 0-back tasks) in younger subjects. Older subjects reached the maximal values for this EEG parameter during the less WM demanding 0-back task. They showed a rapid development of an alpha ERS that reached its maximal amplitude at around 800 ms after stimulus onset. In younger subjects, the late alpha ERS occurred between 1,200 and 2,000 ms and its amplitude was significantly higher compared with elders. Frontal theta ERS culmination peak decreased in a task-independent manner in older compared with younger cases. Only in younger individuals, there was a significant decrease in the phasic frontal theta ERS amplitude in the 2- and 3-back tasks compared with the detection and 0-back tasks. These observations suggest that older adults display a rapid mobilization of their neural generators within the parietal cortex to manage very low demanding WM tasks. Moreover, they are less able to activate frontal theta generators during attentional tasks compared with younger persons.

Maladie d'Alzheimer : Etude des marqueurs pathologiques dans le cortex frontal humain et corrélations anatomo-cliniques

La maladie d'Alzheimer (MA), forme de démence la plus fréquente, est caractérisée précocement par des troubles de la mémoire, puis par une détérioration cognitive progressive, corrélée avec la progression des lésions cérébrales que sont les dépôts de protéine ß-amyloïde, notamment dans les plaques séniles, et la dégénérescence neurofibrillaire qui touche en priorité les grands neurones pyramidaux de l'hippocampe et du cortex cérébral. La perte ou les dommages synaptiques sont aussi prépondérants et conduisent à la mort neuronale et à la perte de réseaux fonctionnels notamment au niveau des protéines présynaptiques comme la synaptophysine et postsynaptiques comme PSD-95 (Leuba et al. 2008), ainsi que des récepteurs NMDA (NMDAR) liés à PSD-95 et jouant un rôle prédominant dans le fonctionnement synaptique. Notre étude s'est portée une des régions du cortex frontal correspondant à l'aire de Brodmann 10, encore peu étudiée dans la littérature scientifique, qui peut être touchée de manière plus ou moins importante dans la MA, entraînant des troubles de l'humeur et du comportement ainsi que des répercussions sur les fonctions exécutives. L'étude a pour but d'identifier et de quantifier les dépôts de protéine ß-amyloïde et les lésions neurofibrillaires ainsi que les changements de protéines synaptiques et de récepteurs NMDA dans cette région entre une population contrôle et AD, et de la comparer avec d'autres régions déjà partiellement étudiées dans le laboratoire, notamment l'aire 9 qui lui est adjacente et les aires cingulaires 24 et 25. L'analyse est faite de manière qualitative et semi-quantitative au microscope optique sur des coupes colorées avec des méthodes immunohistochimiques. De possibles corrélations anatomo-cliniques sont recherchées dans les cas AD. La région FC10 est touchée par la MA avec une présence de plaques séniles et de dégénérescences neurofibrillaires plus marquées chez les cas atteints de la MA ce qui n'est pas le cas des protéines synaptiques. Le comportement des deux marqueurs pathologiques dans FC10 est comparable aux autres régions cérébrales étudiées notamment à la région adjacente, FC9, contrairement aux marqueurs synaptiques qui selon la région ont un comportement plus variable. L'effet de l'âge dans l'évolution de la physiopathologie de la MA pour les marqueurs pathologiques a été mis en évidence dans la région FC10. Les régions EC et FC9 n'ont pas montré de microhémorragie synonyme d'une possible contribution vasculaire. L'étude de cette région a permis de mettre en évidence l'implication de FC10 dans la MA. Elle montre des points communs avec les autres régions cérébrales notamment vis-à-vis des plaques séniles et des DNF.

The "handwriting brain": a meta-analysis of neuroimaging studies of motor versus orthographic processes.

INTRODUCTION: Handwriting is a modality of language production whose cerebral substrates remain poorly known although the existence of specific regions is postulated. The description of brain damaged patients with agraphia and, more recently, several neuroimaging studies suggest the involvement of different brain regions. However, results vary with the methodological choices made and may not always discriminate between "writing-specific" and motor or linguistic processes shared with other abilities. METHODS: We used the "Activation Likelihood Estimate" (ALE) meta-analytical method to identify the cerebral network of areas commonly activated during handwriting in 18 neuroimaging studies published in the literature. Included contrasts were also classified according to the control tasks used, whether non-specific motor/output-control or linguistic/input-control. These data were included in two secondary meta-analyses in order to reveal the functional role of the different areas of this network. RESULTS: An extensive, mainly left-hemisphere network of 12 cortical and sub-cortical areas was obtained; three of which were considered as primarily writing-specific (left superior frontal sulcus/middle frontal gyrus area, left intraparietal sulcus/superior parietal area, right cerebellum) while others related rather to non-specific motor (primary motor and sensorimotor cortex, supplementary motor area, thalamus and putamen) or linguistic processes (ventral premotor cortex, posterior/inferior temporal cortex). CONCLUSIONS: This meta-analysis provides a description of the cerebral network of handwriting as revealed by various types of neuroimaging experiments and confirms the crucial involvement of the left frontal and superior parietal regions. These findings provide new insights into cognitive processes involved in handwriting and their cerebral substrates.

Increased alpha activity and modulations of fronto-parietal balance during motor transitions in the elderly

A hallmark of aging is the sensorimotor deficit, characterized by an increased reaction time and a reduction of motor abilities. Some mechanisms such as motor inhibition deteriorate with aging because of neuronal density alterations and modifications of connections between brain regions. These deficits may be compensated throughout a recruitment of additional areas. Studies have shown that old adults have increased difficulty in performing bimanual coordination tasks compared with young adults. In contrast, motor switching is poorly documented and is expected to engage increasing resources in the elderly. The present study examines performances and electro-cortical correlates of motor switching in young and elderly adults.

Location-independent and location-linked representations of sound objects.

For the recognition of sounds to benefit perception and action, their neural representations should also encode their current spatial position and their changes in position over time. The dual-stream model of auditory processing postulates separate (albeit interacting) processing streams for sound meaning and for sound location. Using a repetition priming paradigm in conjunction with distributed source modeling of auditory evoked potentials, we determined how individual sound objects are represented within these streams. Changes in perceived location were induced by interaural intensity differences, and sound location was either held constant or shifted across initial and repeated presentations (from one hemispace to the other in the main experiment or between locations within the right hemispace in a follow-up experiment). Location-linked representations were characterized by differences in priming effects between pairs presented to the same vs. different simulated lateralizations. These effects were significant at 20-39 ms post-stimulus onset within a cluster on the posterior part of the left superior and middle temporal gyri; and at 143-162 ms within a cluster on the left inferior and middle frontal gyri. Location-independent representations were characterized by a difference between initial and repeated presentations, independently of whether or not their simulated lateralization was held constant across repetitions. This effect was significant at 42-63 ms within three clusters on the right temporo-frontal region; and at 165-215 ms in a large cluster on the left temporo-parietal convexity. Our results reveal two varieties of representations of sound objects within the ventral/What stream: one location-independent, as initially postulated in the dual-stream model, and the other location-linked.

Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein

We investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmann's area 9 from patients with Alzheimer's disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease. Presynaptic protein alpha-synuclein indicated an increased immunohistochemical level, while synaptophysin remained unchanged. MAP2, a somatodendritic microtubule protein, as well as AD markers such as amyloid-beta protein and phosphorylated protein tau showed an increased expression on immunosections in AD. Altogether these changes suggest neuritic and synaptic reorganization in the process of AD. In particular, the significant increase in PSD-95 expression suggests a change in NMDA receptors trafficking and may represent a novel marker of functional significance for the disease.

Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumors invading the parietal area. A case report

Primary objectives: Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. Methods and procedures: Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age¼44, SD¼6.9) were compared during simple uni- and bimanual reaction times (RTs). Main outcomes and results: Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. Conclusion and clinical implications: Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slowgrowing lesions.

Central control of glucose homeostasis: the brain--endocrine pancreas axis.

A large body of data gathered over the last decades has delineated the neuronal pathways that link the central nervous system with the autonomic innervation of the endocrine pancreas, which controls alpha- and beta-cell secretion activity and mass. These are important regulatory functions that are certainly keys for preserving the capacity of the endocrine pancreas to control glucose homeostasis over a lifetime. Identifying the cells involved in controlling the autonomic innervation of the endocrine pancreas, in response to nutrient, hormonal and environmental cues and how these cues are detected to activate neuronal activity are important goals of current research. Elucidation of these questions may possibly lead to new means for preserving or restoring defects in insulin and glucagon secretion associated with type 2 diabetes.

Clinical correlates of frontal intermittent rhythmic delta activity (FIRDA).

Objectives: To investigate the clinical correlates of frontal intermittent rhythmic delta activity (FIRDA). Methods: we prospectively assessed all EEG studies recorded in our center over 3 months for the presence of frontal intermittent rhythmic delta activity (FIRDA). The FIRDA group was compared with a randomly selected control group from among EEGs recorded during the same period. Comparisons among FIRDA and non-FIRDA groups were performed using uni- and multi-variate analyses. Results: We found 36 patients with FIRDA among 559 EEG recordings (6%); the control group consisted of 80 subjects. While epilepsy was more frequent in the control group, structural brain lesions and encephalopathy were independently associated with the occurrence of FIRDA, but we could not identify any specific etiology. Asymmetric FIRDA was associated with an underlying brain lesion. Occasionally, FIRDA was recorded in otherwise healthy subjects during hyperventilation. Conclusion: FIRDA appears more common than previously reported, and is associated with a wide range of lesions and encephalopathic conditions. Significance: FIRDA occurrence should prompt investigations for toxic-metabolic disturbances and for structural lesions (particularly if asymmetric), but does not suggest an epileptic predilection.

Subjective mental time: the functional architecture of projecting the self to past and future.

Abstract Human experience takes place in the line of mental time (MT) created through 'self-projection' of oneself to different time-points in the past or future. Here we manipulated self-projection in MT not only with respect to one's life events but also with respect to one's faces from different past and future time-points. Behavioural and event-related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time-points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re-experienced or pre-experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo-parietal and insular cortices. These behavioural and neural data suggest that self-projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.