In perceptual experiments, within-individual fluctuations in perception are observed across multiple presentations of the same stimuli, a phenomenon that remains only partially understood. Here, by ...means of thulium-yttrium/aluminum-garnet laser and event-related functional MRI, we tested whether variability in perception of identical stimuli relates to differences in prestimulus, baseline brain activity. Results indicate a positive relationship between conscious perception of low-intensity somatosensory stimuli and immediately preceding levels of baseline activity in medial thalamus and the lateral frontoparietal network, respectively, which are thought to relate to vigilance and "external monitoring." Conversely, there was a negative correlation between subsequent reporting of conscious perception and baseline activity in a set of regions encompassing posterior cingulate/precuneus and temporoparietal cortices, possibly relating to introspection and self-oriented processes. At nociceptive levels of stimulation, pain-intensity ratings positively correlated with baseline fluctuations in anterior cingulate cortex in an area known to be involved in the affective dimension of pain. These results suggest that baseline brain-activity fluctuations may profoundly modify our conscious perception of the external world.
Maintenance of oral health is in part managed by the immune-surveillance and antimicrobial functions of polymorphonuclear leukocytes (PMNs), which migrate from the circulatory system through the oral ...mucosal tissues as oral PMNs (oPMNs). In any microorganism-rich ecosystem, such as the oral cavity, PMNs migrate toward various exogenous chemoattractants, phagocytose bacteria, and produce neutrophil extracellular traps (NETs) to immobilize and eliminate pathogens. PMNs obtained from the circulation through venipuncture (hereafter called cPMNs) have been widely studied using various functional assays. We aimed to study the potential of oPMNs in maintaining oral health and therefore compared their chemotactic and antimicrobial functions with cPMNs. To establish chemotactic, phagocytic, and NET forming capacities, oPMNs and cPMNs were isolated from healthy subjects without obvious oral inflammation. Directional chemotaxis toward the chemoattractant fMLP was analyzed using an Insall chamber and video microscopy. fMLP expression was assessed by flow cytometry. Phagocytosis was analyzed by flow cytometry, following PMN incubation with heat-inactivated FITC-labeled micro-organisms. Furthermore, agar plate-based killing assays were performed with
(
). NET formation by oPMNs and cPMNs was quantified fluorimetrically using SYTOX™ Green, following stimulation with either PMA or RPMI medium (unstimulated control). In contrast to cPMNs, the chemotactic responses of oPMNs to fMLP did not differ from controls (mean velocity ± SEM of cPMNs: 0.79 ± 0.24; of oPMNs; 0.10 ± 0.07 micrometer/min). The impaired directional movement toward fMLP by oPMNs was explained by significantly lower fMLP receptor expression. Increased adhesion and internalization of various micro-organisms by oPMNs was observed. oPMNs formed 13 times more NETs than stimulated cPMNs, in both unstimulated and stimulated conditions. Compared to cPMNs, oPMNs showed a limited ability for intracellular killing of
. In conclusion, oPMNs showed exhausted capacity for efficient chemotaxis toward fMLP which may be the result of migration through the oral tissues into the oral cavity, being a highly "hostile" ecosystem. Overall, oPMNs' behavior is consistent with hyperactivity and frustrated killing. Nevertheless, oPMNs most likely contribute to maintaining a balanced oral ecosystem, as their ability to internalize microbes in conjunction with their abundant NET production remains after entering the oral cavity.
Disentangling the vegetative state from the minimally conscious state is often difficult when relying only on behavioral observation. In this study, we explored a new active evoked-related potentials ...paradigm as an alternative method for the detection of voluntary brain activity.
The participants were 22 right-handed patients (10 traumatic) diagnosed as being in a vegetative state (VS) (n = 8) or in a minimally conscious state (MCS) (n = 14). They were presented sequences of names containing the patient's own name or other names, in both passive and active conditions. In the active condition, the patients were instructed to count her or his own name or to count another target name.
Like controls, MCS patients presented a larger P3 to the patient's own name, in the passive and in the active conditions. Moreover, the P3 to target stimuli was higher in the active than in the passive condition, suggesting voluntary compliance to task instructions like controls. These responses were even observed in patients with low behavioral responses (e.g., visual fixation and pursuit). In contrast, no P3 differences between passive and active conditions were observed for VS patients.
The present results suggest that active evoked-related potentials paradigms may permit detection of voluntary brain function in patients with severe brain damage who present with a disorder of consciousness, even when the patient may present with very limited to questionably any signs of awareness.
Macrophage surface receptors are critical for pathogen defense, as they are the gatekeepers for pathogen entry and sensing, which trigger robust immune responses. TREM2 (triggering receptor expressed ...on myeloid cells 2) is a transmembrane surface receptor that mediates anti-inflammatory immune signaling. A recent study showed that TREM2 is a receptor for mycolic acids in the mycobacterial cell wall and inhibits macrophage activation. However, the underlying functional mechanism of how TREM2 regulates the macrophage antimycobacterial response remains unclear. Here, we show that Mycobacterium tuberculosis, the causative agent for tuberculosis, specifically binds to human TREM2 to disable the macrophage antibacterial response. Live but not killed mycobacteria specifically trigger the upregulation of TREM2 during macrophage infection through a mechanism dependent on STING (the stimulator of interferon genes). TREM2 facilitated uptake of M. tuberculosis into macrophages and is responsible for blocking the production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and reactive oxygen species (ROS), while enhancing the production of interferon-β (IFN-β) and IL-10. TREM2-mediated blockade of ROS production promoted the survival of M. tuberculosis within infected macrophages. Consistent with this, genetic deletion or antibody-mediated neutralization of TREM2 reduced the intracellular survival of M. tuberculosis through enhanced production of ROS. Importantly, inhibition of type I IFN signaling in TREM2-overexpressing macrophages restored the ability of these cells to produce inflammatory cytokines and ROS, resulting in normal levels of intracellular bacteria killing. Collectively, our study identifies TREM2 as an attractive host receptor for host-directed antimycobacterial therapeutics. IMPORTANCE Mycobacterium tuberculosis is one of the most ancient bacterial pathogens and remains the leading cause of death from a single bacterial agent. The success of M. tuberculosis relies greatly on its ability to parasitize and disable its host macrophages. Previous studies have found that M. tuberculosis uses its unique cell wall lipids to manipulate the immune response by binding to specific surface receptors on macrophages. Our study reveals that M. tuberculosis binds to TREM2, an immunomodulatory receptor expressed on macrophages, to facilitate a “silent” mode of entry. Increased levels of TREM2 triggered by intracellular sensing of M. tuberculosis promoted the intracellular survival of M. tuberculosis through type I IFN-driven inhibition of reactive oxygen species (ROS) and proinflammatory cytokine production. Importantly, deletion of TREM2 reversed the effects of “silent” entry and resulted in increased production of inflammatory cytokines, generation of ROS, and cell death. As such, antibody-mediated or pharmacological targeting of TREM2 could be a promising strategy for novel treatments against M. tuberculosis infection.
The assessment of voluntary behavior in non-communicative brain injured patients is often challenging due to the existence of profound motor impairment. In the absence of a full understanding of the ...neural correlates of consciousness, even a normal activation in response to passive sensory stimulation cannot be considered as proof of the presence of awareness in these patients. In contrast, predicted activation in response to the instruction to perform a mental imagery task would provide evidence of voluntary task-dependent brain activity, and hence of consciousness, in non-communicative patients. However, no data yet exist to indicate which imagery instructions would yield reliable single subject activation. The aim of the present study was to establish such a paradigm in healthy volunteers. Two exploratory experiments evaluated the reproducibility of individual brain activation elicited by four distinct mental imagery tasks. The two most robust mental imagery tasks were found to be spatial navigation and motor imagery. In a third experiment, where these two tasks were directly compared, differentiation of each task from one another and from rest periods was assessed blindly using a priori criteria and was correct for every volunteer. The spatial navigation and motor imagery tasks described here permit the identification of volitional brain activation at the single subject level, without a motor response. Volunteer as well as patient data Owen, A.M., Coleman, M.R., Boly, M., Davis, M.H., Laureys, S., Pickard J.D., 2006. Detecting awareness in the vegetative state. Science 313, 1402 strongly suggest that this paradigm may provide a method for assessing the presence of volitional brain activity, and thus of consciousness, in non-communicative brain-injured patients.
Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain-behavior ...relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto-cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level-dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark.
MicroRNAs tune cerebral cortical neurogenesis Volvert, M-L; Rogister, F; Moonen, G ...
Cell death and differentiation,
10/2012, Letnik:
19, Številka:
10
Journal Article, Web Resource
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MicroRNAs (miRNAs) are non-coding RNAs that promote post-transcriptional silencing of genes involved in a wide range of developmental and pathological processes. It is estimated that most ...protein-coding genes harbor miRNA recognition sequences in their 3' untranslated region and are thus putative targets. While functions of miRNAs have been extensively characterized in various tissues, their multiple contributions to cerebral cortical development are just beginning to be unveiled. This review aims to outline the evidence collected to date demonstrating a role for miRNAs in cerebral corticogenesis with a particular emphasis on pathways that control the birth and maturation of functional excitatory projection neurons.
Bone marrow stromal cells can differentiate into many types of mesenchymal cells, i.e. osteocyte, chondrocyte and adipocyte, but can also differentiate into non-mesenchymal cells, i.e. neural cells ...under appropriate in vivo experimental conditions (Kopen et al., 1999; Brazelton et al., 2000; Mezey et al., 2000). This neural phenotypic plasticity allows us to consider the utilization of mesenchymal stem cells as cellular material in regenerative medicine. In this study, we demonstrate that cultured adult rat stromal cells can express nestin, an intermediate filament protein predominantly expressed by neural stem cells. Two factors contribute to the regulation of nestin expression by rat stromal cells: serum in the culture medium inhibits nestin expression and a threshold number of passages must be reached below which nestin expression does not occur. Only nestin-positive rat stromal cells are able to form spheres when they are placed in the culture conditions used for neural stem cells. Likewise, only nestin-positive stromal cells are able to differentiate into GFAP (glial fibrillary acidic protein)-positive cells when they are co-cultivated with neural stem cells. We thus demonstrated that adult rat stromal cells in culture express nestin in absence of serum after passaging the cells at least ten times, and we suggest that nestin expression by these cells might be a prerequisite for the acquisition of the capacity to progress towards the neural lineage.
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