Auditory Resting-State Network Connectivity in Tinnitus: A Functional MRI Study

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI “resting-state” connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress leading to disabling chronic tinnitus

Autophagy Interplay with Apoptosis and Cell Cycle Regulation in the Growth Inhibiting Effect of Resveratrol in Glioma Cells

Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv

'Gut health': a new objective in medicine?

'Gut health' is a term increasingly used in the medical literature and by the food industry. It covers multiple positive aspects of the gastrointestinal (GI) tract, such as the effective digestion and absorption of food, the absence of GI illness, normal and stable intestinal microbiota, effective immune status and a state of well-being. From a scientific point of view, however, it is still extremely unclear exactly what gut health is, how it can be defined and how it can be measured. The GI barrier adjacent to the GI microbiota appears to be the key to understanding the complex mechanisms that maintain gut health. Any impairment of the GI barrier can increase the risk of developing infectious, inflammatory and functional GI diseases, as well as extraintestinal diseases such as immune-mediated and metabolic disorders. Less clear, however, is whether GI discomfort in general can also be related to GI barrier functions. In any case, methods of assessing, improving and maintaining gut health-related GI functions are of major interest in preventive medicine

Leader-Containing Uncapped Viral Transcript Activates RIG-I in Antiviral Stress Granules

[Correction]5 Apr 2016: Oh SW, Onomoto K, Wakimoto M, Onoguchi K, Ishidate F, et al. (2016) Correction: Leader-Containing Uncapped Viral Transcript Activates RIG-I in Antiviral Stress Granules. PLOS Pathogens 12(4): e1005563. https://doi.org/10.1371/journal.ppat.1005563RIG-I triggers antiviral responses by recognizing viral RNA (vRNA) in the cytoplasm. However, the spatio-temporal dynamics of vRNA sensing and signal transduction remain elusive. We investigated the time course of events in cells infected with Newcastle disease virus (NDV), a non-segmented negative-strand RNA virus. RIG-I was recruited to viral replication complexes (vRC) and triggered minimal primary type I interferon (IFN) production. RIG-I subsequently localized to antiviral stress granules (avSG) induced after vRC formation. The inhibition of avSG attenuated secondary IFN production, suggesting avSG as a platform for efficient vRNA detection. avSG selectively captured positive-strand vRNA, and poly(A)+ RNA induced IFN production. Further investigations suggested that uncapped vRNA derived from read-through transcription was sensed by RIG-I in avSG. These results highlight how viral infections stimulate host stress responses, thereby selectively recruiting uncapped vRNA to avSG, in which RIG-I and other components cooperate in an efficient antiviral program

SEISMIC REFLECTORS AND UNCONFORMITIES AT PASSIVE CONTINENTAL MARGINS

Vail and co-workers1-3 have recently suggested, based on seismic reflection data available to Exxon, that more than 25 global unconformities occur in Mesozoic-Tertiary age passive continental margins around the world. These data have been used to subdivide the stratigraphical record into several cycles, each of which is controlled by oscillatory changes in sea-level. The resulting scheme has been used as a basis to predict the stratigraphy of passive margins where there is little or no well control4 or where few reflector terminations can be found5. We report here four difficulties with this scheme: (1) during times of minimal continental ice cover changes in the relative rate of sea-level are generally not sufficient to cause unconformities, except in old, slowly subsiding, margins; (2) seismic and biostratigraphical resolution restricts the identification of unconformity-bounded stratigraphical sequences to relatively few in continental shelves; (3) sequence boundaries appear to be best defined on slopes or in regions of active tectonic tilting; and (4) limitations in the sequence analysis technique preclude its use in predictive stratigraphy, especially in shelf and slope regions of margins. © 1984 Nature Publishing Group

Variability Management and Assessment for User Interface Design

User Interface (UI) design remains an open, wicked, complex and multi-faceted problem, owing to the ever increasing variability of design options resulting from multiple contexts of use, i.e., various end-users, heterogeneous devices and computing platforms, as well as their varying environments. Designing multiple UIs for multiple contexts of use inevitably requires an ever growing amount of time and resources that not all organizations are able to afford. Moreover, UI design choices stand on end-users’ needs elicitation, which are recognized to be difficult to evaluate precisely upfront and which require iterative design cycles. All this complex variability should be managed efficiently to maintain time and resources to an acceptable level. To address these challenges, this article proposes a variability management approach integrated into a UI rapid prototyping process, which involves the combination of Model-Driven Engineering, Software Product Lines and Interactive Genetic Algorithms