Dem-Aging: autophagy-related pathologies and the "two faces of dementia".

Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies.

Daily rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability.

Cortical activity patterns are strongly modulated by fast synaptic inhibition mediated through ionotropic, chloride-conducting receptors. Consequently, chloride homeostasis is ideally placed to regulate activity. We therefore investigated the stability of baseline [Cl] in adult mouse neocortex, using in vivo two-photon imaging.

Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2.

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5.

Non-Small Cell Lung Cancer With N1 Involvement or Skip Metastases Presents the Same Survival Outcome: Results From a Multicentric Study.

Background: The prognostic difference among patients affected by NSCLC with hilar metastases only or mediastinal nodes metastases without hilar involvement (skip metastases) is still unclear. Aim of this study is to analyse if prognostic difference are present or if the two groups present the same survival outcome.

Materials And Methods: Data on NSCLC patients from 7 high volume centres (2004-2014) were collected and retrospectively reviewed.

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel.

Microglial extracellular vesicles induce Alzheimer's disease-related cortico-hippocampal network dysfunction.

β-Amyloid is one of the main pathological hallmarks of Alzheimer's disease and plays a major role in synaptic dysfunction. It has been demonstrated that β-amyloid can elicit aberrant excitatory activity in cortical-hippocampal networks, which is associated with behavioural abnormalities. However, the mechanism of the spreading of β-amyloid action within a specific circuitry has not been elucidated yet.

Control of circadian rhythm on cortical excitability and synaptic plasticity.

Living organisms navigate through a cyclic world: activity, feeding, social interactions are all organized along the periodic succession of night and day. At the cellular level, periodic activity is controlled by the molecular machinery driving the circadian regulation of cellular homeostasis. This mechanism adapts cell function to the external environment and its crucial importance is underlined by its robustness and redundancy.

Advancing the scientific study of prehospital mass casualty response through a Translational Science process: the T1 scoping literature review stage.

Purpose: The European Union Horizon 2020 research and innovation funding program awarded the NIGHTINGALE grant to develop a toolkit to support first responders engaged in prehospital (PH) mass casualty incident (MCI) response. To reach the projects' objectives, the NIGHTINGALE consortium used a Translational Science (TS) process. The present work is the first TS stage (T1) aimed to extract data relevant for the subsequent modified Delphi study (T2) statements.

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex.

Ample evidence indicates that environmental stress impairs information processing, yet the underlying mechanisms remain partially elusive. We showed that, in several rodent models of psychopathology, the neurosteroid allopregnanolone (AP) reduces the prepulse inhibition (PPI) of the startle, a well-validated index of sensorimotor gating. Since this GABA receptor activator is synthesized in response to acute stress, we hypothesized its participation in stress-induced PPI deficits.

A Superfolder Green Fluorescent Protein-Based Biosensor Allows Monitoring of Chloride in the Endoplasmic Reticulum.

Though the concentration of chloride has been measured in the cytoplasm and in secretory granules of live cells, it cannot be measured within the endoplasmic reticulum (ER) due to poor fluorescence of existing biosensors. We developed a fluorescent biosensor composed of a chloride-sensitive superfolder GFP and long Stokes-shifted mKate2 for simultaneous chloride and pH measurements that retained fluorescence in the ER lumen. Using this sensor, we showed that the chloride concentration in the ER is significantly lower than that in the cytosol.

Trehalose Treatment in Zebrafish Model of Lafora Disease.

Mutations in the gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD.

Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder.

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown.

Genetically encoded sensors for Chloride concentration.

Insights into chloride regulation in neurons have come slowly, but they are likely to be critical for our understanding of how the brain works. The reason is that the intracellular Cl level ([Cl]) is the key determinant of synaptic inhibitory function, and this in turn dictates all manner of neuronal network function. The true impact on the network will only be apparent, however, if Cl is measured at many locations at once (multiple neurons, and also across the subcellular compartments of single neurons), which realistically, can only be achieved using imaging.

Validation of a prognostic model including the number of harvested lymph-nodes in the setting of non-small cell lung cancer patients undergoing curative resection: a multicenter analysis.

Background: The prognostic role of the extension of lymphadenectomy in non-small-cell lung cancer is still a debated and intriguing issue. The aim of this study is to validate a prognostic score including the number of resected lymph-nodes previously reported using a large multicenter dataset.

Methods: From 01/2002 to 12/2012, data on 4858 NSCLC patients undergoing curative-intent surgery in six institutions were retrospectively reviewed.

Survival Analysis in Single N2 Station Lung Adenocarcinoma: The Prognostic Role of Involved Lymph Nodes and Adjuvant Therapy.

Background: Prognostic factors in patients with single mediastinal station (sN2) involvement continues to be a debated issue.

Methods: Data on 213 adenocarcinoma patients with sN2 involvement and who had undergone complete anatomical lung resection and lymphadenectomy, were retrospectively reviewed. Clinical and pathological characteristics together with adjuvant therapy (AD) and node (N) status classifications (number of resected nodes (#RN), number of metastatic nodes (#MN), and node ratio (#MN/#RN = NR) were analyzed.

Altered Cl homeostasis hinders forebrain GABAergic interneuron migration in a mouse model of intellectual disability.

Impairments of inhibitory circuits are at the basis of most, if not all, cognitive deficits. The impact of OPHN1, a gene associate with intellectual disability (ID), on inhibitory neurons remains elusive. We addressed this issue by analyzing the postnatal migration of inhibitory interneurons derived from the subventricular zone in a validated mouse model of ID (OPHN1 mice).

detection of murine glioblastoma through Raman and reflectance fiber-probe spectroscopies.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. With a worldwide incidence rate of 2 to 3 per 100,000 people, it accounts for more than 60% of all brain cancers; currently, its 5-year survival rate is . GBM treatment relies mainly on surgical resection.

Modelling genetic mosaicism of neurodevelopmental disorders in vivo by a Cre-amplifying fluorescent reporter.

Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of these diseases and of the cell-autonomous effects of specific mutations requires the generation of sparse mosaic models, in which the genotype of each neuron is univocally identified by the expression of a fluorescent protein in vivo. Here, we show a dual-color reporter system that, when expressed in a floxed mouse line for a target gene, leads to the creation of mosaics with tunable degree.

External validation of the N descriptor in the proposed tumour-node-metastasis subclassification for lung cancer: the crucial role of histological type, number of resected nodes and adjuvant therapy.

Objectives: Overlapping survival curves for N1b (multiple N1 stations), N2a2 (single N2 station + N1 involvement) and N2a1 (skip N2 metastasis) limit the current tumour-node-metastasis (TNM) node (N) subclassification for node involvement. We validated externally the proposed subclassification.

Methods: Clinical records from a multicentric database comprising 1036 patients with pulmonary adenocarcinoma (ADC) or squamous cell carcinoma with N1/N2 involvement who underwent, from January 2002 to December 2014, complete lung resections were retrospectively reviewed.

Prognostic score for survival with pulmonary carcinoids: the importance of associating clinical with pathological characteristics.

Objectives: Lung carcinoids (LCs) are staged using the non-small-cell lung cancer tumour/node/metastasis staging system; the possibility of an LC-specific staging system is still being debated. The goal of our study was to construct a composite prognostic score for LC.

Methods: From January 2002 to December 2014, data from 293 patients who underwent surgical treatment for LC in 7 research institutes were retrospectively analysed.

Mediastinal Up-Staging During Surgery in Non-Small-Cell Lung Cancer: Which Mediastinal Lymph Node Metastasis Patterns Better Predict The Outcome? A Multicenter Analysis.

Background: Unexpected N2 involvement occurs in approximately 10% to 20% of patients with non-small-cell lung cancer (NSCLC) and patients' prognostic factors remain unclear. The aim of this study was to evaluate prognostic factors in these patients.

Methods: From January 2002 to December 2012, we retrospectively analyzed data of 550 patients with NSCLC with preoperative negative, but pathologic positive N2 involvement, who underwent anatomical lung resection and hilo-mediastinal lymphadenectomy, obtained from 6 institutions.

Evolution of Epileptiform Activity in Zebrafish by Statistical-Based Integration of Electrophysiology and 2-Photon Ca Imaging.

The study of sources and spatiotemporal evolution of ictal bursts is critical for the mechanistic understanding of epilepsy and for the validation of anti-epileptic drugs. Zebrafish is a powerful vertebrate model representing an excellent compromise between system complexity and experimental accessibility. We performed the quantitative evaluation of the spatial recruitment of neuronal populations during physiological and pathological activity by combining local field potential (LFP) recordings with simultaneous 2-photon Ca imaging.

Transient Cognitive Impairment in Epilepsy.

Impairments of the dialog between excitation and inhibition (E/I) is commonly associated to neuropsychiatric disorders like autism, bipolar disorders and epilepsy. Moderate levels of hyperexcitability can lead to mild alterations of the EEG and are often associated with cognitive deficits even in the absence of overt seizures. Indeed, various testing paradigms have shown degraded performances in presence of acute or chronic non-ictal epileptiform activity.