Synapses, Synaptic Activity and Intraneuronal Aβ in Alzheimer's Disease

β-Amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer's disease. Aberrant β-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of β-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between β-amyloid and synapses became even tighter when it was discovered that β-amyloid accumulates within synapses and that synaptic activity modulates β-amyloid secretion. Currently, a central question in Alzheimer's disease research is what role synaptic activity plays in the disease process, and how specifically β-amyloid is involved in the synaptic dysfunction that characterizes the disease

PI and OPG/RANKL levels in human osteoblast cells

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effect of a timebase mismatch in two way optical frequency transfer

Two-way frequency transfer on optical fibers is a powerful technique for the comparison of distant clocks over long and ultra-long hauls. In contrast to traditional Doppler noise cancellation, it is capable of sustaining higher link attenuation, mitigating the need of optical amplification and regeneration and thus reducing the setup complexity. We investigate the ultimate limitations of the two-way approach on a 300 km multiplexed fiber haul, considering fully independent setups and acquisition systems at the two link ends. We derive a theoretical model to predict the performance deterioration due to a bad synchronisation of the measurements, which is confirmed by experimental results. This study demonstrates that two-way optical frequency transfer is a reliable and performing technique, capable of sustaining remote clocks comparisons at the resolution, and is relevant for the development of a fiber network of continental scale for frequency metrology in Europe

SATURN: A Technological Demonstration Mission for Distributed SAR Imaging

The OHB-Italia S.p.A-led consortium is in the midst of Phase B of SATURN (Synthetic AperTure radar cUbesat foRmation flyiNg), part of ALCOR, an Italian Space Agency (ASI) programme promoting the development of the next generation Italian CubeSats. SATURN is a demonstration mission that features Multiple-Input-Multiple-Output (MIMO) technology applied to a Swarm of CubeSats equipped with Synthetic Aperture Radar (SAR) for Earth Observation. MIMO is based on cooperative active sensors, where each one transmits signals and receives the illuminated common area backscatter related to the entire swarm, increasing measurement performances with a trend approximatively equal to the square of the number of sensors. The complete SATURN constellation features 16 mini-swarms, each of 3 CubeSats, spread over 4 SSOs equally spaced by 3 hours of local time. The constellation is designed to provide an average revisit time of 1.5 h and an interferometric revisit time of 1 day worldwide. The aim of this demonstration mission is to verify MIMO technology applied to SAR on a mini-swarm of 3 CubeSats in close formation on a Low Earth Down-Dusk Sun Synchronous Orbit. Using OHB-I’s M3Multi Mission Modular platform equipped with a miniaturized SAR Instrument, developed by ARESYS S.r.l. and Airbus Italia S.p.A., our mission is able to achieve a resolution of 5x5 m over a 30 km swath. Thus, SATURN enables low-cost, scalable SAR missions for affordable access to space for public and private entities, overcoming the single point of failure of one large and complex satellite. Subsequent swarms, deploying from 3 to 48 CubeSats, are expected to bring technological innovations and improve Italy’s competitiveness in the European and global Earth Observation scenario

Ultrastable laser interferometry for earthquake detection with terrestrial and submarine cables

Detecting ocean-floor seismic activity is crucial for our understanding of the interior structure and dynamic behavior of Earth. However, 70% of the planet’s surface is covered by water, and seismometer coverage is limited to a handful of permanent ocean bottom stations. We show that existing telecommunication optical fiber cables can detect seismic events when combined with state-of-the-art frequency metrology techniques by using the fiber itself as the sensing element. We detected earthquakes over terrestrial and submarine links with lengths ranging from 75 to 535 kilometers and a geographical distance from the earthquake’s epicenter ranging from 25 to 18,500 kilometers. Implementing a global seismic network for real-time detection of underwater earthquakes requires applying the proposed technique to the existing extensive submarine optical fiber network

Comparing Remote Atomic Clocks via VLBI Networks and Fiber Optic Links: the LIFT/MetGeSp Perspective

Very Long Baseline Interferometry experiments require an extremely precise synchronization between the atomic clocks keeping the time and frequency standards at radiotelescope observatories. Recently the availability of fiber optic links from a few radio observatories and their national metrological institutes has made the streaming of extremely stable frequency standards via optical atomic clocks possible (even two orders of magnitudes better than Rubidium or Hydrogen maser standards). Firstly, we present the infrastructure of the Italian Link for Frequency and Time (LIFT) and results of the MetGeSp project aimed at finally creating a common clock between two of the antennas of the VLBI Italian Network. Secondly, the results are shown from VLBI experiments in which the rms phase noise was used to accurately compare the synchronicity of atomic clocks located at a few European stations (Medicina, Noto, Yebes, Torun, and Matera). VLBI clock timing proves a valid alternative to satellite-based techniques such as the Global Navigation Satellite System or the Two-Way Satellite Time and Frequency Transfer

Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies

Synapses represent an important target of Alzheimer disease (AD), and alterations of their excitability are among the earliest changes associated with AD development. Synaptic activation has been shown to be protective in models of AD, and deep brain stimulation (DBS), a surgical strategy that modulates neuronal activity to treat neurological and psychiatric disorders, produced positive effects in AD patients. However, the molecular mechanisms underlying the protective role(s) of brain stimulation are still elusive. We have previously demonstrated that induction of synaptic activity exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing the macroautophagy/autophagy flux and lysosomal degradation of pathological MAPT/Tau. We now provide evidence that TFEB (transcription factor EB), a master regulator of lysosomal biogenesis and autophagy, is a key mediator of this cellular response. In cultured primary neurons from FTD-transgenic mice, synaptic stimulation inhibits MTORC1 signaling, thus promoting nuclear translocation of TFEB, which, in turn, induces clearance of MAPT/Tau oligomers. Conversely, synaptic activation fails to promote clearance of toxic MAPT/Tau in neurons expressing constitutively active RRAG GTPases, which sequester TFEB in the cytosol, or upon TFEB depletion. Activation of TFEB is also confirmed in vivo in DBS-stimulated AD mice. We also demonstrate that DBS reduces pathological MAPT/Tau and promotes neuroprotection in Parkinson disease patients with tauopathy. Altogether our findings indicate that stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau. This mechanism, underlying the protective effect of DBS, provides encouraging support for the use of synaptic stimulation as a therapeutic treatment against tauopathies.This work was supported by the ELKARTEK [KK-2020/00034]; Spanish Ministry of Science and Innovation [PID2019-109724RB-I00]; CIBERNED [CB06/0005/0076]; T.V. is supported by AIRC, IG 2017 #20661, and Italian Ministery of University and Research grant [PRIN2020CLZ5XWTV]

Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and b-amyloid (Ab)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer’s disease (AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Ab1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Ab-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Ab42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Ab-related synaptic dysfunctio

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: a voxel-based morphometry approach exploiting Monte Carlo simulations

Purpose: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. Methods: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. Results: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. Conclusions: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments