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Titanium and titanium nitride layers were alternately sputtered on a high resistivity silicon wafer to obtain a multilayer film structure, for a total thickness ranging between 34 and 180 nm. The electrical resistance of the Ti/TiN film was characterized from room temperature down to the superconducting transition. Both the resistivity just above the transition and the critical temperature were investigated as a function of the total film thickness and the single TiN layer thickness, respectively. The obtained resistivity range is 67–312 μΩ cm. Exploiting the proximity effect, we were able to tune the critical temperature in the 0.29–4.5 K range. A comparison between experimental data and theoretical models is proposed in order to facilitate the a priori design of superconducting detectors. [ABSTRACT FROM AUTHOR]

We present a method to search for transient gravitational waves using a network of detectors with different spectral and directional sensitivities: the interferometer Virgo and the bar detector AURIGA. The data analysis method is based on the measurements of the correlated energy in the network by means of a weighted cross-correlation. To limit the computational load, this coherent analysis step is performed around time-frequency coincident triggers selected by an excess power event trigger generator tuned at low thresholds. The final selection of gravitational wave candidates is performed by a combined cut on the correlated energy and on the significance as measured by the event trigger generator. The method has been tested on one day of data of AURIGA and Virgo during September 2005. The outcomes are compared to the results of a stand-alone time-frequency coincidence search. We discuss the advantages and the limits of this approach, in view of a possible future joint search between AURIGA and one interferometric detector. [ABSTRACT FROM AUTHOR]

The first simultaneous operation of the AURIGA detector and the LIGO observatory was an opportunity to explore real data, joint analysis methods between two very different types of gravitational wave detectors: resonant bars and interferometers. This paper describes a coincident gravitational wave burst search, where data from the LIGO interferometers are cross-correlated at the time of AURIGA candidate events to identify coincident transients. The analysis pipeline is tuned with two thresholds, on the signal-to-noise ratio of AURIGA candidate events and on the significance of the cross-correlation test in LIGO. The false alarm rate is estimated by introducing time shifts between data sets and the network detection efficiency is measured by adding simulated gravitational wave signals to the detector output. The simulated waveforms have a significant fraction of power in the narrower AURIGA band. In the absence of a detection, we discuss how to set an upper limit on the rate of gravitational waves and to interpret it according to different source models. Due to the short amount of analyzed data and to the high rate of non-Gaussian transients in the detectors' noise at the time, the relevance of this study is methodological: this was the first joint search for gravitational wave bursts among detectors with such different spectral sensitivity and the first opportunity for the resonant and interferometric communities to unify languages and techniques in the pursuit of their common goal. [ABSTRACT FROM AUTHOR]

Krabbe disease (KD) is a genetic disorder caused by the absence of the galactosylceramidase (GALC) functional enzyme. No cure is currently available. Here, we investigate the mechanotransduction process in primary fibroblasts collected from the twitcher mouse, a natural KD murine model. Thanks to mechanotransduction, cells can sense their environment and convert external mechanical stimuli into biochemical signals that result in intracellular changes. In GALC-deficient fibroblasts, we show that focal adhesions (FAs), the protein clusters necessary to adhere and migrate, are increased, and that single-cell migration and wound healing are impaired. We also investigate the involvement of the autophagic process in this framework. We show a dysregulation in the FA turnover: here, the treatment with the autophagy activator rapamycin boosts cell migration and improves the clearance of FAs in GALC-deficient fibroblasts. We propose mechanosensing impairment as a novel potential pathological mechanism in twitcher fibroblasts, and more in general in Krabbe disease.

Lysosomal storage disorders (LSDs) are a vast group of more than 50 clinically identified metabolic diseases. They are singly rare, but they affect collectively 1 on 5,000 live births. They result in most of the cases from an enzymatic defect within lysosomes, which causes the subsequent augmentation of unwanted substrates. This accumulation process leads to plenty of clinical signs, determined by the specific substrate and accumulation area. The majority of LSDs present a broad organ and tissue engagement. Brain, connective tissues, viscera and bones are usually afflicted. Among them, brain disease is markedly frequent (two-thirds of LSDs). The most clinically employed approach to treat LSDs is enzyme replacement therapy (ERT), which is practiced by administering systemically the missed or defective enzyme. It represents a healthful strategy for 11 LSDs at the moment, but it solves the pathology only in the case of Gaucher disease. This approach, in fact, is not efficacious in the case of LSDs that have an effect on the central nervous system (CNS) due to the existence of the blood-brain barrier (BBB). Additionally, ERT suffers from several other weak points, such as low penetration of the exogenously administered enzyme to poorly vascularized areas, the development of immunogenicity and infusion-associated reactions (IARs), and, last but not least, the very high cost and lifelong needed. To ameliorate these weaknesses lot of efforts have been recently spent around the development of innovative nanotechnology-driven ERT strategies. They may boost the power of ERT and minimize adverse reactions by loading enzymes into biodegradable nanomaterials. Enzyme encapsulation into biocompatible liposomes, micelles, and polymeric nanoparticles, for example, can protect enzymatic activity, eliminating immunologic reactions and premature enzyme degradation. It can also permit a controlled release of the payload, ameliorating pharmacokinetics and pharmacodynamics of the drug. Additionally, the potential to functionalize the surface of the nanocarrier with targeting agents (antibodies or peptides), could promote the passage through biological barriers. In this review we examined the clinically applied ERTs, highlighting limitations that do not allow to completely cure the specific LSD. Later, we critically consider the nanotechnology-based ERT strategies that have beenin-vitroand/orin-vivotested to improve ERT efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca 2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9-25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

Peripheral nerve injuries are a common condition in which a nerve is damaged, affecting more than one million people every year. There are still no efficient therapeutic treatments for these injuries. Artificial scaffolds can offer new opportunities for nerve regeneration applications; in this framework, chitosan is emerging as a promising biomaterial. Here, we set up a simple and effective method for the production of micro-structured chitosan films by solvent casting, with high fidelity in the micro-pattern reproducibility. Three types of chitosan directional micro-grooved patterns, presenting different levels of symmetricity, were developed for application in nerve regenerative medicine: gratings (GR), isosceles triangles (ISO) and scalene triangles (SCA). The directional patterns were tested with a Schwann cell line. The most asymmetric topography (SCA), although it polarized the cell shaping less efficiently, promoted higher cell proliferation and a faster cell migration, both individually and collectively, with a higher directional persistence of motion. Overall, the use of micro-structured asymmetrical directional topographies may be exploited to enhance the nerve regeneration process mediated by chitosan scaffolds.

During neuronal development, neuronal cells read extracellular stimuli from the micro/nano-environment within which they exist, retrieving essential directionality and wiring information. Here, focal adhesions (FAs-protein clusters anchoring integrins to cytoskeleton) act as sensors, by integrating signals from both the extracellular matrix environment and chemotactic factors, contributing to the final neuronal pathfinding and migration. In the processes that orchestrate neuronal development, the important function of ubiquitin E3A ligase (UBE3A) is emerging. UBE3A has crucial functions in the brain and changes in its expression levels lead to neurodevelopmental disorders: the lack of UBE3A leads to Angelman syndrome (AS, OMIN 105830), while its increase causes autisms (Dup15q-autism). By using nano/micro-structured anisotropic substrates we previously showed that UBE3A-deficient neurons have deficits in contact guidance (Tonazzini et al, Mol Autism 2019). Here, we investigate the adhesion and migration dynamics of UBE3A-silenced SH-SY5Y neuroblastoma cells in vitro by exploiting nano/micro-grooved substrates. We analyze the molecular processes regulating the development of FAs by transfection with EGFP-vector encoding for paxillin, a protein of FA clusters, and by live-cell total-internal-reflection-fluorescence microscopy. We show that UBE3A-silenced SH-SY5Y cells have impaired FA morphological development and pathway activation, which lead to a delayed adhesion and also explain the defective contact guidance in response to directional topographical stimuli. However, UBE3A-silenced SH-SY5Y cells show an overall normal migration behavior, in terms of speed and ability to follow the GRs directional stimulus. Only the collective cell migration upon cell gaps was slightly delayed for UBE3Ash SHs. Overall, the deficits of UBE3Ash SHS-SY5Y cells in FA maturation/sensing and in collective migration may have patho-physiological implications, in AS condition, considering the much more complex stimuli that neurons find in vivo during the neurodevelopment.

Despite the unquestionable empirical success of quantum theory, witnessed by the recent uprising of quantum technologies, the debate on how to reconcile the theory with the macroscopic classical world is still open. Spontaneous collapse models are one of the few testable solutions so far proposed. In particular, the continuous spontaneous localization (CSL) model has become subject of intense experimental research. Experiments looking for the universal force noise predicted by CSL in ultrasensitive mechanical resonators have recently set the strongest unambiguous bounds on CSL. Further improving these experiments by direct reduction of mechanical noise is technically challenging. Here, we implement a recently proposed alternative strategy that aims at enhancing the CSL noise by exploiting a multilayer test mass attached on a high quality factor microcantilever. The test mass is specifically designed to enhance the effect of CSL noise at the characteristic length r_{c}=10^{-7}  m. The measurements are in good agreement with pure thermal motion for temperatures down to 100 mK. From the absence of excess noise, we infer a new bound on the collapse rate at the characteristic length r_{c}=10^{-7}  m, which improves over previous mechanical experiments by more than 1 order of magnitude. Our results explicitly challenge a well-motivated region of the CSL parameter space proposed by Adler.

Regenerative medicine is continuously facing new challenges and it is searching for new biocompatible, green/natural polymer materials, possibly biodegradable and non-immunogenic. Moreover, the critical importance of the nano/microstructuring of surfaces is overall accepted for their full biocompatibility and in vitro/in vivo performances. Chitosan is emerging as a promising biopolymer for tissue engineering and its application can be further improved by exploiting its nano/microstructuration. Here, we report the state of the art of chitosan films and scaffolds nano/micro-structuration. We show that it is possible to obtain, by solvent casting, chitosan thin films with good mechanical properties and to structure them at the microscale and even nanoscale level, with resolutions down to 100 nm.

Spontaneous collapse models predict that a weak force noise acts on any mechanical system, as a consequence of the collapse of the wave function. Significant upper limits on the collapse rate have been recently inferred from precision mechanical experiments, such as ultracold cantilevers and the space mission LISA Pathfinder. Here, we report new results from an experiment based on a high-Q cantilever cooled to millikelvin temperatures, which is potentially able to improve the current bounds on the continuous spontaneous localization (CSL) model by 1 order of magnitude. High accuracy measurements of the cantilever thermal fluctuations reveal a nonthermal force noise of unknown origin. This excess noise is compatible with the CSL heating predicted by Adler. Several physical mechanisms able to explain the observed noise have been ruled out.

A search for a new scalar field, called moduli, has been performed using the cryogenic resonant-mass AURIGA detector. Predicted by string theory, moduli may provide a significant contribution to the dark matter (DM) component of our Universe. If this is the case, the interaction of ordinary matter with the local DM moduli, forming the Galaxy halo, will cause an oscillation of solid bodies with a frequency corresponding to the mass of moduli. In the sensitive band of AURIGA, some 100 Hz at around 1 kHz, the expected signal, with Q=△f/f∼10^{6}, is a narrow peak, △f∼1  mHz. Here the detector strain sensitivity is h_{s}∼2×10^{-21}  Hz^{-1/2}, within a factor of 2. These numbers translate to upper limits at 95% C.L. on the moduli coupling to ordinary matter (d_{e}+d_{m_{e}})≲10^{-5} around masses m_{ϕ}=3.6×10^{-12}  eV, for the standard DM halo model with ρ_{DM}=0.3  GeV/cm^{3}.

Superconducting Quantum Interference Device (SQUID) microsusceptometers have been widely used to study magnetic properties of materials at microscale. As intrinsically balanced devices, they could also be exploited for direct SQUID-detection of nuclear magnetic resonance (NMR) from micron sized samples, or for SQUID readout of mechanically detected NMR from submicron sized samples. Here, we demonstrate a double balancing technique that enables achievement of very low residual imbalance of a SQUID microsusceptometer over a wide bandwidth. In particular, we can generate ac magnetic fields within the SQUID loop as large as 1 mT, for frequencies ranging from dc up to a few MHz. As an application, we demonstrate direct detection of NMR from (1)H spins in a glycerol droplet placed directly on top of the 20 μm SQUID loops.

We analyze heat and work fluctuations in the gravitational wave detector AURIGA, modeled as a macroscopic electromechanical oscillator in contact with a thermostat and cooled by an active feedback system. The oscillator is driven to a steady state by the feedback cooling, equivalent to a viscous force. The experimentally measured fluctuations are in agreement with our theoretical analysis based on a stochastically driven Langevin system. The asymmetry of the fluctuations of the absorbed heat characterizes the oscillator's nonequilibrium steady state and reveals the extent to which a feedback cooled system departs from equilibrium in a statistical mechanics perspective.

We apply a feedback cooling technique to simultaneously cool the three electromechanical normal modes of the ton-scale resonant-bar gravitational wave detector AURIGA. The measuring system is based on a dc superconducting quantum interference device (SQUID) amplifier, and the feedback cooling is applied electronically to the input circuit of the SQUID. Starting from a bath temperature of 4.2 K, we achieve a minimum temperature of 0.17 mK for the coolest normal mode. The same technique, implemented in a dedicated experiment at subkelvin bath temperature and with a quantum limited SQUID, could allow to approach the quantum ground state of a kilogram-scale mechanical resonator.

At the time when the giant flare of SGR1806-20 occurred, the AURIGA "bar" gravitational-wave (GW) detector was on the air with a noise performance close to stationary Gaussian. This allows us to set relevant upper limits, at a number of frequencies in the vicinities of 900 Hz, on the amplitude of the damped GW wave trains, which, according to current models, could have been emitted, due to the excitation of normal modes of the star associated with the peak in x-ray luminosity.

A randomized controlled study has been carried out in order to check the activity of caerulein in the treatment of biliary and renal colic. In 88% out of 107 patients caerulein, 1 ng/kg IV, relieved biliary colic and had no side effects. To elucidate the mechanism of action of the peptide, 22 cholecystectomized patients, showing a dilation of the common bile duct (CBD), were submitted to caerulein treatment under echo-control. Reduction of CBD caliber was noticed when the dilatation was due to functional obstruction, whereas an organic obstruction of the terminal tract of CBD was found in the non-responding patients. Caerulein appears to be an effective agent in relieving biliary colic through a relaxation of Oddi's sphincter, and may be used in ultrasound differential diagnostics of terminal bile duct obstruction. Caerulein, 75 ng/kg intramuscularly, relieved renal colic in 75% of the examined patients; it is suggested that the effect of caerulein in this syndrome is due to central analgesic action.