Autophagy-lysosome pathway alteration in ocular surface manifestations in Fabry disease patients

Background: Fabry disease (FD) is a rare X-linked, lysosomal storage disorder caused by mutations in the alpha-galactosidase gene and characterized by neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and ocular manifestations. The aim of this study is to characterize morphological, functional and autophagy-lysosome pathway alterations of the ocular surface in FD patients.Methods: Eleven subjects with a diagnosis of FD and fifteen healthy control subjects were examined. All patients underwent ocular surface slit lamp examination, corneal aesthesiometry and in vivo confocal laser-scanning microscopy (CCM). Conjunctival impression cytology was performed in six FD patients and six controls, to assess for expression of two markers of the autophagy-lysosome pathway: the microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP2).Results: Cornea verticillata and increased conjunctival vessel tortuosity were detected respectively in 67% and 33% of patients with FD. Compared with healthy subjects, patients affected by FD showed a significant reduction in corneal nerve fiber length, density and nerve branching on CCM and a significantly increased expression of LC3 on conjunctival impression cytology (p < 0.001). No changes were observed in the conjunctival expression of LAMP2 between the two groups.Conclusions: This study shows that FD is associated with ocular surface alterations including corneal and conjunctival morphology, innervation and vascularization changes. Our data demonstrate an increased expression of LC3 protein in patients with FD, suggesting that alteration of the autophagy-lysosome pathway may play a role in the occurrence of ocular manifestations

A Laplace transform method for energy multigroup hybrid discrete ordinates slab lattice calculations

In typical lattice cells where a highly absorbing, small fuel element is embedded in the moderator, a large weakly absorbing medium, high-order transport methods become unnecessary. In this work we describe a hybrid discrete ordinates (SN) method for energy multigroup slab lattice calculations. This hybrid SN method combines the convenience of a low-order SN method in the moderator with a high-order SN method in the fuel. The idea is based on the fact that in weakly absorbing media whose physical size is several neutron mean free paths in extent, even the S2 method (P1 approximation), leads to an accurate result. We use special fuel-moderator interface conditions and the Laplace transform (LTSN) analytical numerical method to calculate the two-energy group neutron flux distributions and the thermal disadvantage factor. We present numerical results for a range of typical model problems

A Laplace transform method for energy multigroup hybrid discrete ordinates slab lattice calculations

In typical lattice cells where a highly absorbing, small fuel element is embedded in the moderator, a large weakly absorbing medium, high-order transport methods become unnecessary. In this work we describe a hybrid discrete ordinates (SN) method for energy multigroup slab lattice calculations. This hybrid SN method combines the convenience of a low-order SN method in the moderator with a high-order SN method in the fuel. The idea is based on the fact that in weakly absorbing media whose physical size is several neutron mean free paths in extent, even the S2 method (P1 approximation), leads to an accurate result. We use special fuel-moderator interface conditions and the Laplace transform (LTSN) analytical numerical method to calculate the two-energy group neutron flux distributions and the thermal disadvantage factor. We present numerical results for a range of typical model problems

Limitations to Electrical Probing of Spontaneous Polarization in Ferroelectric-Dielectric Heterostructures

An accurate estimate of the ferroelectric polarization in ferroelectric-dielectric stacks is important from a materials science perspective, and it is also crucial for the development of ferroelectric based electron devices. This paper revisits the theory and application of the PUND technique in Metal-Ferroelectric-Dielectric-Metal (MFDM) structures by using analytical derivations and numerical simulations. In an MFDM structure the results of the PUND technique may largely differ from the polarization actually switched in the stack, which in turn is different from the remnant polarization of the underlying ferroelectric. The main hindrances that prevent PUND measurements from providing a good estimate of the polarization switching in MFDM stacks are thus discussed. The inspection of the involved physical quantities, not always accessible in experiments, provides a useful insight about the main sources of the errors in the PUND technique, and clarifies the delicate interplay between the depolarization field and the charge injection and trapping in MFDM stacks with a thin dielectric layer

The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity

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Bridging Large-Signal and Small-Signal Responses of Hafnium-Based Ferroelectric Tunnel Junctions

Ferroelectric Tunnel Junctions (FTJs) op- erating as memristors are promising electron devices to realize artificial synapses for neuromorphic computing. But the understanding of their operation requires an in-depth electrical characterization. In this work, an in- house validated experimental setup is employed along with novel experimental methodologies to investigate the large-signal (LS) and small-signal (AC) responses of FTJs. For the first time to our knowledge, our exper- iments and physics-based simulations, help to explain the discrepancies between LS and AC experiments reported in previous literature

Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis

Bromodomain and extraterminal domain (BET) protein inhibition hinders glioblastoma progression by inducing autophagy-dependent differentiation

Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant primary brain tumor, and it is characterized by a high recurrence incidence and poor prognosis due to the presence of a highly heterogeneous mass of stem cells with self-renewal capacity and stemness maintenance ability. In recent years, the epigenetic landscape of GBM has been explored and many epigenetic alterations have been investigated. Among the investigated epigenetic abnormalities, the bromodomain and extra-terminal domain (BET) chromatin readers have been found to be significantly overexpressed in GBM. In this work, we investigated the effects of BET protein inhibition on GBM cell reprogramming. We found that the pan-BET pharmacological inhibitor JQ1 was able to promote a differentiation program in GBM cells, thus impairing cell proliferation and enhancing the toxicity of the drug Temozolomide (TMZ). Notably, the pro-differentiation capability of JQ1 was prevented in autophagy-defective models, suggesting that autophagy activation is necessary for BET protein activity in regulating glioma cell fate. Given the growing interest in epigenetic therapy, our results further support the possibility of introducing a BET-based approach in GBM clinical management

mTOR inhibition leads to SRC-mediated EGFR internalisation and degradation in glioma cells

Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration