Redox sensitivity of tyrosine hydroxylase activity and expression in dopaminergic dysfunction

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson’s disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression. The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.peer-reviewe

Techniques in Neuroscience

Microdialysis cerebral technique has been widely employed in order to study neurotransmitter release. This technique presents numerous advantages such as it allows work with sample in vivo from freely moving animals. Different drugs in different points implanted probes in several brain areas can be infused simultaneously by means of microdialysis. Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopamine (DA) neurons in the nigrostriatal system, which in turn produces profound neurochemical changes within the basal ganglia, representing the neural substrate for Parkinsonian motor symptoms. Over the years, a broad variety of experimental models of the disease have been developed and applied in diverse animal species. The two most common toxin models used employ 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenilpyridinium ion (MPTP/MPP+), either given systemically or locally applied into the nigrostriatal pathway, to resemble PD features in animals. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, although with different mechanisms. Since in vivo microdialysis coupled to high-performance liquid chromatography (HPLC) is an established technique for studying physiological, pharmacological, and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid, here we describe a rapid and simple microdialysis technique that allows the direct quantitative study of the damage produced by 6-OHDA and MPP+ toxins on dopaminergic (DAergic) striatal terminals of rat brain.peer-reviewe

WEUSEDTO—Water End USE Dataset and TOols: An open water end use consumption dataset and data analytics tools

Globalization, climate changes, innovative technologies and new human habits have increased atten- tion to water conservation and management. Therefore, behavioural studies became a key element to understand how and when water is used in residential environment. Water End USE Dataset and TOols (WEUSEDTO), an open water end use consumption dataset and data analytics tools, has been released to help researchers, water utilities and companies to test models and algorithms on real water consumption data. The dataset combines with some notebook python able to analyse high-resolution water data (data recorded with 1 sample per second) to provide several tools to manage raw data, compute statistical analysis, learn fixture usage and generate synthetic simulation models. In addition, washbasin flow data were used as a test case to illustrate the main features of WEUSEDTO: providing volume and duration of single events, classifying usages and simulating user’s behaviour

Geometrically Induced Selectivity and Unidirectional Electroosmosis in Uncharged Nanopores

Selectivity towards positive and negative ions in nanopores is often associated with electroosmotic flow, the control of which is pivotal in several micro-nanofluidic technologies. Selectivity is traditionally understood to be a consequence of surface charges that alter the ion distribution in the pore lumen. Here we present a purely geometrical mechanism to induce ionic selectivity and electroosmotic flow in uncharged nanopores and we tested it via molecular dynamics simulations. Our approach exploits the accumulation of charges, driven by an external electric field, in a coaxial cavity that decorates the membrane close to the pore entrance. The selectivity was shown to depend on the applied voltage and results to be completely inverted when reverting the voltage. The simultaneous inversion of ionic selectivity and electric field direction causes a unidirectional electroosmotic flow. We developed a quantitatively accurate theoretical model for designing pore geometry to achieve the desired electroosmotic velocity. Finally, we demonstrate that unidirectional electroosmosis also occurs for a biological pore whose structure presents a coaxial cavity surrounding the pore constriction. The capability to induce ion selectivity without altering the pore lumen shape or the surface charge paves the way to a more flexible design of selective membranes

Marked efficacy of Rituximab in multifocal motor neuropathy associated with chronic lymphocytic leukemia

The authors describe a patient who presented a multifocal motor neuropathy (MMN) associated with a high anti-ganglioside antibody (anti-GM1 and anti-GD1) titer at the clinical onset of a B-cell chronic lymphocytic leukemia (B-CLL). Immunomodulation (IVIg plus cyclosporine) resulted in a neurological improvement and reduced anti-ganglioside antibody titers, both of which remained stable for at least six years. After this period, the patient had a severe relapse of the neuropathy, which was independent of the clinical course of the B-CLL. Both IVIg and cyclophosphamide were ineffective, and the patient became tetraplegic within six months; in the meantime, the patient displayed an increased antiganglioside antibody titer. Treatment with rituximab (RTX), which is designed to selectively inhibit B cell function, resulted in a dramatic, prompt and long-lasting neurological improvement as well as a reduced anti-ganglioside antibody titer. Although there are no previous reports of MMN in patients with B-CLL, the efficacy of RTX in the treatment of MMN in this patient may be considered remarkable. The expansion of B-cell clones may be a prerequisite for RTX effectiveness in MMN, and in dysimmune neuropathies in general

Marked efficacy of rituximab in multifocal motor neuropathy associated with chronic lymphocytic leukemia

The authors describe a patient who presented a multifocal motor neuropathy (MMN) associated with a high anti-ganglioside antibody (anti-GM1 and anti-GD1) titer at the clinical onset of a B-cell chronic lymphocytic leukemia (B-CLL). Immunomodulation (IVIg plus cyclosporine) resulted in a neurological improvement and reduced anti-ganglioside antibody titers, both of which remained stable for at least six years. After this period, the patient had a severe relapse of the neuropathy, which was independent of the clinical course of the B-CLL. Both IVIg and cyclophosphamide were ineffective, and the patient became tetraplegic within six months; in the meantime, the patient displayed an increased antiganglioside antibody titer. Treatment with rituximab (RTX), which is designed to selectively inhibit B cell function, resulted in a dramatic, prompt and long-lasting neurological improvement as well as a reduced antiganglioside antibody titer. Although there are no previous reports of MMN in patients with B-CLL, the eficacy of RTX in the treatment of MMN in this patient may be considered remarkable. The expansion of B-cell clones may be a prerequisite for RTX effectiveness in MMN, and in dysimmune neuropathies in general

Design optimization of a high-speed synchronous reluctance machine

Synchronous reluctance machines, including the per¬manent magnet assisted variants are competitive motor topologies if the application requires high efficiency and a cost effective solution with a high flux weakening capability. However, increas¬ing operating speeds incur challenging design and development decisions, mainly in order to find design solutions that ensure the machines structural integrity without compromising the overall performance. In this paper, a comprehensive design procedure for high speed synchronous reluctance machines is presented. In order to validate the procedure, a 5 kW, 80000 rpm machine is considered. The proposed strategy consists of a two-step procedure in which the electromagnetic and structural designs have been properly decoupled dividing the design space in two subsets. Each subset mainly affects the electromagnetic or the structural performances. Several structural design optimizations have been then performed with the aim of finding the optimal trade-off between the rotor geometrical complexity (that defines the required computational resources) and the electromagnetic performance. The reported experimental tests of the prototyped machine validate the proposed design strategy which can be used as general guidelines on the structural design of synchronous reluctance machines

CSI-based fingerprinting for indoor localization using LTE Signals

Abstract This paper addresses the use of channel state information (CSI) for Long Term Evolution (LTE) signal fingerprinting localization. In particular, the paper proposes a novel CSI-based signal fingerprinting approach, where fingerprints are descriptors of the "shape" of the channel frequency response (CFR) calculated on CSI vectors, rather than direct CSI vectors. Experiments have been carried out to prove the feasibility and the effectiveness of the proposed method and to study the impact on the localization performance of (i) the bandwidth of the available LTE signal and (ii) the availability of more LTE signals transmitted by different eNodeB (cell diversity). Comparisons with other signal fingerprinting approaches, such as the ones based on received signal strength indicator or reference signal received power, clearly show that using LTE CSI, and in particular, descriptors as fingerprints, can bring relevant performance improvement

Virus and host factors affecting the clinical outcome of bluetongue virus infection

Bluetongue is a major infectious disease of ruminants caused by bluetongue virus (BTV), an arbovirus transmitted by Culicoides. Here, we assessed virus and host factors influencing the clinical outcome of BTV infection using a single experimental framework. We investigated how mammalian host species, breed, age, BTV serotypes, and strains within a serotype, affect the clinical course of bluetongue. Results obtained indicate that in small ruminants there is a marked difference in the susceptibility to clinical disease induced by BTV at the host species level, but less so at the breed level. No major differences in virulence were found between divergent serotypes (BTV-8 and BTV-2). However, we observed striking differences in virulence between closely related strains of the same serotype collected towards the beginning and the end of the European BTV-8 outbreak. As observed previously, differences in disease severity were also observed when animals were infected with either blood from a BTV-infected animal or from the same virus isolated in cell culture. Interestingly, with the exception of two silent mutations, full viral genome sequencing showed identical consensus sequences of the virus before and after cell culture isolation. However, deep sequencing analysis revealed a marked decrease in the genetic diversity of the viral population after passaging in mammalian cells. In contrast, passaging in Culicoides cells increased the overall number of low frequency variants compared to virus never passaged in cell culture. Thus, Culicoides might be a source of new viral variants and viral population diversity can be another factor influencing BTV virulence