A drift chamber with a new type of straws for operation in vacuum Azorskiy, N.; Glonti, L.; Gusakov, Yu ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
07/2016, Volume:
824
Journal Article
Peer reviewed
A 2150×2150mm2 registration area drift chamber capable of working in vacuum is presented. Thin-wall tubes (straws) of a new type are used in the chamber. A large share of these 9.80mm diameter drift ...tubes are made in Dubna from metalized 36µm Mylar film welded along the generatrix using an ultrasonic welding machine created at JINR. The main features of the chamber and some characteristics of the drift tubes are described. Four such chambers with the X, Y, U, V coordinates each, containing 7168 straws in total, are designed and produced at JINR and CERN. They are installed in the vacuum volume of the NA62 setup in order to study the ultra-rare decay K+→π+vv¯ and to search for and study rare meson decays. In autumn 2014 the chambers were used for the first time for the data taking in the experimental run of the NA62 at CERN׳s SPS.
The NA62 experiment at the CERN SPS is aimed at measuring the branching fraction of the ultrarare decay K+ → π+v with ~10% precision by collecting ~1013 kaon decays in two years of data taking. This ...amount of data will allow to carry out a wide program of searching for rare and forbidden (within the Standard Model) K+ and π0 decays, including sterile neutrinos, lepton flavor violating modes, exotic particles (e.g. "dark photons"). The expected performances of the NA62 setup will allow to improve existing limits for several decay modes.
In familial and sporadic amyotrophic lateral sclerosis (ALS) and in rodent models of the disease, alterations in the ubiquitin-proteasome system (UPS) may be responsible for the accumulation of ...potentially harmful ubiquitinated proteins, leading to motor neuron death. In the spinal cord of transgenic mice expressing the familial ALS superoxide dismutase 1 (SOD1) gene mutation G93A (SOD1G93A), we found a decrease in constitutive proteasome subunits during disease progression, as assessed by real-time PCR and immunohistochemistry. In parallel, an increased immunoproteasome expression was observed, which correlated with a local inflammatory response due to glial activation. These findings support the existence of proteasome modifications in ALS vulnerable tissues. To functionally investigate the UPS in ALS motor neurons in vivo, we crossed SOD1G93A mice with transgenic mice that express a fluorescently tagged reporter substrate of the UPS. In double-transgenic UbG76V-GFP /SOD1G93A mice an increase in UbG76V-GFP reporter, indicative of UPS impairment, was detectable in a few spinal motor neurons and not in reactive astrocytes or microglia, at symptomatic stage but not before symptoms onset. The levels of reporter transcript were unaltered, suggesting that the accumulation of UbG76V-GFP was due to deficient reporter degradation. In some motor neurons the increase of UbG76V-GFP was accompanied by the accumulation of ubiquitin and phosphorylated neurofilaments, both markers of ALS pathology. These data suggest that UPS impairment occurs in motor neurons of mutant SOD1-linked ALS mice and may play a role in the disease progression.
Amyotrophic lateral sclerosis is heterogeneous with high variability in the speed of progression even in cases with a defined genetic cause such as superoxide dismutase 1 (SOD1) mutations. We ...reported that SOD1(G93A) mice on distinct genetic backgrounds (C57 and 129Sv) show consistent phenotypic differences in speed of disease progression and life-span that are not explained by differences in human SOD1 transgene copy number or the burden of mutant SOD1 protein within the nervous system. We aimed to compare the gene expression profiles of motor neurons from these two SOD1(G93A) mouse strains to discover the molecular mechanisms contributing to the distinct phenotypes and to identify factors underlying fast and slow disease progression. Lumbar spinal motor neurons from the two SOD1(G93A) mouse strains were isolated by laser capture microdissection and transcriptome analysis was conducted at four stages of disease. We identified marked differences in the motor neuron transcriptome between the two mice strains at disease onset, with a dramatic reduction of gene expression in the rapidly progressive (129Sv-SOD1(G93A)) compared with the slowly progressing mutant SOD1 mice (C57-SOD1(G93A)) (1276 versus 346; Q-value ≤ 0.01). Gene ontology pathway analysis of the transcriptional profile from 129Sv-SOD1(G93A) mice showed marked downregulation of specific pathways involved in mitochondrial function, as well as predicted deficiencies in protein degradation and axonal transport mechanisms. In contrast, the transcriptional profile from C57-SOD1(G93A) mice with the more benign disease course, revealed strong gene enrichment relating to immune system processes compared with 129Sv-SOD1(G93A) mice. Motor neurons from the more benign mutant strain demonstrated striking complement activation, over-expressing genes normally involved in immune cell function. We validated through immunohistochemistry increased expression of the C3 complement subunit and major histocompatibility complex I within motor neurons. In addition, we demonstrated that motor neurons from the slowly progressing mice activate a series of genes with neuroprotective properties such as angiogenin and the nuclear factor (erythroid-derived 2)-like 2 transcriptional regulator. In contrast, the faster progressing mice show dramatically reduced expression at disease onset of cell pathways involved in neuroprotection. This study highlights a set of key gene and molecular pathway indices of fast or slow disease progression which may prove useful in identifying potential disease modifiers responsible for the heterogeneity of human amyotrophic lateral sclerosis and which may represent valid therapeutic targets for ameliorating the disease course in humans.
Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The ...pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.
Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the
C9ORF72
gene is ...the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein. How C9orf72 haploinsufficiency contributes to disease has not been resolved. Here we identify the synapsin family of synaptic vesicle proteins, the most abundant group of synaptic phosphoproteins, as novel interactors of C9orf72 at synapses and show that C9orf72 plays a cell-autonomous role in the regulation of excitatory synapses. We mapped the interaction of C9orf72 and synapsin to the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin, and show interaction of the endogenous proteins in synapses. Functionally, C9orf72 deficiency reduced the number of excitatory synapses and decreased synapsin levels at remaining synapses in vitro in hippocampal neuron cultures and in vivo in the hippocampal mossy fibre system of C9orf72 knockout mice. Consistent with synaptic dysfunction, electrophysiological recordings identified impaired excitatory neurotransmission and network function in hippocampal neuron cultures with reduced C9orf72 expression, which correlated with a severe depletion of synaptic vesicles from excitatory synapses in the hippocampus of C9orf72 knockout mice. Finally, neuropathological analysis of post-mortem sections of C9ALS/FTD patient hippocampus with C9orf72 haploinsufficiency revealed a marked reduction in synapsin, indicating that disruption of the interaction between C9orf72 and synapsin may contribute to ALS/FTD pathobiology. Thus, our data show that C9orf72 plays a cell-autonomous role in the regulation of neurotransmission at excitatory synapses by interaction with synapsin and modulation of synaptic vesicle pools, and identify a novel role for C9orf72 haploinsufficiency in synaptic dysfunction in C9ALS/FTD.
Thermohydraulic measurements in liquid metal test blanket modules for ITER require reliable sensors for detection of temperature and magnetohydrodynamic properties of the flow such as the ...distribution of electric potential. The latter one can be directly compared with numerical simulations or interpreted in terms of local liquid metal flow rates. Combined temperature-potential probes may serve for both purposes for sensing temperature and potential values, while remaining relatively small in size. By comparison with results obtained using other sensing techniques or theoretical results, the present paper confirms that such measurements in magnetohydrodynamic liquid metal flows may yield accurate data for potential.
Increased intracellular calcium (Ca), which might be the consequence of an excess influx through Ca-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, plays a crucial ...role in degeneration of motor neurons. Previously we demonstrated that the presymptomatic application of AMPA receptor antagonist, talampanel, could reduce Ca elevation in spinal motor neurons of mice carrying the G93A mutation of superoxide dismutase 1 (SOD1), modeling amyotrophic lateral sclerosis (ALS). It remained to be examined whether the remote, functionally semi-autonomous motor axon terminals could be rescued from the Ca overload, or if the terminals, where the degeneration possibly starts, already experience intractable changes at early time points. Thus using electron microscopic techniques, we measured the Ca level of motor axon terminals in the interosseus muscle of the SOD1 mutant animals, which are prototypes of vulnerable nerve endings in ALS. In line with the results obtained in the perikarya, talampanel treatment could reduce Ca increase evoked by the presence of mutant SOD1 in the axon terminals if the treatment was started presymptomatically but not at an early symptomatic stage. We also tested the Ca level in the cell bodies and axon terminals of the oculomotor neurons, which are resistant to the disease. Neither Ca increase, nor talampanel effect could be demonstrated at either time point. This is consistent with the observations that oculomotor neurons contain increased level of Ca buffer, which could reduce excess Ca load, and they also express glutamate receptor subunit type 2, which renders AMPA receptors impermeable to Ca.
•Mutant SOD1 in mice causes Ca increase in motor axon terminals vulnerable in ALS.•AMPA receptor antagonist at presymptomatic stage reduces Ca in motor axon terminals.•AMPA receptor antagonist at early symptomatic stage has no effect on Ca increase.•Oculomotor neurons which are resistant in ALS do not have elevated Ca in mSOD1 mice.•AMPA receptor antagonist does not influence Ca level in mouse oculomotor neurons.
Out-of-hospital cardiac arrest is one of the leading causes of mortality worldwide. The goal of resuscitation is often meant as the return of spontaneous circulation (ROSC). However, ROSC is only one ...of the steps towards survival. The post-ROSC phase is still a challenging one during which the risk of death is all but averted. Morbidity and mortality are exceedingly high due to cardiovascular and neurologic issues; for this reason, post ROSC care relies on international guidelines, the latest being published on April 2021. Since then, several studies have become available covering a variety of topics of crucial importance for post-resuscitation care such as the interpretation of the post-ROSC ECG, the timing of coronary angiography, the role of complete myocardial revascularization and targeted temperature management. This narrative review focuses on these new evidences, in order to further improve clinical practice, and on the need for a multidisciplinary and integrated system of care.Out-of-hospital cardiac arrest is one of the leading causes of mortality worldwide. The goal of resuscitation is often meant as the return of spontaneous circulation (ROSC). However, ROSC is only one of the steps towards survival. The post-ROSC phase is still a challenging one during which the risk of death is all but averted. Morbidity and mortality are exceedingly high due to cardiovascular and neurologic issues; for this reason, post ROSC care relies on international guidelines, the latest being published on April 2021. Since then, several studies have become available covering a variety of topics of crucial importance for post-resuscitation care such as the interpretation of the post-ROSC ECG, the timing of coronary angiography, the role of complete myocardial revascularization and targeted temperature management. This narrative review focuses on these new evidences, in order to further improve clinical practice, and on the need for a multidisciplinary and integrated system of care.
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