As part of an ongoing program to constrain the factors affecting phase stability in nuclear waste containment glasses, the thermodynamic and kinetic factors influencing molybdenum oxide solubility in ...a borosilicate melt have been studied. A simplified system has been chosen to study how Mo oxide is transferred from solid effluent residues (calcines) to glass. The model calcines used are pure Na2MoO4 and a more complex mixture of Na2MoO4 and Al-bearing phases. These solid residues are mixed with a borosilicate glass frit and heat treated isothermally at temperatures in the range 700–1000 °C for times ranging from 2 min to 8 h. The mineralogy of the mixtures has been followed as a function of temperature and time using XRD and 27Al and 23Na MAS NMR spectroscopy, while the structure and composition of the amorphous phase have been studied by 11B MAS NMR and electron microprobe. The results obtained illustrate that while the dissolution of Al-rich calcines can modify the structure of the borosilicate network this does not affect either the MoO3 content of the liquid at saturation, or the characteristic time-scale required to reach saturation. In detail, the variation of the Mo content of the liquid at saturation can be described by an Arrhenian temperature dependence with an activation energy of 30 ± 5 kJ/mol and the time-scale required to reach saturation, can be described by an exponential function of time. This time-scale also shows Arrhenian temperature dependence with an activation energy of 225 ± 25 kJ/mol, a value identical within uncertainty to that associated with viscous flow. Using the experimental results, a numerical model for dissolution along variable temperature-time paths has been developed. These models indicate that for systems that are capable of complete dissolution grain-size is one of the most important parameter controlling the efficiency of the dissolution process.
P2X receptors are nonselective cation channels gated by extracellular ATP. Recombinant mammalian P2X subunits assemble in homomeric ionotropic ATP receptors that differ by their agonist sensitivity ...and desensitization rate in heterologous expression systems. Using site-directed mutagenesis and voltage clamp recording in Xenopus oocytes, we identified the highly conserved protein kinase C site TX(K/R) located in the intracellular N terminus of P2X subunits as a critical determinant of kinetics in slowly desensitizing (time constant, >1 min) rat P2X(2) receptors. Mutant receptors P2X(2)T18A, T18N, and K20T devoid of this consensus site exhibited quickly desensitizing properties (time constant, <1 s). In contrast with wild-type receptors, mutant P2X(2) receptors with truncated C terminus exhibited variable cell-specific kinetics with quickly desensitizing currents converted to slowly desensitizing currents by phorbol ester-mediated stimulation of protein kinase C. Phosphorylation of Thr(18) was demonstrated directly by immunodetection using specific monoclonal antibodies directed against the phosphothreonine-proline motif. Our data indicate that both phosphorylation of the conserved threonine residue in the N-terminal domain by protein kinase C and interaction between the two cytoplasmic domains of P2X(2) subunits are necessary for the full expression of slowly desensitizing ATP-gated channels.
In the context of the national Cancer Plans of France that have changed the healthcare landscape, it has become necessary to better document and assess the related actions, and to promote research ...and understanding. The national cancer cohort, an exhaustive population-based cohort, was set up on the basis of the National Health Data System (SNDS) by the French National Cancer Institute.
The aim is to describe the French national cancer cohort.
All people living in France (67 million population) with universal insurance coverage and diagnosed, treated or followed up for a cancer, such as survivors, are included and will be followed up for 25 years. It contains all healthcare consumptions and reimbursements (i.e. hospitalization, outpatient care, medication…) since 2010. Every year, around 650 000 new cases are included.
From 2010 to 2015, 6.2 million subjects have been included. Most subjects were entered in 2010, in 2015 it concerned 0.6 million. In 2015, the median age was 65 54-76; 51% were women. The primary cancer organ could be attributed with certitude to 87% of the people. The most frequent locations were skin (16%), breast (15%), prostate (12%), colon-rectum (11%) and lung (9%). In 2015, 40% of included subjects underwent surgery for cancer, 16% chemotherapy at hospital and 11% at least one session of radiotherapy.
Based on SNDS, the cancer cohort has been designed to study cancer care use in the short-, medium- and long-term, and evaluate healthcare and public health policies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fast inhibitory synaptic transmission in the brain relies on ionotropic GABA
A
receptors (GABA
A
R). Eighteen genes code for GABA
A
R subunits, but little is known about the ε subunit. Our aim was to ...identify the synaptic transmission properties displayed by native receptors incorporating ε. Immunogold localization detected ε at synaptic sites on locus coeruleus (LC) neurons. In situ hybridization revealed prominent signals from ε, and θ mRNAs, some low β1 and β3 signals, and no γ signal. Using in vivo extracellular and in vitro patch-clamp recordings in LC, we established that neuron firing rates, GABA-activated currents, and mIPSC charge were insensitive to the benzodiazepine flunitrazepam (FLU), in agreement with the characteristics of recombinant receptors including an ε subunit. Surprisingly, LC provided binding sites for benzodiazepines, and GABA-induced currents were potentiated by diazepam (DZP) in the micromolar range. A number of GABA
A
R ligands significantly potentiated GABA-induced currents, and zinc ions were only active at concentrations above 1 μM, further indicating that receptors were not composed of only α and β subunits, but included an ε subunit. In contrast to recombinant receptors including an ε subunit, GABA
A
R in LC showed no agonist-independent opening. Finally, we determined that mIPSCs, as well as ensemble currents induced by ultra-fast GABA application, exhibited surprisingly slow rise times. Our work thus defines the signature of native GABA
A
R with a subunit composition including ε: differential sensitivity to FLU and DZP and slow rise time of currents. We further propose that α
3,
β
1/3,
θ and ε subunits compose GABA
A
R in LC.
The mammalian P2X receptor gene family encodes two-transmembrane domain nonselective cation channels gated by extracellular ATP. Anatomical localization data obtained by in situ hybridization and ...immunocytochemistry have shown that neuronal P2X subunits are expressed in specific but overlapping distribution patterns. Therefore, the native ionotropic ATP receptors diversity most likely arises from interactions between different P2X subunits that generate hetero-multimers phenotypically distinct from homomeric channels. Rat P2X1 and P2X5 mRNAs are localized within common subsets of peripheral and central sensory neurons as well as spinal motoneurons. The present study demonstrates a functional association between P2X1 and P2X5 subunits giving rise to hybrid ATP-gated channels endowed with the pharmacology of P2X1 and the kinetics of P2X5. When expressed in Xenopus oocytes, hetero-oligomeric P2X1+5 ATP receptors were characterized by slowly desensitizing currents highly sensitive to the agonist alpha,beta-methylene ATP (EC50 = 1.1 microM) and to the antagonist trinitrophenyl ATP (IC50 = 64 nM), observed with neither P2X1 nor P2X5 alone. Direct physical evidence for P2X1+5 co-assembly was provided by reciprocal subunit-specific co-purifications between epitope-tagged P2X1 and P2X5 subunits transfected in HEK-293A cells.
1 University Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Bordeaux, France;
2 Department of Pharmacology, School of Medicine, University of the Basque Country, ...Vizcaya, Spain; and
3 Leeds Institute of Genetics, Therapeutics and Health (LIGHT), University of Leeds, Leeds, United Kingdom
Submitted 13 March 2009;
accepted in final form 21 July 2009
ABSTRACT
Fast inhibitory synaptic transmission in the brain relies on ionotropic GABA A receptors (GABA A R). Eighteen genes code for GABA A R subunits, but little is known about the subunit. Our aim was to identify the synaptic transmission properties displayed by native receptors incorporating . Immunogold localization detected at synaptic sites on locus coeruleus (LC) neurons. In situ hybridization revealed prominent signals from , and mRNAs, some low β1 and β3 signals, and no signal. Using in vivo extracellular and in vitro patch-clamp recordings in LC, we established that neuron firing rates, GABA-activated currents, and mIPSC charge were insensitive to the benzodiazepine flunitrazepam (FLU), in agreement with the characteristics of recombinant receptors including an subunit. Surprisingly, LC provided binding sites for benzodiazepines, and GABA-induced currents were potentiated by diazepam (DZP) in the micromolar range. A number of GABA A R ligands significantly potentiated GABA-induced currents, and zinc ions were only active at concentrations above 1 µM, further indicating that receptors were not composed of only and β subunits, but included an subunit. In contrast to recombinant receptors including an subunit, GABA A R in LC showed no agonist-independent opening. Finally, we determined that mIPSCs, as well as ensemble currents induced by ultra-fast GABA application, exhibited surprisingly slow rise times. Our work thus defines the signature of native GABA A R with a subunit composition including : differential sensitivity to FLU and DZP and slow rise time of currents. We further propose that 3, β 1/3, and subunits compose GABA A R in LC.
Address for reprint requests and other correspondence: M. Garret, CNRS UMR 5227, Université de Bordeaux2, 146 rue Leo Saignat, 33076 Bordeaux cedex, France (E-mail maurice.garret{at}u-bordeaux2.fr ).
: We report here the structural and functional
characterization of an ionotropic P2X ATP receptor from the lower vertebrate
zebrafish (Danio rerio). The full‐length cDNA encodes a 410‐amino
acid‐long ...channel subunit zP2X3, which shares only 54% identity
with closest mammalian P2X subunits. When expressed in Xenopus
oocytes in homomeric form, ATP‐gated zP2X3 channels evoked a unique
nonselective cationic current with faster rise time, faster kinetics of
desensitization, and slower recovery than any other known P2X channel.
Interestingly, the order of agonist potency for this P2X receptor was found
similar to that of distantly related P2X7 receptors, with
benzoylbenzoyl ATP (EC50 = 5 μM) ≫ ATP
(EC50 = 350 μM) = ADP > α,β‐methylene ATP
(EC50 = 480 μM). zP2X3 receptors are highly
sensitive to blockade by the antagonist trinitrophenyl ATP (IC50
< 5 nM) but are weakly sensitive to the noncompetitive antagonist
pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulfonic acid.
zP2X3 subunit mRNA is exclusively expressed at high levels in trigeminal neurons and Rohon‐Beard cells during embryonic development, suggesting that neuronal P2X receptors mediating fast ATP responses were selected early in the vertebrate phylogeny to play an important role in sensory pathways.
A man presents an atypical neurological disorder. The diagnosis of aortic dissection is evoked with anisotension, but it consists in a paradoxical embolism in the presence of a permeable foramen oval ...since he presents with a proximal pulmonary embolus and a thrombus in the humeral artery.
P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X(4) subtype, upregulated in activated microglia, ...is thought to play a critical role in the development of tactile allodynia following peripheral nerve injury. Posttranslational regulation of P2X(4) function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P(2) (PIP(2)) and PI(3,4,5)P(3) (PIP(3)), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X(4) receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP(2) and PIP(3) with wortmannin significantly decreased P2X(4) current amplitude and P2X(4)-mediated calcium entry measured in patch clamp recordings and ratiometric ion imaging, respectively. Wortmannin-induced depletion of phosphoinositides in Xenopus oocytes decreased the current amplitude of P2X(4) responses by converting ATP into a partial agonist. It also decreased their recovery from desensitization and affected their kinetics. Injection of phosphoinositides in wortmannin-treated oocytes reversed these effects and application of PIP(2) on excised inside-out macropatches rescued P2X(4) currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X(4) subunit (Cys(360)-Val(375)) using an in vitro binding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP(2) and PIP(3) on P2X(4) function through direct channel-lipid interactions.
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