Search results for "tPA"
showing 10 items of 770 documents
Resistance to third-generation cephalosporins in Escherichia coli in the French community: The times they are a-changin'?
2020
Since the early 2000s, Escherichia coli resistance to third-generation cephalosporins (3GCs) has been increasing in all European countries, mainly due to the spread of extended spectrum β-lactamases (ESBLs). Here we present a retrospective study that combines resistance of E. coli to 3GCs and quinolones with data on antibiotic use in the community in a region of Northeastern France.Since 2012, an observational surveillance of antimicrobial resistance and antibiotic use in the community was conducted: data on antimicrobial resistance in E. coli isolates were collected from 11 private laboratories, and consumption data were collected from the three main healthcare insurances.A significant dec…
Identification of the Privileged Position in the Imidazo[1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transfera…
2017
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Because the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure-activity relationship. We have identified the privileged position in the core scaffold of the imidazo[1,2-a]pyridine r…
Sng1 associates with Nce102 to regulate the yeast Pkh–Ypk signalling module in response to sphingolipid status
2016
International audience; All cells are delimited by biological membranes, which are consequently a primary target of stress-induced damage. Cold alters membrane functionality by decreasing lipid fluidity and the activity of membrane proteins. In Saccharomyces cerevisiae, evidence links sphingolipid homeostasis and membrane phospholipid asymmetry to the activity of the Ypk1/2 proteins, the yeast orthologous of the mammalian SGK1-3 kinases. Their regulation is mediated by different protein kinases, including the PDK1 orthologous Pkh1/2p, and requires the function of protein effectors, among them Nce102p, a component of the sphingolipid sensor machinery. Nevertheless, the mechanisms and the act…
α2 isoform of Na+,K+-ATPase via Na+,Ca2+ exchanger modulates myelin basic protein synthesis in oligodendrocyte lineage cells in vitro
2018
Abstract Oligodendrocytes in the CNS myelinate neuronal axons, facilitating rapid propagation of action potentials. Myelin basic protein (MBP) is an essential component of myelin and its absence results in severe hypomyelination. In oligodendrocyte lineage cell (OLC) monocultures MBP synthesis starts at DIV4. Ouabain (10 nM), a Na+,K+-ATPase (NKA) blocker, stimulates MBP synthesis. As OLCs express the α2 isoform of NKA (α2-NKA) that has a high affinity for ouabain, we hypothesized that α2-NKA mediates this effect. Knockdown of α2-NKA with small interfering (si)RNA (α2-siRNA) significantly potentiated MBP synthesis at DIV4 and 5. This effect was completely blocked by KB-R7943 (1 μM), a Na+,C…
A Thermodynamic Model of Monovalent Cation Homeostasis in the Yeast Saccharomyces cerevisiae
2016
Cationic and heavy metal toxicity is involved in a substantial number of diseases in mammals and crop plants. Therefore, the understanding of tightly regulated transporter activities, as well as conceiving the interplay of regulatory mechanisms, is of substantial interest. A generalized thermodynamic description is developed for the complex interplay of the plasma membrane ion transporters, membrane potential and the consumption of energy for maintaining and restoring specific intracellular cation concentrations. This concept is applied to the homeostasis of cation concentrations in the yeast cells of S. cerevisiae. The thermodynamic approach allows to model passive ion fluxes driven by the…
Intracellular ion signaling influences myelin basic protein synthesis in oligodendrocyte precursor cells
2016
Myelination in the central nervous system depends on axon-oligodendrocyte precursor cell (OPC) interaction. We suggest that myelin synthesis may be influenced by [Na+]i and [Ca2+]i signaling in OPCs. Experiments were performed in mouse cultured OPCs at day in vitro (DIV) 2-6 or acute slices of the corpus callosum at postnatal days (P) 10-30. Synthesis of Myelin Basic Protein (MBP), an "executive molecule of myelin", was used as readout of myelination. Immunohistological data revealed that MBP synthesis in cultured OPCs starts around DIV4. Transient elevations of resting [Ca2+]i and [Na+]i levels were observed in the same temporal window (DIV4-5). At DIV4, but not at DIV2, both extracellular…
SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidr…
2019
Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-c…
Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney
2021
Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed a…
RPGR protein complex regulates proteasome activity and mediates store-operated calcium entry
2018
Ciliopathies are a group of genetically heterogeneous disorders, characterized by defects in cilia genesis or maintenance. Mutations in the RPGR gene and its interacting partners, RPGRIP1 and RPGRIP1L, cause ciliopathies, but the function of their proteins remains unclear. Here we show that knockdown (KD) of RPGR, RPGRIP1 or RPGRIP1L in hTERT-RPE1 cells results in abnormal actin cytoskeleton organization. The actin cytoskeleton rearrangement is regulated by the small GTPase RhoA via the planar cell polarity (PCP) pathway. RhoA activity was upregulated in the absence of RPGR, RPGRIP1 or RPGRIP1L proteins. In RPGR, RPGRIP1 or RPGRIP1L KD cells, we observed increased levels of DVl2 and DVl3 pr…
The RAB GTPase RAB18 modulates macroautophagy and proteostasis
2017
Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positi…