Search results for "mutant"
showing 10 items of 670 documents
Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid de…
2012
Alzheimer's disease (AD) is characterized by amyloid-beta deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1(-/-) mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its …
Postnatal alterations of the inhibitory synaptic responses recorded from cortical pyramidal neurons in the Lis1/sLis1 mutant mouse
2006
Mutations in the mouse Lis1 gene produce severe alterations in the developing cortex. We have examined some electrophysiological responses of cortical pyramidal neurons during the early postnatal development of Lis/sLis1 mutant mice. In P7 and P30 Lis1/sLis1 neurons we detected a lower frequency and slower decay phase of mIPSCs, and at P30 the mIPSCs amplitude and the action potential duration were reduced. Zolpidem (an agonist of GABAA receptors containing the alpha1 subunit) neither modified the amplitude nor the decay time of mIPSCs at P7 in Lis1/sLis1 neurons, whereas it increased the decay time at P30. The levels of GABAA receptor alpha1 subunit mRNA were reduced in the Lis1/sLis1 brai…
Sometimes less is more—the impact of the number of His residues on the stability of Zn(ii)–SmtB and BigR4 α-5 domain complexes
2021
The increasing number of antibiotic-resistant pathogens has become one of the major health problems of modern times, including infections caused by Mycobacterium tuberculosis. One of the possible mammalian immune system responses to mycobacterial infection is the increase of the zinc(II) concentration in phagosomes to a toxic level. The mycobacterial SmtB protein belongs to the family of ArsR/SmtB transcription regulators. In the presence of high concentrations of metals, SmtB dissociates from DNA and activates the expression of metal efflux proteins. In this work, we focus on the α5 zinc(II) binding domains of SmtB/BigR4 proteins (the latter being the SmtB homolog from non-pathogenic M. sm…
Structural Domains of the <em>Bacillus thuringiensis</em> Vip3Af Protein Unraveled by Tryptic Digestion of Alanine Mutants
2019
Vip3 proteins are increasingly used in insect control in transgenic crops. To shed light on the structure of these proteins, we used the approach of trypsin fragmentation of mutants altering the conformation of the Vip3Af protein. From an alanine scanning on Vip3Af, we selected mutants with an altered proteolytic pattern. Based on the protease digestion patterns, their effect on oligomer formation, and theoretical cleavage sites, we generated a map of the Vip3Af protein with five domains, which match some of the domains proposed independently by two in silico models. Domain I ranges from aa12-198, domain II from aa199-313, domain III from aa314-526, domain IV from aa527-668 and domain V fro…
Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease
2012
Background Allergic asthma is a T H 2-promoted hyperreactivity with an immediate, IgE, and mast cell–dependent response followed by eosinophil-dominated inflammation and airway obstruction. Objective Because costimulation by CD28 is essential for T H 2 but not T H 1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite–induced airway inflammation. Methods To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site–specific mouse anti-mouse mAb blocking CD28 engagement. Results We show …
Dissection of the relative contribution of the Schizosaccharomyces pombe Ctr4 and Ctr5 proteins to the copper transport and cell surface delivery fun…
2011
The Ctr1 family of proteins mediates high-affinity copper (Cu) acquisition in eukaryotic organisms. In the fission yeastSchizosaccharomyces pombe, Cu uptake is carried out by a heteromeric complex formed by the Ctr4 and Ctr5 proteins. Unlike human andSaccharomyces cerevisiaeCtr1 proteins, Ctr4 and Ctr5 are unable to function independently in Cu acquisition. Instead, both proteins physically interact with each other to form a Ctr4–Ctr5 heteromeric complex, and are interdependent for secretion to the plasma membrane and Cu transport activity. In this study, we usedS. cerevisiaemutants that are defective in high-affinity Cu uptake to dissect the relative contribution of Ctr4 and Ctr5 to the Cu…
Transport of C(4)-dicarboxylates in Wolinella succinogenes.
2000
ABSTRACT C 4 -dicarboxylate transport is a prerequisite for anaerobic respiration with fumarate in Wolinella succinogenes , since the substrate site of fumarate reductase is oriented towards the cytoplasmic side of the membrane. W. succinogenes was found to transport C 4 -dicarboxylates (fumarate, succinate, malate, and aspartate) across the cytoplasmic membrane by antiport and uniport mechanisms. The electrogenic uniport resulted in dicarboxylate accumulation driven by anaerobic respiration. The molar ratio of internal to external dicarboxylate concentration was up to 10 3 . The dicarboxylate antiport was either electrogenic or electroneutral. The electroneutral antiport required the prese…
Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes.
2011
Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre(+/-), iDTR(+/-) offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre(-/-), iDTR(+/-) mice were used as GH-intact controls. AOiGHD im…
The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-l…
2012
TPS3637 Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are prog…
Disruption of the Candida albicans ATC1 gene encoding a cell-linked acid trehalase decreases hypha formation and infectivity without affecting resist…
2007
In Candida albicans, the ATC1 gene, encoding a cell wall-associated acid trehalase, has been considered as a potentially interesting target in the search for new antifungal compounds. A phenotypic characterization of the double disruptant atc1Delta/atc1Delta mutant showed that it was unable to grow on exogenous trehalose as sole carbon source. Unlike actively growing cells from the parental strain (CAI4), the atc1Delta null mutant displayed higher resistance to environmental insults, such as heat shock (42 degrees C) or saline exposure (0.5 M NaCl), and to both mild and severe oxidative stress (5 and 50 mM H(2)O(2)), which are relevant during in vivo infections. Parallel measurements of int…