Cholesterol-dependent complement activation has been proposed as a factor that might influence the pathogenesis of atherosclerosis. Although antibodies to cholesterol conjugates have been reported, cholesterol is widely regarded as a poorly immunogenic substance. Monoclonal IgM complement-fixing antibodies to cholesterol were obtained in the present study after immunizing mice with liposomes containing high amounts of cholesterol (71 mol % relative to phosphatidylcholine) and lipid A as an adjuvant. Clones were selected for the ability of secreted antibodies to react with liposomes containing 71% cholesterol but not with liposomes containing 43% cholesterol. The antibodies also reacted with crystalline cholesterol in a solid-phase enzyme-linked immunosorbent assay. Binding of monoclonal antibodies to the surface of crystalline cholesterol was demonstrated by electron microscopy by utilizing a second antibody (anti-IgM) labeled with colloidal gold. The immunization period required to induce monoclonal antibodies was very short (3 days) and a high fraction of the hybrid cells (at least 70%) were secreting detectable antibodies to cholesterol. The results demonstrate that cholesterol can be a highly immunogenic molecule and that complement-fixing antibodies to cholesterol can be readily obtained.
Incubation of fibroblasts derived from patients with type-C Niemann-Pick disease with low density lipoprotein results in excessive intracellular accumulation of unesterified cholesterol. Cytochemical techniques revealed that this abnormal cholesterol accumulation is associated not only with a massive storage of cholesterol in lysosomes but also with a premature cholesterol enrichment of the Golgi complex. Cholesterol appeared also in the Golgi complex of some normal fibroblasts after 24 hr of low density lipoprotein loading. These findings indicate that components of the Golgi complex play a role in the intracellular translocation of exogenously derived cholesterol and that disruptions of the cholesterol transport pathway at the Golgi may, in part, be responsible for the deficiency in cholesterol utilization in type-C Niemann-Pick fibroblasts.
Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM...
Purified perigranular and plasma membranes isolated from rat peritoneal mast cells were examined for Ca2+- and Mg2+-dependent ATPase activity. Isolated perigranular membranes contained only a low-affinity Ca2+- or Mg2+-dependent ATPase (Km greater than 0.5 mM). The plasma membranes contained both a low-affinity Ca2+- or Mg2+-dependent ATPase (Km = 0.4 mM, Vmax. = 20 nmol of Pi/min per mg), as well as a high-affinity Ca2+- and Mg2+-dependent ATPase (Km = 0.2 microM, Vmax. = 6 nmol of Pi/min per mg).
In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as “SMCX,” is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.
Unesterified cholesterol-rich lipid particles were isolated from human and cholesterol-fed rabbit aortas. These particles have been previously reported to constitute the initial lipid deposition in atherosclerotic lesion development. Purification of the particles was accomplished with microfiltration, gel filtration chromatography, and density gradient centrifugation. Particles from both human and rabbit aortas had a density of between 1.02 g/ml and 1.08 g/ml with a peak at d = 1.036 g/ml. These particles had a high molar ratio of unesterified cholesterol to phospholipid (2.4:1 in rabbit, 2.6:1 in human) and a high percentage of their cholesterol in an unesterified form (82% in rabbit, 76% in human). The particles had diameters between 700 and 3000 A and showed unilamellar and multilamellar structures. Freeze-fractured particles had smooth fracture faces and sometimes contained a smooth-surfaced core. Upon incubation with filipin, particles showed typical filipin-sterol complexes, demonstrating the presence of unesterified cholesterol. The particles we have isolated may constitute an early pathologic form of accumulated cholesterol in developing lesions and may represent a degradation product of infiltrated plasma low-density lipoprotein.
Structure-based design was used to develop a focused library of A-ring-modified diphenyl ether InhA inhibitors. From this library of analogs, two high-affinity alkyl-substituted diphenyl ethers, 6PP and 8PP, were selected for advanced study into their in vitro activity against Mycobacterium tuberculosis clinical isolates, their in vivo properties, and their signature response mode of action. 6PP and 8PP demonstrated enhanced activity against whole bacteria and showed activity in a rapid macrophage model of infection. In addition, transcriptional profiling revealed that the A-ring modifications of 6PP and 8PP increased the specificity of each analog for InhA. Both analogs had substantially longer half-lives in serum than did the parent compound, exhibited a fivefold reduction in cytotoxicity compared to the parent compound, and were well tolerated when administered orally at 300 mg/kg of body weight in animal models. Thus, the A-ring modifications increased the affinity and whole-cell specificity of the compounds for InhA and increased their bioavailability. The next step in optimization of the pharmacophore for preclinical evaluation is modification of the B ring to increase the bioavailability to that required for oral delivery.
Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin (Dox)-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is, therefore, important to understand how NRG1, via erbB2, protects the heart against Dox cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins [cardiac troponin I (cTnI) and cardiac troponin T (cTnT)] and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT, and cardiac troponin C (cTnC) and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2...
The delta-sarcoglycan-deficient hamster is an excellent model to study muscular dystrophy. Gait disturbances, important clinically, have not been described in this animal model. We applied ventral plane videography (DigiGait) to analyze gait in BIO TO-2 dystrophic and BIO F1B control hamsters walking on a transparent treadmill belt. Stride length was ∼13% shorter (P < .05) in TO-2 hamsters at 9 months of age compared to F1B hamsters. Hindlimb propulsion duration, an indicator of muscle strength, was shorter in 9-month-old TO-2 (247 ± 8 ms) compared to F1B hamsters (272 ± 11 ms; P < .05). Braking duration, reflecting generation of ground reaction forces, was delayed in 9-month-old TO-2 (147 ± 6 ms) compared to F1B hamsters (126 ± 8 ms; P < .05). Hindpaw eversion, evidence of muscle weakness, was greater in 9-month-old TO-2 than in F1B hamsters (17.7 ± 1.2° versus 8.7 ± 1.6°; P < .05). Incline and decline walking aggravated gait disturbances in TO-2 hamsters at 3 months of age. Several gait deficits were apparent in TO-2 hamsters at 1 month of age. Quantitative gait analysis demonstrates that dystrophic TO-2 hamsters recapitulate functional aspects of human muscular dystrophy. Early detection of gait abnormalities in a convenient animal model may accelerate the development of therapies for muscular dystrophy.
In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as “SMCX,” is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.; Lars Riff Jensen...
Cette recherche s'intéresse aux perceptions des personnes itinérantes sur leur judiciarisation et leurs incarcérations. La judiciarisation s'opère suite à la remise de constats d'infractions en lien avec les règlementations municipales de la ville, celles de la Société des Transports de Montréal ainsi que le Code de Sécurité Routière. Elle relève donc de la procédure pénale, par opposition au code criminel et concerne des infractions mineures, souvent en lien avec des incivilités. Ultimement, la judiciarisation conduit à l'emprisonnement faute de paiement de l'amende. L'objectif de cette recherche est de mieux comprendre les perceptions à partir d'une compréhension des effets au plan matériel, des relations entretenues avec les différents acteurs socio-judiciaires et du regard que les personnes portent sur la justice à partir de leur expérience. Ancrée dans un cadre théorique fondé sur la reconnaissance (Honneth, 2000), l'expérience de judiciarisation et de l'incarcération est conçue et révélatrice d'un rapport entre la personne itinérante et le système de justice. Pour réaliser cette étude, deux méthodologies complémentaires ont été utilisées. La première s'appuie sur 29 entrevues réalisées avec des personnes itinérantes...
Toujours en évolution le droit maritime est constamment en train de se moderniser. Depuis ses débuts Ie droit maritime essaie de s'adapter aux réalités de son temps. Le changement fut lent et difficile à atteindre. Au départ la pratique voulait qu'un transporteur maritime puisse échapper à presque toute responsabilité. L'application des coutumes du domaine et du droit contractuel avait laissé place aux abus et aux inégalités de pouvoir entre transporteurs maritimes et chargeurs/propriétaires de marchandises. La venue du vingtième siècle changea tout. L'adoption des Règles de la Haye, Haye / Nisby et Hambourg a transforme Ie système de transport de marchandise par mer tel qu'on Ie connaissait jusqu'à date. Ainsi une évolution graduelle marqua l'industrie maritime, parallèlement Ie droit maritime se développa considérablement avec une participation judiciaire plus active. De nos jours, les transporteurs maritimes sont plus responsables, or cela n'empêche pas qu'ils ne sont pas toujours capables de livrer leurs cargaisons en bonne condition. Chaque fois qu'un bateau quitte Ie port lui et sa cargaison sont en danger. De par ce fait, des biens sont perdus ou endommages en cours de route sous la responsabilité du transporteur. Malgré les changements et l'évolution dans les opérations marines et l'administration du domaine la réalité demeure telle que Ie transport de marchandise par mer n' est pas garanti it. cent pour cent. Dans les premiers temps...
Chao, Fei-Fei; Blanchette-Mackie, E. Joan; Chen, Ya-Jun; Dickens, Benjamin F.; Berlin, Elliott; Amende, Lynn M.; Skarlatos, Sonia I.; Gamble, Wilbert; Resau, James H.; Mergner, Wolfgang T.; Kruth, Howard S.
The authors' laboratory, using histochemicalmethods, previously identified two types of cholesterol-containing lipid particles in the extracellular spaces of human atherosclerotic lesions, one particle enriched in esterified cholesterol and the other particle enriched in unesterified cholesterol. The authors isolated and characterized these lipid particles. The esterified cholesterol-rich lipid particle was a small lipid droplet and differed from intracellular lipid dropletsfound in foam cells with respect to size and chemical composition. It had an esterified cholesterol core surrounded by aphospholipidunesterified cholesterol monolayer. Some aqueous spaces were seen within the particle core. Unesterified cholesterol-rich lipid particles were multilamellated, solid structures and vesicles comprised of single or multiple lamellas. The esterified cholesterol-rich particle had a density <1.01 g/ml, whereas the unesterified cholesterol-rich particle had a density between 1.03 and 1.05 g/ml. Both particles were similar in size fraction, whereas palmitate, stearate, oleate, and linoleate were predominant in the phospholipid fraction. The origins and the role of these two unusual lipid particles in vessel wall cholesterol metabolism remain to be determined.
Let $G=G(K)$ be a simple algebraic group defined over an algebraically closed
field $K$ of characteristic $p>0$. A subgroup $X$ of $G$ is said to be
$G$-completely reducible if, whenever it is contained in a parabolic subgroup
of $G$, it is contained in a Levi subgroup of that parabolic. A subgroup $X$ of
$G$ is said to be $G$-irreducible if $X$ is in no parabolic subgroup of $G$;
and $G$-reducible if it is in some parabolic of $G$. In this thesis, we
consider the case that $G$ is of exceptional type. When $G$ is of type $G_2$ we
find all conjugacy classes of closed, connected, reductive subgroups of $G$.
When $G$ is of type $F_4$ we find all conjugacy classes of closed, connected,
reductive $G$-reducible subgroups $X$ of $G$. Thus we also find all
non-$G$-completely reducible closed, connected, reductive subgroups of $G$.
When $X$ is closed, connected and simple of rank at least two, we find all
conjugacy classes of $G$-irreducible subgroups $X$ of $G$. Together with the
work of Amende in [Ame05] classifying irreducible subgroups of type $A_1$ this
gives a complete classification of the simple subgroups of $G$.
Amongst the classification of subgroups of $G=F_4(K)$ we find infinite
collections of subgroups $X$ of $G$ which are maximal amongst all reductive
subgroups of $G$ but not maximal subgroups of $G$; thus they are not contained
in any maximal reductive subgroup of $G$. The connected...
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Amende honorable is a defunct delictual remedy for defamation that originated in medieval canon law and became part of South African law through Roman-Dutch law. This remedy is aimed at restoring the dignity of the plaintiff by an apology from the defendant. It has fallen into disuse in South Africa, but recently, within the framework of restorative justice, South Africa's highest courts have reassessed the suitability of this remedy in restoring the dignity of the plaintiff by an apology from the defendant. Importantly, on various occasions they commented on its interrelation with the African principle of ubuntu which is regarded as a fundamental postulate of African customary law and in effect the foundation of restorative justice in African jurisprudence. In this article I address the suitability of any comparison of the equitable principles of Roman-Dutch law as expressed in the remedy of amende honorable and the equitable principles of African jurisprudence rooted in ubuntu.