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991.
Alvarez M Tremintin G Wang J Eng M Kao YH Jeong J Ling VT Borisov OV 《Analytical biochemistry》2011,(1):17-25
Recombinant monoclonal antibodies (MAbs) have become one of the most rapidly growing classes of biotherapeutics in the treatment of human disease. MAbs are highly heterogeneous proteins, thereby requiring a battery of analytical technologies for their characterization. However, incompatibility between separation and subsequent detection is often encountered. Here we demonstrate the utility of a generic on-line liquid chromatography–mass spectrometry (LC-MS) method operated in a two-dimensional format toward the rapid characterization of MAb charge and size variants. Using a single chromatographic system capable of running two independent gradients, up to six fractions of interest from an ion exchange (IEC) or size exclusion (SEC) separation can be identified by trapping and desalting the fractions onto a series of reversed phase trap cartridges with subsequent on-line analysis by mass spectrometry. Analysis of poorly resolved and low-level peaks in the IEC or SEC profile was facilitated by preconcentrating fractions on the traps using multiple injections. An on-line disulfide reduction step was successfully incorporated into the workflow, allowing more detailed characterization of modified MAbs by providing chain-specific information. The system is fully automated, thereby enabling high-throughput analysis with minimal sample handling. This technology provides rapid data turnaround time, a much needed feature during product characterization and development of multiple biotherapeutic proteins. 相似文献
992.
The contractile function of vascular smooth muscle cells within the media of resistance arterioles is tightly connected to the role of these blood vessels in the maintenance of blood pressure homeostasis. Thus, much effort has been made to understand the intracellular signaling pathways that control vascular smooth muscle cell contractility with the aim that this knowledge will provide important clues for reducing the impact of uncontrolled blood pressure in our society. A key set of surface receptors, the G-protein coupled receptors, has been widely associated with the regulation of vascular smooth muscle cell contractility. Indeed, many of the current treatments for hypertension involve selective inhibition of these receptors. More recently, we have begun to understand the cellular mechanisms whereby G-protein coupled pathways are connected to the contractile machinery of the vascular smooth muscle cells. What has emerged is a view where there are multiple intracellular control points for G-protein signaling that coordinate and focus the extracellular stimuli into meaningful physiologic responses. This work will examine some of the recent advances in our understanding of G-protein signaling and its regulation of contractile function in vascular smooth muscle cells. 相似文献
993.
Morissette G Bawolak MT Marceau F 《Canadian journal of physiology and pharmacology》2011,89(7):505-512
Local anesthetics, like many other cationic drugs, induce a vacuolar and macroautophagic cytopathology that has been observed in vivo and in various cell types; some also induce cytotoxicity of mitochondrial origin (apoptosis and necrosis) and it is not known whether the 2 types of toxicity overlap or interact. We compared bupivacaine with a more hydrophilic agent, lidocaine, for morphological, functional, and toxicological responses in a previously exploited nonneuronal system, primary smooth muscle cells. Bupivacaine induced little vacuolization (≥2.5?mmol/L, 4?h), but elicited autophagic accumulation (≥0.5?mmol/L, 4?h) and was massively cytotoxic at 2.5-5?mmol/L (4-24?h), the latter effect being unabated by the V-ATPase inhibitor bafilomycin A1. Lidocaine exerted little cytotoxicity at and below 5?mmol/L for 24?h, but intensely induced the V-ATPase-dependent vacuolar and autophagic cytopathology. Bupivacaine was more potent than lidocaine in disrupting mitochondrial potential, as judged by Mitotracker staining (significant proportions of cells affected in the 1-5 and 5-10?mmol/L concentration ranges, respectively). The addition of mitochondrial-inactivating toxins antimycin A and oligomycin to lidocaine (2.5?mmol/L) reproduced the profile of bupivacaine action (low intensity of vacuolization and retained autophagic accumulation). The high potency of bupivacaine as a mitochondrial toxicant eclipses the benign vacuolar and autophagic response seen with more hydrophilic local anesthetics. 相似文献
994.
Many organisms exhibit phenotypic plasticity; producing alternate phenotypes depending on the environment. Individuals can be plastic (intragenerational or direct plasticity), wherein individuals of the same genotype produce different phenotypes in response to the environments they experience. Alternatively, an individual's phenotype may be under the control of its parents, usually the mother (transgenerational or indirect plasticity), so that mother's genotype determines the phenotype produced by a given genotype of her offspring. Under what conditions does plasticity evolve to have intragenerational as opposed to transgenerational genetic control? To explore this question, we present a population genetic model for the evolution of transgenerational and intragenerational plasticity. We hypothesize that the capacity for plasticity incurs a fitness cost, which is borne either by the individual developing the plastic phenotype or by its mother. We also hypothesize that individuals are imperfect predictors of future environments and their capacity for plasticity can lead them occasionally to make a low‐fitness phenotype for a particular environment. When the cost, benefit and error parameters are equal, we show that there is no evolutionary advantage to intragenerational over transgenerational plasticity, although the rate of evolution of transgenerational plasticity is half the rate for intragenerational plasticity, as predicted by theory on indirect genetic effects. We find that transgenerational plasticity evolves when mothers are better predictors of future environments than offspring or when the fitness cost of the capacity for plasticity is more readily borne by a mother than by her developing offspring. We discuss different natural systems with either direct intragenerational plasticity or indirect transgenerational plasticity and find a pattern qualitatively in accord with the predictions of our model. 相似文献
995.
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997.
Through niche construction, organisms modify their environments in ways that can alter how selection acts on themselves and their offspring. However, the role of niche construction in shaping developmental and evolutionary trajectories, and its importance for population divergences and local adaptation, remains largely unclear. In this study, we manipulated both maternal and larval niche construction and measured the effects on fitness‐relevant traits in two rapidly diverging populations of the bull‐headed dung beetle, Onthophagus taurus. We find that both types of niche construction enhance adult size, peak larval mass, and pupal mass, which when compromised lead to a synergistic decrease in survival. Furthermore, for one measure, duration of larval development, we find that the two populations have diverged in their reliance on niche construction: larval niche construction appears to buffer against compromised maternal niche construction only in beetles from Western Australia, but not in beetles from the Eastern United States. We discuss our results in the context of rapid adaptation to novel conditions and the role of niche construction therein. 相似文献
998.
Campiche Remo Jackson Eileen Laurent Guillaume Roche Magalie Gougeon Sarah Séroul Pierre Ströbel Simon Massironi Marco Gempeler Mathias 《International journal of peptide research and therapeutics》2020,26(1):181-189
International Journal of Peptide Research and Therapeutics - Aging of skin manifests in loss of volume and firming due to degradation of extracellular matrix components such as collagen and... 相似文献
999.
Laurent?Michaud Frédéric?Coutenier Guillaume?Podevin Arnaud?Bonnard Fran?ois?Becmeur Naziha?Khen-Dunlop Frédéric?Auber Aude?Maurel Thomas?Gelas Martine?Dassonville Corinne?Borderon Alain?Dabadie Dominique?Weil Christian?Piolat Anne?Breton Djamal?Djeddi Alain?Morali Florence?Bastiani Thierry?Lamireau Frédéric?GottrandEmail author 《Orphanet journal of rare diseases》2013,8(1):186
Background
Congenital esophageal stenosis (CES) is a rare condition frequently associated with esophageal atresia (EA). There are limited data from small series about the presentation, treatment, and outcomes of CES.Methods
Medical records of all patients with CES included in the French Network on Esophageal Malformations and Congenital Diseases were reviewed retrospectively with regard to diagnosis, treatment, and outcome.Results
Over 18 years, 61 patients (30 boys) had CES, and 29 (47%) of these patients also had EA. The mean age at diagnosis was 24 months (1 day to 14 years) and was younger in patients with CES and EA than in those with isolated CES (7 vs. 126 months, p?<?0.05). Twenty-one of the 61 patients with CES had no clinical symptoms: in three patients, the findings were incidental, and in 18 of the 29 patients with associated EA, CES was diagnosed at the time of surgical repair of EA or during a postoperative systematic esophageal barium study. In the 40 other patients, at diagnosis, 50% presented with dysphasia, 40% with vomiting, 50% with food impaction, and 42% with respiratory symptoms. Diagnosis of CES was confirmed by esophageal barium study (56/61) and/or esophageal endoscopy (50/61). Sixteen patients had tracheobronchial remnants (TBR), 40 had fibromuscular stenosis (FMS), and five had membrane stenosis (MS). Thirty-four patients (56%) were treated by dilation only (13/34 remained asymptomatic at follow-up); 15 patients were treated by dilation but required later surgery because of failure (4/15 remained asymptomatic at follow-up); and nine patients had a primary surgical intervention (4/9 were asymptomatic at follow-up). Dilation was complicated by esophageal perforation in two patients (3.4%). At follow-up, dysphagia remained in 36% (21/58) of patients, but the incidence did not differ between the EA and the isolated CS groups (10/29 vs. 7/32, p?=?0.27).Conclusions
CS diagnosis can be delayed when associated with EA. Dilation may be effective for treating patients with FMS and MS, but surgical repair is often required for those with TBR. Our results show clearly that, regardless of the therapeutic option, dysphagia occurs frequently, and patients with CES should be followed over the long term.1000.