Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle   总被引：1，自引：0，他引：1  

Molinari M  Calanca V  Galli C  Lucca P  Paganetti P 《Science (New York, N.Y.)》2003,299(5611):1397-1400

The mechanisms that determine how folding attempts are interrupted to target folding-incompetent proteins for endoplasmic reticulum-associated degradation (ERAD) are poorly defined. Here the alpha-mannosidase I-like protein EDEM was shown to extract misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle. EDEM overexpression resulted in faster release of folding-incompetent proteins from the calnexin cycle and earlier onset of degradation, whereas EDEM down-regulation prolonged folding attempts and delayed ERAD. Up-regulation of EDEM during ER stress may promote cell recovery by clearing the calnexin cycle and by accelerating ERAD of terminally misfolded polypeptides.  相似文献   

Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning     

Aiuti A  Slavin S  Aker M  Ficara F  Deola S  Mortellaro A  Morecki S  Andolfi G  Tabucchi A  Carlucci F  Marinello E  Cattaneo F  Vai S  Servida P  Miniero R  Roncarolo MG  Bordignon C 《Science (New York, N.Y.)》2002,296(5577):2410-2413

Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated. Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions (including antigen-specific responses), and lower toxic metabolites. Both patients are currently at home and clinically well, with normal growth and development. These results indicate the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID.  相似文献   

Unique chromatin remodeling and transcriptional regulation in spermatogenesis   总被引：1，自引：0，他引：1  

Sassone-Corsi P 《Science (New York, N.Y.)》2002,296(5576):2176-2178

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A gene expression map for the euchromatic genome of Drosophila melanogaster     

Stolc V  Gauhar Z  Mason C  Halasz G  van Batenburg MF  Rifkin SA  Hua S  Herreman T  Tongprasit W  Barbano PE  Bussemaker HJ  White KP 《Science (New York, N.Y.)》2004,306(5696):655-660

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Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein     

Kochendoerfer GG  Chen SY  Mao F  Cressman S  Traviglia S  Shao H  Hunter CL  Low DW  Cagle EN  Carnevali M  Gueriguian V  Keogh PJ  Porter H  Stratton SM  Wiedeke MC  Wilken J  Tang J  Levy JJ  Miranda LP  Crnogorac MM  Kalbag S  Botti P  Schindler-Horvat J  Savatski L  Adamson JW  Kung A  Kent SB  Bradburne JA 《Science (New York, N.Y.)》2003,299(5608):884-887

We report the design and total chemical synthesis of "synthetic erythropoiesis protein" (SEP), a 51-kilodalton protein-polymer construct consisting of a 166-amino-acid polypeptide chain and two covalently attached, branched, and monodisperse polymer moieties that are negatively charged. The ability to control the chemistry allowed us to synthesize a macromolecule of precisely defined covalent structure. SEP was homogeneous as shown by high-resolution analytical techniques, with a mass of 50,825 +/-10 daltons by electrospray mass spectrometry, and with a pI of 5.0. In cell and animal assays for erythropoiesis, SEP displayed potent biological activity and had significantly prolonged duration of action in vivo. These chemical methods are a powerful tool in the rational design of protein constructs with potential therapeutic applications.  相似文献   

High-accuracy ab initio rotation-vibration transitions for water     

Polyansky OL  Császár AG  Shirin SV  Zobov NF  Barletta P  Tennyson J  Schwenke DW  Knowles PJ 《Science (New York, N.Y.)》2003,299(5606):539-542

The spectrum of water vapor is of fundamental importance for a variety of processes, including the absorption and retention of sunlight in Earth's atmosphere. Therefore, there has long been an urgent need for a robust and accurate predictive model for this spectrum. In our work on the high-resolution spectrum of water, we report first-principles calculations that approach experimental accuracy. To achieve this, we performed exceptionally large electronic structure calculations and considered a variety of effects, including quantum electrodynamics, which have routinely been neglected in studies of small many-electron molecules. The high accuracy of the resulting ab initio procedure is demonstrated for the main isotopomers of water.  相似文献   

Materials science. In praise of pores     

Colombo P 《Science (New York, N.Y.)》2008,322(5900):381-383

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The limits of water pumps     

Wang L  D'Odorico P 《Science (New York, N.Y.)》2008,321(5885):36-37

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Experimental evidence supports a sex-specific selective sieve in mitochondrial genome evolution     

Innocenti P  Morrow EH  Dowling DK 《Science (New York, N.Y.)》2011,332(6031):845-848

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Arrhythmias and transient changes in cardiac function after topical administration of one drop of phenylephrine 10% in an adult cat undergoing conjunctival graft     

Franci P  Leece EA  McConnell JF 《Veterinary anaesthesia and analgesia》2011,38(3):208-212

HistoryA 2-year-old, entire female, Somali cat weighing 3.8 kg was admitted for a conjunctival graft on the right eye, for treatment of an acute descemetocele. Medetomidine 4.2 μg kg^?1 and methadone 0.2 mg kg^?1 were administered by intramuscular injection as preanaesthetic medication. Anaesthesia was induced using diazepam 0.26 mg kg^?1 and propofol 4 mg kg^?1 administered by intravenous (IV) injection. Following endotracheal intubation, anaesthesia was maintained with isoflurane delivered in oxygen (1 L minute^?1) and nitrous oxide (2 L minute^?1) via a non-rebreathing system. Twenty minutes after induction of anaesthesia, one drop of a 10% phenylephrine hydrochloride solution was administered topically to the right eye.Physical examinationAfter phenylephrine administration, a decrease in heart rate (from 95 to 80 beats minute^?1) and an increase in arterial blood pressure occurred. The pulse then became difficult to palpate manually and multifocal ventricular premature contractions were observed on the electrocardiogram.ManagementNitrous oxide was discontinued and the isoflurane vaporizer setting was decreased from 1.5% to 0.5%. Lidocaine 1 mg kg^?1 IV was administered, this resulted in ventricular bigeminy. The quality of the femoral pulse improved and was regular in rhythm and character. Surgery was completed as fast as possible. The bigeminy progressively disappeared and before disconnecting the cat from the breathing system, there was a normal sinus rhythm with a heart rate of 85 beats minute^?1.Follow-upEchocardiography was performed during recovery and showed mitral and aortic valve insufficiency and dilation of the left ventricle, suggesting a reduction in systolic function. Echocardiography was repeated the following day and was normal.ConclusionsIn order to diminish the potential for cardiovascular sequelae associated with systemic absorption of ocular phenylephrine, less concentrated solutions, smaller drop size or different instillation techniques should be considered for topical use in small patients.  相似文献