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991.
The stability of therapeutic antibodies is a prime pharmaceutical concern. In this work we examined thermal stability differences between human IgG1 and IgG4 Fab domains containing the same variable regions using the thermofluor assay. It was found that the IgG1 Fab domain is up to 11°C more stable than the IgG4 Fab domain containing the same variable region. We investigated the cause of this difference with the aim of developing a molecule with the enhanced stability of the IgG1 Fab and the biological properties of an IgG4 Fc. We found that replacing the seven residues, which differ between IgG1 C(H) 1 and IgG4 C(H) 1 domains, while retaining the native IgG1 light-heavy interchain disulfide (L-H) bond, did not affect thermal stability. Introducing the IgG1 type L-H interchain disulfide bond (DSB) into the IgG4 Fab resulted in an increase in thermal stability to levels observed in the IgG1 Fab with the same variable region. Conversely, replacement of the IgG1 L-H interchain DSB with the IgG4 type L-H interchain DSB reduced the thermal stability. We utilized the increased stability of the IgG1 Fab and designed a hybrid antibody with an IgG1 C(H) 1 linked to an IgG4 Fc via an IgG1 hinge. This construct has the expected biophysical properties of both the IgG4 Fc and IgG1 Fab domains and may therefore be a pharmaceutically relevant format.  相似文献   
992.
Franciscanas Pontoporia blainvillei are small dolphins endemic to Brazil, Uruguay and Argentina. During routine pathologic examinations, chronic pneumonia associated with cholesterol deposits was found in 16.7% of stranded and incidentally bycaught franciscanas (n = 60), and was more frequent in dolphins from the Brazilian state of S?o Paulo (Franciscana Management Area II) and frequently accompanied by splenic lymphoid hyperplasia. It is unclear why these otherwise uncommon lesions were relatively frequent in the studied dolphins, and further research is advised.  相似文献   
993.
The efficiency of gene expression in all organisms depends on the nucleotide composition of the coding region. GC content and codon usage are the two key sequence features known to influence gene expression, but the underlying molecular mechanisms are not entirely clear. Here we have determined the relative contributions of GC content and codon usage to the efficiency of nuclear gene expression in the unicellular green alga Chlamydomonas reinhardtii. By comparing gene variants that encode an identical amino acid sequence but differ in their GC content and/or codon usage, we show that codon usage is the key factor determining translational efficiency and, surprisingly, also mRNA stability. By contrast, unfavorable GC content affects gene expression at the level of the chromatin structure by triggering heterochromatinization. We further show that mutant algal strains that permit high‐level transgene expression are less susceptible to epigenetic transgene suppression and do not establish a repressive chromatin structure at the transgenic locus. Our data disentangle the relationship between GC content and codon usage, and suggest simple strategies to overcome the transgene expression problem in Chlamydomonas.  相似文献   
994.
995.
The aim of the study was to develop a simple and reliable method for differentiation of the two phenotypic, very similar Eurasian and North American beavers. Hair bulbs were plucked as tissue samples from the fur of living animals. The mitochondrial cytochrome b locus was amplified by polymerase chain reaction and sequenced. The fragments of the two species differed at 44/41 nucleotide sites. RsaI recognised two mutations, resulting in a restriction fragment length polymorphism that seems to be species specific, as could be revealed by the banding pattern. Zoo Biol 19:511-515, 2000. Copyright 2000 Wiley-Liss, Inc.  相似文献   
996.
Nineteen adults who had acute glomerulonephritis were reviewed with respect to the clinical course and long-term follow-up. The age range was from 17 to 55 years. Only one patient died during the acute episode. In 11 cases, onset occurred between November and January and 15 of the patients had a known respiratory tract infection three to 30 days before the onset. The most important symptoms noted were weight gain, edema, dyspnea, oliguria and red or smoky urine. The most prominent physical signs were elevated blood pressure, edema, abnormalities in the chest and fever of over 100° F. Fifteen patients showed roentgen evidence of pulmonary vascular congestion, pleural effusion, cardiomegaly, pneumonia or a combination of these abnormalities. All the patients had proteinuria and red blood cells in the urine, and half of them had red blood cell casts. Azotemia, when present, subsided in 9.4 days. The average diastolic pressure was 105 mm. of mercury and the mean fall was 26 mm. in 23.5 days. At six months, nine of the 13 patients still being observed continued to show proteinuria or microscopic hematuria (seven showed both). A late follow-up of ten patients showed one to have significant hypertension and one to have early functional impairment and inconstant proteinuria. In these cases the average blood pressure was 140/91 mm. as compared with 119/74 mm. at the time of discharge.Sporadic glomerulonephritis in adults presents essentially the same pattern as it does in children. Urinary abnormalities may persist for months or even years, and neither the present series nor those reported by others clearly reveal the ultimate prognosis.  相似文献   
997.
998.
Human growth is influenced not only by environmental and internal factors but also by a large number of different genes. One of these genes, SHOX, is believed to play a major role in growth, since defects in this homeobox-containing gene on the sex chromosomes lead to syndromal short stature (Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, and Turner syndrome) as well as to idiopathic short stature. We have analyzed 118 unrelated patients with Leri-Weill dyschondrosteosis and >1,500 patients with idiopathic short stature for deletions encompassing SHOX. Deletions were detected in 34% of the patients with Leri-Weill dyschondrosteosis and in 2% of the patients with idiopathic short stature. For 27 patients with Leri-Weill dyschondrosteosis and for 6 with idiopathic short stature, detailed deletion mapping was performed. Analysis was performed by polymerase chain reaction with the use of pseudoautosomal polymorphic markers and by fluorescence in situ hybridization with the use of cosmid clones. Here, we show that, although the identified deletions vary in size, the vast majority (73%) of patients tested share a distinct proximal deletion breakpoint. We propose that the sequence present within this proximal deletion breakpoint "hotspot" region predisposes to recurrent breaks.  相似文献   
999.
1000.
Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-γ and TNF-α. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN-γ, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-γ and suggesting them as possible therapeutic tools against IA.  相似文献   
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