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This article does not have an abstract 相似文献
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Mischa R. Müller Kenneth Saunders Christopher Grace Macy Jin Nicole Piche-Nicholas John Steven Ronan O’Dwyer Leeying Wu Lam Khetemenee Yulia Vugmeyster Timothy P. Hickling Lioudmila Tchistiakova Stephane Olland Davinder Gill Allan Jensen Caroline J. Barelle 《MABS-AUSTIN》2012,4(6):673-685
Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies. 相似文献
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Gilberto Sousa Alves Laurence O’Dwyer Alina Jurcoane Viola Oertel-Kn?chel Christian Kn?chel David Prvulovic Felipe Sudo Carlos Eduardo Alves Letice Valente Denise Moreira Fabian Fuβer Tarik Karakaya Johannes Pantel Eliasz Engelhardt Jerson Laks 《PloS one》2012,7(12)
Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia. 相似文献
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Surveys and questionnaires are regularly used in studies of human–animal relationships. However, little attention has been given to understanding how survey participants are provided with instructions for the selection of a single animal within a multi-pet household, let alone the implications for reporting and interpreting data. We reviewed the instructions for the selection of an individual animal in studies addressing emotional or psychological attachment between people and dogs. By searching multidisciplinary journals from the year 2000 onwards, we identified a total of 128 papers, of which 63 met the inclusion criteria. Where selection criteria/instructions were not clear, authors were contacted. One in five studies (21%, or n = 13) did not report their instructions. When provided, instructions varied considerably. The most commonly provided direction was “favorite/closest relationship” (n = 12, or 19%). The remainder (n = 38, or 60%) were spread across eight different categories. Around half of the studies used a validated questionnaire that already contained an instruction, though a similar proportion of studies implemented author-designed instruments. Overall, the common absence and inconsistency of instructions for individual dog selection is taken to imply that there is no standard expectation or approach for instructions to be reported in studies of human relationships with dogs, or human–animal relationships more generally. We recommend further research on the implication of selection methods to ensure that instructions can be matched with specific research aims. 相似文献
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Jessica K. Holien Benjamin Seibt Veena Roberts Evelyn Salvaris Michael W. Parker Peter J. Cowan Karen M. Dwyer 《Bioorganic & medicinal chemistry letters》2018,28(2):202-206
Adenosine is considered the canonical ligand for the adenosine 2B receptor (A2BR). A2BR is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A2BR signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A2BR.The computational modeling suggested that AMP interacts with more favorable energy to A2BR compared with adenosine. Furthermore, AMPαS, a non-hydrolyzable form of AMP, increased calcium uptake by Chinese hamster ovary (CHO) cells expressing the human A2BR, indicating preferential signaling via the Gq pathway. Therefore, a putative AMP-A2BR interaction is supported by the computational modeling data and the biological results suggest this interaction involves preferential Gq activation. These data provide further insights into the role of purinergic signaling in the pathophysiology of renal IRI. 相似文献
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Rats were trained to discriminate short or long durations of houselight illumination using a choice procedure. During the test phase of each trial, the left and right levers were presented with an auditory cue above one of them on (cued lever) while the other was off (uncued lever). The auditory cue was presented immediately after sample offset and the levers were inserted after the auditory cue had been presented for 2 s. For half of the rats, the correct response following the short sample was to press the cued lever, while following the long sample, it was to press the uncued lever. This was reversed for the remaining rats. Following acquisition of the discrimination, two different types of delay tests were administered. In the first set, the delay between offset of the sample and onset of the auditory cue was manipulated (Cue Delay Test). In the second set, the delay between onset of the auditory cue and entry of the levers into the chamber was manipulated (Response Delay Test). Cue Delay testing resulted in a choose-long bias at the longer delays. Response Delay testing did not result in a systematic response bias and there was little forgetting over the delay interval. These data suggest that the rats did not stop the internal clock when the nominal sample was offset, but allowed it to keep running until the auditory cue was presented. The data from the Response Delay Test indicate that either a response decision was made based on the clock reading as soon as the auditory cue was presented, or the clock reading itself was retained over the delay with no subjective shortening and little forgetting. 相似文献