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11.
(+/-)-(2R,3R,5R)-[2-(1'-S-acetamido-3'-methyl)butyl-3-methoxycarbonyl]tetrahydrofuran-5-carboxylic acid (9) and (+/-)-(2R,3R,5R)-[2-(1'-S-acetamido-3'-methyl)butyl-3-(4'-imidazolyl)]tetrahydrofuran 5-carboxylic acid (14) were synthesized as inhibitors of influenza neuraminidase (NA). Both compounds 9 and 14 inhibit influenza NA A with an IC(50) of about 0.5 microM and NA B with an IC(50) of 1.0 microM.  相似文献   
12.
Most species pairs are isolated through the collective action of a suite of barriers. Recent work has shown that cryptic barriers such as conspecific sperm precedence can be quite strong, suggesting that they evolve quickly. However, because the strength of multiple barriers has been formally quantified in very few systems, the relative speed with which conspecific sperm precedence evolves remains unclear. Here, we measure the strength of both conspecific sperm precedence and cryptic non-competitive isolation between the hybridizing sister species, Chrysochus auratus and C. cobaltinus (Coleoptera: Chrysomelidae), and compare the strength of those barriers to the strength of other known reproductive barriers in this system. Overall, cryptic barriers in this system are weaker than other barriers, indicating that they have not evolved rapidly. Furthermore, their evolution has been asymmetric. Non-competitive barriers substantially reduce the production of hybrid offspring by C. auratus females but not by C. cobaltinus females. In multiply-mated C. cobaltinus females, heterospecific sperm outcompete conspecific sperm, as evidenced by the fact that heterospecific males sired disproportionately more offspring than predicted from the results for singly-mated females. In C. auratus females, neither sperm type has a competitive advantage. Such asymmetries explain why nearly all F1 hybrids in the field are from crosses between C. cobaltinus females and C. auratus males. We discuss these findings in terms of understanding the cost of mating 'mistakes' in the Chrysochus hybrid zone. In addition, our discovery that 95% confidence intervals for commonly-used isolation statistics can be very wide has important implications for speciation research. Specifically, to avoid biases in the interpretation of such isolation metrics, we suggest that studies should routinely include error estimates in their analyses of reproductive isolation.  相似文献   
13.
Alterations in bone remodeling are a major public health issue, as therapeutic options for widespread bone disorders such as osteoporosis and tumor-induced osteolysis are still limited. Therefore, a detailed understanding of the regulatory mechanism governing bone cell differentiation in health and disease are of utmost clinical importance. Here we report a novel function of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a member of the immunoglobulin superfamily involved in inflammation and tumorigenesis, in the physiologic regulation of bone remodeling. Assessing the expression of all members of the murine Ceacam family in bone tissue and marrow, we found CEACAM1 and CEACAM10 to be differentially expressed in both bone-forming osteoblasts and bone-resorbing osteoclasts. While Ceacam10-deficient mice displayed no alteration in structural bone parameters, static histomorphometry demonstrated a reduced trabecular bone mass in mice lacking CEACAM1. Furthermore, cellular and dynamic histomorphometry revealed an increased osteoclast formation in Ceacam1-deficient mice, while osteoblast parameters and the bone formation rate remained unchanged. In line with these findings, we detected accelerated osteoclastogenesis in Ceacam1-deficient bone marrow cells, while osteoblast differentiation, as determined by mineralization and alkaline phosphatase assays, was not affected. Therefore, our results provide in vivo and in vitro evidence for a physiologic role of CEACAM1 in the regulation of osteoclastogenesis.  相似文献   
14.
Seitz AR  Kim R  Shams L 《Current biology : CB》2006,16(14):1422-1427
Numerous studies show that practice can result in performance improvements on low-level visual perceptual tasks [1-5]. However, such learning is characteristically difficult and slow, requiring many days of training [6-8]. Here, we show that a multisensory audiovisual training procedure facilitates visual learning and results in significantly faster learning than unisensory visual training. We trained one group of subjects with an audiovisual motion-detection task and a second group with a visual motion-detection task, and compared performance on trials containing only visual signals across ten days of training. Whereas observers in both groups showed improvements of visual sensitivity with training, subjects trained with multisensory stimuli showed significantly more learning both within and across training sessions. These benefits of multisensory training are particularly surprising given that the learning of visual motion stimuli is generally thought to be mediated by low-level visual brain areas [6, 9, 10]. Although crossmodal interactions are ubiquitous in human perceptual processing [11-13], the contribution of crossmodal information to perceptual learning has not been studied previously. Our results show that multisensory interactions can be exploited to yield more efficient learning of sensory information and suggest that multisensory training programs would be most effective for the acquisition of new skills.  相似文献   
15.
Paenibacillus larvae, the etiological agent of the globally occurring epizootic American Foulbrood (AFB) of honey bees, causes intestinal infections in honey bee larvae which develop into systemic infections inevitably leading to larval death. Massive brood mortality might eventually lead to collapse of the entire colony. Molecular mechanisms of host-microbe interactions in this system and of differences in virulence between P. larvae genotypes are poorly understood. Recently, it was demonstrated that the degradation of the peritrophic matrix lining the midgut epithelium is a key step in pathogenesis of P. larvae infections. Here, we present the isolation and identification of PlCBP49, a modular, chitin-degrading protein of P. larvae and demonstrate that this enzyme is crucial for the degradation of the larval peritrophic matrix during infection. PlCBP49 contains a module belonging to the auxiliary activity 10 (AA10, formerly CBM33) family of lytic polysaccharide monooxygenases (LPMOs) which are able to degrade recalcitrant polysaccharides. Using chitin-affinity purified PlCBP49, we provide evidence that PlCBP49 degrades chitin via a metal ion-dependent, oxidative mechanism, as already described for members of the AA10 family. Using P. larvae mutants lacking PlCBP49 expression, we analyzed in vivo biological functions of PlCBP49. In the absence of PlCBP49 expression, peritrophic matrix degradation was markedly reduced and P. larvae virulence was nearly abolished. This indicated that PlCBP49 is a key virulence factor for the species P. larvae. The identification of the functional role of PlCBP49 in AFB pathogenesis broadens our understanding of this important family of chitin-binding and -degrading proteins, especially in those bacteria that can also act as entomopathogens.  相似文献   
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Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that the saturated alkane dialkyl units provided the most active analogs.  相似文献   
19.
Functional changes in sensorimotor representation occur in response to use and lesion throughout life. Emerging evidence suggests that functional changes are paralleled by respective macroscopic structural changes. In the present study we used voxel-based morphometry to investigate sensorimotor cortex in subjects with congenitally malformed upper extremities. We expected increased or decreased grey matter to parallel the enlarged or reduced functional representations we reported previously. More specifically, we expected decreased grey matter values in lateral sensorimotor cortex related to compromised hand function and increased grey matter values in medial sensorimotor cortex due to compensatory foot use. We found a medial cluster of grey matter increase in subjects with frequent, hand-like compensatory foot use. This increase was predominantly seen for lateral premotor, supplementary motor, and motor areas and only marginally involved somatosensory cortex. Contrary to our expectation, subjects with a reduced number of fingers, who had shown shrinkage of the functional hand representation previously, did not show decreased grey matter values within lateral sensorimotor cortex. Our data suggest that functional plastic changes in sensorimotor cortex can be associated with increases in grey matter but may also occur in otherwise macroscopically normal appearing grey matter volumes. Furthermore, macroscopic structural changes in motor and premotor areas may be observed without respective changes in somatosensory cortex.  相似文献   
20.
We report a first of its kind functional cell surface display of nucleic acid polymerase and its directed evolution to efficiently incorporate 2′-O-methyl nucleotide triphosphates (2′-OMe-NTPs). In the development of polymerase cell surface display, two autotransporter proteins (Escherichia coli adhesin involved in diffuse adherence and Pseudomonas aeruginosa esterase A [EstA]) were employed to transport and anchor the 68-kDa Klenow fragment (KF) of E. coli DNA polymerase I on the surface of E. coli. The localization and function of the displayed KF were verified by analysis of cell outer membrane fractions, immunostaining, and fluorometric detection of synthesized DNA products. The EstA cell surface display system was applied to evolve KF for the incorporation of 2′-OMe-NTPs and a KF variant with a 50.7-fold increased ability to successively incorporate 2′-OMe-NTPs was discovered. Expanding the scope of cell-surface displayable proteins to the realm of polymerases provides a novel screening tool for tailoring polymerases to diverse application demands in a polymerase chain reaction and sequencing-based biotechnological and medical applications. Especially, cell surface display enables novel polymerase screening strategies in which the heat-lysis step is bypassed and thus allows the screening of mesophilic polymerases with broad application potentials ranging from diagnostics and DNA sequencing to replication of synthetic genetic polymers.  相似文献   
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