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1.
An investigation was undertaken to quantify and correlate the nuclear and DNA-content modifications in the different grades of noninvasive urothelial papillary carcinoma. Nuclear area and a roundness factor were studied by histomorphometry in 35 cases, and the DNA content was analyzed in 27 cases. The values of the nuclear area and the roundness factor increased from normal-looking urothelium to grade 3 tumors. The DNA-content analysis indicated a progressive change of ploidy and the presence of an aneuploid (greater than 4c) population in some of the grade 2 and grade 3 lesions. A high coefficient of correlation between the nuclear abnormalities and the DNA content was found.  相似文献   
2.
A novel and efficient tagArray technology was developed that allows rapid identification of antibodies which bind to receptors with a specific expression profile, in the absence of biological information. This method is based on the cloning of a specific, short nucleotide sequence (tag) in the phagemid coding for each phage-displayed antibody fragment (phage-Ab) present in a library. In order to set up and validate the method we identified about 10,000 different phage-Abs binding to receptors expressed in their native form on the cell surface (10 k Membranome collection) and tagged each individual phage-Ab. The frequency of each phage-Ab in a given population can at this point be inferred by measuring the frequency of its associated tag sequence through standard DNA hybridization methods. Using tiny amounts of biological samples we identified phage-Abs binding to receptors preferentially expressed on primary tumor cells rather than on cells obtained from matched normal tissues. These antibodies inhibited cell proliferation in vitro and tumor development in vivo, thus representing therapeutic lead candidates.  相似文献   
3.
Scavenger receptor class B type I (SR-BI) is an essential receptor for hepatitis C virus (HCV) and a cell surface high-density-lipoprotein (HDL) receptor. The mechanism of SR-BI-mediated HCV entry, however, is not clearly understood, and the specific protein determinants required for the recognition of the virus envelope are not known. HCV infection is strictly linked to lipoprotein metabolism, and HCV virions may initially interact with SR-BI through associated lipoproteins before subsequent direct interactions of the viral glycoproteins with SR-BI occur. The kinetics of inhibition of cell culture-derived HCV (HCVcc) infection with an anti-SR-BI monoclonal antibody imply that the recognition of SR-BI by HCV is an early event of the infection process. Swapping and single-substitution mutants between mouse and human SR-BI sequences showed reduced binding to the recombinant soluble E2 (sE2) envelope glycoprotein, thus suggesting that the SR-BI interaction with the HCV envelope is likely to involve species-specific protein elements. Most importantly, SR-BI mutants defective for sE2 binding, although retaining wild-type activity for receptor oligomerization and binding to the physiological ligand HDL, were impaired in their ability to fully restore HCVcc infectivity when transduced into an SR-BI-knocked-down Huh-7.5 cell line. These findings suggest a specific and direct role for the identified residues in binding HCV and mediating virus entry. Moreover, the observation that different regions of SR-BI are involved in HCV and HDL binding supports the hypothesis that new therapeutic strategies aimed at interfering with virus/SR-BI recognition are feasible.Hepatitis C virus (HCV) is a global blood-borne pathogen, with 3% of the world''s population chronically infected. Most infections are asymptomatic, yet 60 to 80% become persistent and lead to severe fibrosis and cirrhosis, hepatic failure, or hepatocellular carcinoma (3). Currently available therapies are limited to the administration of pegylated alpha interferon in combination with ribavirin, which are expensive and often unsuccessful, with significant side effects (23, 36). Thus, the development of novel therapeutic approaches against HCV remains a high priority (18, 40, 60). Targeting the early steps of HCV infection may represent one such option, and much effort is being devoted to uncovering the mechanism of viral attachment and entry.The current view is that HCV entry into target cells occurs after attachment to specific cellular receptors via its surface glycoproteins E1 and E2 (27). The molecules to which HCV initially binds might constitute a diverse collection of cellular proteins, carbohydrates, and lipids that concentrate viruses on the cell surface and determine to a large extent which cell types, tissues, and organisms HCV can infect.CD81, claudin 1 (CLDN1), occludin (OCLN), and scavenger receptor class B type I (SR-BI) were previously shown to play essential roles in HCV cell entry (15, 22, 26, 35, 42, 43, 50, 63, 64).Recent reports suggest that CD81 engagement triggers intracellular signaling responses, ultimately leading to actin remodeling and the relocalization of CD81 to tight junctions (TJ) (11). Thus, CD81 may function as a bridge between the initial interaction of the virus with receptors on the basolateral surface of the hepatocyte and the TJ where two of the HCV entry molecules, CLDN1 and OCLN, are located. CD81 acts as a postbinding factor, and the TJ proteins CLDN1 and OCLN seem to be involved in late steps of HCV entry, such as HCV glycoprotein-dependent cell fusion (9, 11, 22). The discovery of TJ proteins as entry factors has added complexity to the model of HCV entry, suggesting parallels with other viruses like coxsackievirus B infection, where an initial interaction of the viral particle with the primary receptor decay-accelerating factor induces the lateral movement of the virus from the luminal surface to TJ, where coxsackievirus B binds coxsackievirus-adenovirus receptor and internalization takes place (17).Much less is known about the specific role of SR-BI in virus entry: neither the specific step of the entry pathway that SR-BI is involved in nor the protein determinants that mediate such processes are known. SR-BI is a lipoprotein receptor of 509 amino acids (aa) with cytoplasmic C- and N-terminal domains separated by a large extracellular domain (1, 13, 14). It is expressed primarily in liver and steroidogenic tissues, where it mediates selective cholesteryl ester uptake from high-density lipoprotein (HDL) and may act as an endocytic receptor (45, 46, 51, 52). SR-BI was originally identified as being a putative receptor for HCV because it binds soluble E2 (sE2) through interactions with E2 hypervariable region 1 (HVR1) (8, 50). RNA interference studies as well as the ability to block both HCV pseudoparticles (HCVpp) and cell culture-derived HCV (HCVcc) infections with anti SR-BI antibodies have confirmed its involvement in the HCV entry process (7, 8, 15, 26, 33, 63). Intriguingly, lipoproteins were previously shown to modulate HCV infection through SR-BI (12). It was indeed previously demonstrated that two natural ligands of SR-BI, HDL and oxidized low-density lipoprotein, can improve and inhibit HCV entry, respectively (57, 59). Moreover, small-molecule inhibitors of SR-BI-mediated lipid transfer (block of lipid transfer BLT-3 and BLT-4) abrogate the stimulation of HCV infectivity by human serum or HDL, suggesting that the enhancement of viral infection might be dependent on the lipid exchange activity of SR-BI (20, 58).We previously generated high-affinity monoclonal antibodies (MAbs) specific for human SR-BI and showed that they were capable of inhibiting the binding of SR-BI to sE2 and blocking HCVcc infection of human hepatoma cells (15). The HDL-induced enhancement of infection had no impact on the ability of the anti-SR-BI MAbs to block HCV infection, and the antibodies were effective in counteracting HCV infection even in the absence of lipoproteins. These data demonstrated that SR-BI participates in the HCV infection process as an entry receptor by directly interacting with viral glycoproteins. Here we have used one of the anti-SR-BI MAbs to show that SR-BI participates in an early step of HCV infection. By assays of binding of sE2 to SR-BI molecules from different species and to SR-BI mutants, we identified species-specific SR-BI protein residues that are required for sE2 binding. The functional significance of these observations was confirmed by the finding that SR-BI mutants with reduced binding to sE2 were also impaired in their ability to restore the infectivity of an SR-BI-knocked-down Huh-7.5 cell line. Finally, we demonstrated that SR-BI mutants with impaired sE2 binding can still form oligomeric structures and that they can bind the physiological ligand HDL and mediate cholesterol efflux, suggesting that distinct protein determinants are responsible for the interaction with HDL and the HCV particle.  相似文献   
4.

Background

Most research on the roles of auditory information and its interaction with vision has focused on perceptual performance. Little is known on the effects of sound cues on visually-guided hand movements.

Methodology/Principal Findings

We recorded the sound produced by the fingers upon contact as participants grasped stimulus objects which were covered with different materials. Then, in a further session the pre-recorded contact sounds were delivered to participants via headphones before or following the initiation of reach-to-grasp movements towards the stimulus objects. Reach-to-grasp movement kinematics were measured under the following conditions: (i) congruent, in which the presented contact sound and the contact sound elicited by the to-be-grasped stimulus corresponded; (ii) incongruent, in which the presented contact sound was different to that generated by the stimulus upon contact; (iii) control, in which a synthetic sound, not associated with a real event, was presented. Facilitation effects were found for congruent trials; interference effects were found for incongruent trials. In a second experiment, the upper and the lower parts of the stimulus were covered with different materials. The presented sound was always congruent with the material covering either the upper or the lower half of the stimulus. Participants consistently placed their fingers on the half of the stimulus that corresponded to the presented contact sound.

Conclusions/Significance

Altogether these findings offer a substantial contribution to the current debate about the type of object representations elicited by auditory stimuli and on the multisensory nature of the sensorimotor transformations underlying action.  相似文献   
5.
cDNA expression libraries displayed on lambda phage have been successfully employed to identify partners involved in antibody–antigen, protein– protein and DNA–protein interactions and represent a novel approach to functional genomics. However, as in all other cDNA expression libraries based on fusion to a carrier polypeptide, a major issue of this system is the absence of control over the translation frame of the cDNA. As a consequence, a large number of clones will contain lambda D/cDNA fusions, resulting in the foreign sequence being translated on alternative reading frames. Thus, many phage will not display natural proteins, but could be selected, as they mimic the binding properties of the real ligand, and will hence interfere with the selection outcome. Here we describe a novel lambda vector for display of exogenous peptides at the C-terminus of the capsid D protein. In this vector, translation of fusion peptides in the correct reading frame allows efficient in vivo biotinylation of the chimeric phage during amplification. Using this vector system we constructed three libraries from human hepatoma cells, mouse hepatocytic MMH cells and from human brain. Clones containing open reading frames (ORFs) were rapidly selected by streptavidin affinity chromatography, leading to biological repertoires highly enriched in natural polypeptides. We compared the selection outcome of two independent experiments performed using an anti-GAP-43 monoclonal antibody on the human brain cDNA library before and after ORF enrichment. A significant increase in the efficiency of identification of natural target peptides with very little background of false-positive clones was observed in the latter case.  相似文献   
6.
Human social interactions often require people to take a different perspective than their own. Although much research has been done on egocentric spatial representation in a solo context, little is known about how space is mapped in relation to other bodies. Here we used a spatial perspective-taking paradigm to investigate whether observing a person holding his arms crossed over the body midline has an impact on the encoding of left/right and front/back spatial relations from that person’s perspective. In three experiments, we compared performance in a task in which spatial judgments were made from the perspective of the participant or from that of a co-experimenter. Depending on the experimental condition, the participant’s and the co-experimenter’s arms were either crossed or not crossed over the midline. Our results showed that crossing the arms had a specific effect on spatial judgments based on a first-person perspective. More specifically, the responses corresponding to the dominant hand side were slower in the crossed than in the uncrossed arms condition. Crucially, a similar effect was also found when the participants adopted the perspective of a person holding his arms crossed, but not when the other person’s arms were held in an unusual but uncrossed posture. Taken together these findings indicate that egocentric space and altercentric space are similarly coded in neurocognitive maps structured with respect to specific body segments.  相似文献   
7.
8.
The envelope glycoprotein E2 of hepatitis C virus (HCV) is the target of neutralizing antibodies and is presently being evaluated as an HCV vaccine candidate. HCV binds to human cells through the interaction of E2 with the tetraspanin CD81, a putative viral receptor component. We have analyzed four different E2 proteins from 1a and 1b viral isolates for their ability to bind to recombinant CD81 in vitro and to the native receptor displayed on the surface of Molt-4 cells. A substantial difference in binding efficiency between these E2 variants was observed, with proteins derived from 1b subtypes showing significantly lower binding than the 1a protein. To elucidate the mechanism of E2-CD81 interaction and to identify critical regions responsible for the different binding efficiencies of the E2 variants, several mutants were generated in E2 protein regions predicted by computer modeling to be exposed on the protein surface. Functional analysis of these E2 derivatives revealed that at least two distinct domains are responsible for interaction with CD81. A first segment centered around amino acid residues 613 to 618 is essential for recognition, while a second element including the two hypervariable regions (HVRs) modulates E2 receptor binding. Binding inhibition experiments with anti-HVR monoclonal antibodies confirmed this mapping and supported the hypothesis that a complex interplay between the two HVRs of E2 is responsible for modulating receptor binding, possibly through intramolecular interactions. Finally, E2 proteins from different isolates displayed a profile of binding to human hepatic cells different from that observed on Molt-4 cells or isolated recombinant CD81, indicating that additional factors are involved in viral recognition by target liver cells.  相似文献   
9.

Background

Research on multisensory integration during natural tasks such as reach-to-grasp is still in its infancy. Crossmodal links between vision, proprioception and audition have been identified, but how olfaction contributes to plan and control reach-to-grasp movements has not been decisively shown. We used kinematics to explicitly test the influence of olfactory stimuli on reach-to-grasp movements.

Methodology/Principal Findings

Subjects were requested to reach towards and grasp a small or a large visual target (i.e., precision grip, involving the opposition of index finger and thumb for a small size target and a power grip, involving the flexion of all digits around the object for a large target) in the absence or in the presence of an odour evoking either a small or a large object that if grasped would require a precision grip and a whole hand grasp, respectively. When the type of grasp evoked by the odour did not coincide with that for the visual target, interference effects were evident on the kinematics of hand shaping and the level of synergies amongst fingers decreased. When the visual target and the object evoked by the odour required the same type of grasp, facilitation emerged and the intrinsic relations amongst individual fingers were maintained.

Conclusions/Significance

This study demonstrates that olfactory information contains highly detailed information able to elicit the planning for a reach-to-grasp movement suited to interact with the evoked object. The findings offer a substantial contribution to the current debate about the multisensory nature of the sensorimotor transformations underlying grasping.  相似文献   
10.
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