Demographic consequences of invasion by a native, controphic competitor to an insular bird population.

Species invasions and range shifts can lead to novel competitive interactions between historically resident and colonizing species, but the demographic consequences of such interactions remain controversial. We present results from field experiments and 45 years of demographic monitoring to test the hypothesis that the colonization of Mandarte Is., BC, Canada, by fox sparrows (Passerella iliaca) caused the long-term decline of the resident population of song sparrows (Melospiza melodia). Several lines of evidence indicate that competition with fox sparrows for winter food reduced over-winter survival in juvenile song sparrows by 48% from 1960 to 2015, enforcing population decline despite an increase in annual reproductive rate in song sparrows over the same period. Preference for locally abundant seeds presented at experimental arenas suggested complete overlap in diet in song and fox sparrows, and observations at arenas baited with commercial seed showed that fox sparrows displaced song sparrows in 91-100% of interactions in two periods during winter. In contrast, we found no evidence of interspecific competition for resources during the breeding season. Our results indicate that in the absence of marked shifts in niche dimension, range expansions by dominant competitors have the potential to cause the extirpation of historically resident species when competitive interactions between them are strong and resources not equitably partitioned.

Evolution of precopulatory and post-copulatory strategies of inbreeding avoidance and associated polyandry.

Inbreeding depression is widely hypothesized to drive adaptive evolution of precopulatory and post-copulatory mechanisms of inbreeding avoidance, which in turn are hypothesized to affect evolution of polyandry (i.e. female multiple mating). However, surprisingly little theory or modelling critically examines selection for precopulatory or post-copulatory inbreeding avoidance, or both strategies, given evolutionary constraints and direct costs, or examines how evolution of inbreeding avoidance strategies might feed back to affect evolution of polyandry. Selection for post-copulatory inbreeding avoidance, but not for precopulatory inbreeding avoidance, requires polyandry, whereas interactions between precopulatory and post-copulatory inbreeding avoidance might cause functional redundancy (i.e. 'degeneracy') potentially generating complex evolutionary dynamics among inbreeding strategies and polyandry. We used individual-based modelling to quantify evolution of interacting precopulatory and post-copulatory inbreeding avoidance and associated polyandry given strong inbreeding depression and different evolutionary constraints and direct costs. We found that evolution of post-copulatory inbreeding avoidance increased selection for initially rare polyandry and that evolution of a costly inbreeding avoidance strategy became negligible over time given a lower-cost alternative strategy. Further, fixed precopulatory inbreeding avoidance often completely precluded evolution of polyandry and hence post-copulatory inbreeding avoidance, but fixed post-copulatory inbreeding avoidance did not preclude evolution of precopulatory inbreeding avoidance. Evolution of inbreeding avoidance phenotypes and associated polyandry is therefore affected by evolutionary feedbacks and degeneracy. All else being equal, evolution of precopulatory inbreeding avoidance and resulting low polyandry is more likely when post-copulatory inbreeding avoidance is precluded or costly, and evolution of post-copulatory inbreeding avoidance greatly facilitates evolution of costly polyandry.

Cervical and lumbar spinal arthroplasty: clinical review.

In contrast to cervical and lumbar fusion procedures, the principal aim of disk arthroplasty is to recapitulate the normal kinematics and biomechanics of the spinal segment affected. Following decompression of the neural elements, disk arthroplasty allows restoration of disk height and maintenance of spinal alignment. Based on clinical observations and biomechanical testing, the anticipated advantage of arthroplasty over standard arthrodesis techniques has been a proposed reduction in the development of symptomatic ALD. In this review of cervical and lumbar disk arthroplasty, we highlight the clinical results and experience with standard fusion techniques, incidence of ALD in the population of patients with surgical fusion, and indications for arthroplasty, as well as the biomechanical and clinical outcomes following arthroplasty. In addition, we introduce the devices currently available and provide a critical appraisal of the clinical evidence regarding arthroplasty procedures.

Sensitivity of N170 and late positive components to social categorization and emotional valence.

Previous experiments have shown that categorization of people into two distinct fictive groups has an impact on cognitive processes. The main objective of the present study was to examine whether this mere categorization improves information processing speed and alters early and late onset ERPs during a social judgment task. In a group membership situation, in-group evaluation enhanced information processing speed and occipito-temporal N170 amplitudes, associated with orthographic processing, compared to out-group evaluation, more so for positive than negative attributes. Moreover, negative adjectives elicited larger N170 amplitudes and faster information processing speed than positive adjectives. In contrast, positive adjectives in a non-membership context enhanced a late positive component in prefrontal regions. These results reflect the existence of a motivational top-down influence due to social categorization in early perceptual stages of word processing. These findings are also in accord with the existence of two distinct systems of evaluation, the first implicating an automatic processing represented in occipito-temporal neocortex and the other a more controlled processing represented in PFC.

Influence of visual constraints in the trajectory formation of grasping movements.

The main objective of the present study is to show that the visual context can influence the trajectory formation of grasping movements. We asked participants to reach and grasp a cylinder disposed at three different positions: -20 degrees , 0 degrees and 20 degrees of eccentricity with respect to the midsagittal axis. Grasping movements were performed in a direct and in an indirect visual feedback condition (i.e., controlled through a vertical video display). Results revealed that for grasping movements directed toward objects located at -20 degrees and 0 degrees , path curvatures of the wrist, the thumb and the index finger were significantly straighter in the indirect visual feedback condition. However, no significant difference concerning hand path curvature was observed when the movement was directed toward the object located at 20 degrees . This suggests that grasping movements controlled through a remote visual feedback tend to be planned in extrinsic space and that the effect of the visual context on movement planning appears to be not isotropic over the workspace.

Dissociation between "where" and "how" judgements of one's own motor performance in a video-controlled reaching task.

The aim of the present study is to show that the sensorimotor system makes a differential use of visual and internal (proprioception and efferent copy) signals when evaluating either the spatial or the dynamical components of our own motor response carried out under a remote visual feedback. Subjects were required to monitor target-directed pointings from the images furnished by a video camera overhanging the workspace. By rotating the camera, the orientation of the movement perceived on the screen was either changed by 45 degrees (visual bias) or maintained in conformity with the actual trajectory (0 degrees ). In either condition, after completing twenty pointings, participants had to evaluate their visuomotor performance in two non visual testing: They were both asked to reach the target in a single movement (evaluation of "how to reach the target"), and to evaluate the mapping of the spatial layout where they acted (evaluations of "where the starting position was and, what movement direction was"). Results revealed that though motor performance in the 45 degrees conditions was adapted to the visuomotor conflict, participants' evaluation of the spatial aspect of the performance was affected by the biased visual information. A different pattern was revealed for the evaluation of "how" the target was reached which was not affected by the visual bias. Thus, it is suggested that segregated processing of visual and kinesthetic information occurs depending upon the dimension of the performance that is judged. Visual information prevails when identifying the spatial context of a motor act whereas proprioception and/or efferent copy related signals are privileged when evaluating the dynamical component of the response.

Visual and motor constraints on trajectory planning in pointing movements.

The aim of the present study was to show that planning and controlling the trajectory of a pointing movement is influenced not solely by physical constraints but also by visual constraints. Subjects were required to point towards different targets located at 20 degrees , 40 degrees , 60 degrees and 80 degrees of eccentricity. Movements were either constrained (i.e. two-dimensional movements) or unconstrained (i.e. three-dimensional movements). Furthermore, movements were carried out either under a direct or a remote visual control (use of a video system). Results revealed that trajectories of constrained movements were nearly straight whatever the eccentricity of the target and the type of visual control. A different pattern was revealed for unconstrained movements. Indeed, under direct vision the trajectory curvature increased as the eccentricity augmented, whereas under indirect vision, trajectories remained nearly straight whatever the eccentricity of the target. Thus, movements controlled through a remote visual feedback appear to be planned in extrinsic space as constrained movements.

Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin.

Formation of the immunological synapse requires TCR signal-dependent protein redistribution. However, the specific molecular mechanisms controlling protein relocation are not well defined. Moesin is a widely expressed phospho-protein that links many transmembrane molecules to the cortical actin cytoskeleton. Here, we demonstrate that TCR-induced exclusion of the large sialoprotein CD43 from the synapse is an active event mediated by its reversible binding to moesin. Our results also reveal that relocalization of moesin is associated with changes in the phosphorylation status of this cytoskeletal adaptor protein. Finally, these findings raise the possibility that the change in moesin localization resulting from TCR engagement modifies the overall topology of the lymphocyte membrane and facilitates molecular interactions at the site of presenting cell contact.

The free energy landscape for beta hairpin folding in explicit water.

The folding free energy landscape of the C-terminal beta hairpin of protein G has been explored in this study with explicit solvent under periodic boundary condition and OPLSAA force field. A highly parallel replica exchange method that combines molecular dynamics trajectories with a temperature exchange Monte Carlo process is used for sampling with the help of a new efficient algorithm P3ME/RESPA. The simulation results show that the hydrophobic core and the beta strand hydrogen bond form at roughly the same time. The free energy landscape with respect to various reaction coordinates is found to be rugged at low temperatures and becomes a smooth funnel-like landscape at about 360 K. In contrast to some very recent studies, no significant helical content has been found in our simulation at all temperatures studied. The beta hairpin population and hydrogen-bond probability are in reasonable agreement with the experiment at biological temperature, but both decay more slowly than the experiment with temperature.

Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells.

Iron is essential for cell proliferation, heme synthesis, and a variety of cellular metabolic processes. In most cells, transferrin receptor-mediated endocytosis is a major pathway for cellular iron uptake. Recently, transferrin receptor 2 (TfR2), another receptor for transferrin, was cloned. High levels of expression of TfR2 messenger RNA (mRNA) occur in the liver, as well as in HepG2 (a hepatoma cell line) and K562 (an erythroid leukemia cell line). In this study, TfR2 mRNA expression was analyzed in hematological cell lines, normal erythroid cells at various stages of differentiation, and leukemia and preleukemia cells. High levels of TfR2 expression occurred in all of the erythroid cell lines that were examined. Erythroid-specific expression of TfR2 protein in bone marrow cells was confirmed by immunohistochemical staining. Expression of TfR2 mRNA was high in normal CD34(+) erythroid precursor cells, and levels decreased during erythroid differentiation in vitro. Levels of expression of TfR2-alpha mRNA were significantly higher in erythroleukemia (M6) marrow samples than in nonmalignant control marrow samples. In addition, relatively higher levels of TfR2-alpha mRNA expression occurred in some samples of myelodysplastic syndrome that had erythroid hyperplasia in bone marrow, acute myelogenous leukemia M1, M2, and chronic myelogenous leukemia. Expression profiles of normal members of the erythroid lineage suggest that TfR2-alpha may be a useful marker of early erythroid precursor cells. The clinical significance of TfR2-alpha expression in leukemia cells remains to be determined.

Regulation of expression of murine transferrin receptor 2.

Complementary and genomic DNA for the murine transferrin receptor 2 (TfR2) were cloned and mapped to chromosome 5. Northern blot analysis showed that high levels of expression of murine TfR2 occurred in the liver, whereas expression of TfR1 in the liver was relatively low. During liver development, TfR2 was up-regulated and TfR1 was down-regulated. During erythrocytic differentiation of murine erythroleukemia (MEL) cells induced by dimethylsulfoxide, expression of TfR1 increased, whereas TfR2 decreased. In MEL cells, expression of TfR1 was induced by desferrioxamine, an iron chelator, and it was reduced by ferric nitrate. In contrast, levels of TfR2 were not affected by the cellular iron status. Reporter assay showed that GATA-1, an erythroid-specific transcription factor essential for erythrocytic differentiation at relatively early stages, enhanced TfR2 promoter activity. Interestingly, FOG-1, a cofactor of GATA-1 required for erythrocyte maturation, repressed the enhancement of the activity by GATA-1. Also, CCAAT-enhancer binding protein, which is abundant in liver, enhanced the promoter activity. Thus, tissue distribution of TfR2 was consistent with the reporter assays. Expression profiles of TfR2 were different from those of TfR1, suggesting unique functions for TfR2, which may be involved in iron metabolism, hepatocyte function, and erythrocytic differentiation.

The art of the probable: system control in the adaptive immune system.

The immune system provides very effective host defense against infectious agents. Although many details are known about the cells and molecules involved, a broader "systems engineering" view of this complex system is just beginning to emerge. Here the argument is put forward that stochastic events, potent amplification mechanisms, feedback controls, and heterogeneity arising from spatially dispersed cell interactions give rise to many of the gross properties of the immune system. A better appreciation of these underlying features will not only add to our basic understanding of how immunity develops or goes awry, but also illuminate new directions for manipulating the system in prophylactic and therapeutic settings.

The transmembrane segment of invariant chain mediates binding to MHC class II molecules in a CLIP-independent manner.

Invariant chain (Ii) association with MHC class II molecules is strongly dependent upon interaction of CLIP (Ii exon 3, residues 81 - 104) with the peptide binding groove of the class II dimer. This dominant interaction does not adequately explain, however, the efficient association of Ii with class II molecules of diverse allelic and isotypic origin, which have markedly different affinities for synthetic peptides corresponding to CLIP. In agreement with other recent observations, we demonstrate here that class II molecules with occupied binding sites unable to engage CLIP maintain association with Ii in mild detergent. The association is direct and not mediated through unoccupied class II chains bound to properly assembled and loaded class II dimers, nor is it mediated through chaperones. The site of this CLIP-independent binding has been mapped using truncation mutants and an Ii-human transferrin receptor chimeric protein to the transmembrane segment of Ii. The existence of multiple low-affinity sites of interaction between MHC class II and Ii helps explain how effective occupancy of all newly synthesized class II molecules can occur despite substantial variations in the strength of CLIP-dependent association that arise from class II binding domain polymorphism. These data establishing a site of Ii-MHC class II association N-terminal to CLIP also provide new insight into the possible functional relationship between the sequential endocytic proteolysis of Ii from its C terminus and a series of contact sites with MHC class II molecules spread from the transmembrane region through to the tip of the lumenal segment of Ii.

TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type.

Thymocyte selection involves signaling by TCR engaging diverse self-peptide:MHC molecule ligands on various cell types in the cortex and medulla. Here we separately analyze early and late stages of selection to better understand how presenting cell type, ligand quality, and the timing of TCR signaling contribute to intrathymic differentiation. TCR transgenic CD4+CD8+ thymocytes (double positive (DP)) from MHC-deficient mice were stimulated using various presenting cells and ligands. The resulting CD69high cells were isolated and evaluated for maturation in reaggregate cultures with wild-type or MHC molecule-deficient thymic stroma with or without added hemopoietic dendritic cells (DC). Production of CD4+ T cells required TCR signaling in the reaggregates, indicating that transient recognition of self-ligands by DP is inadequate for full differentiation. DC bearing a potent agonist ligand could initiate positive selection, producing activated thymocytes that matured into agonist-responsive T cells in reaggregates lacking the same ligand. DC could also support the TCR signaling necessary for late maturation. These results argue that despite the negative role assigned to DC in past studies, neither the peptide:MHC molecule complexes present on DC nor any other signals provided by these cells stimulate only thymocyte death. These findings also indicate that unique epithelial ligands are not necessary for positive selection. They provide additional insight into the role of ligand quality in selection events and support the concept that following initiation of maturation from the DP state, persistent TCR signaling is characteristic of and perhaps required by T cells.

Opening a window on thymic positive selection: developmental changes in the influence of cosignaling by integrins and CD28 on selection events induced by TCR engagement.

How TCR and non-TCR signals are integrated by thymocytes to generate a decision to undergo either positive or negative selection remains incompletely understood. Recent evidence suggests that TCR signal transduction changes its quality during thymocyte maturation, but whether the contributions of various cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the possible selective roles of specific costimulatory pathways in induction of differentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD4+CD8+ thymocyte differentiation as measured by CD69 up-regulation/coreceptor down-modulation was conducted in parallel with an analysis of induction of death. Using transfected cells varying in their surface display of ICAM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation without substantially affecting induction of death among CD4+CD8+ cells, a property that is lost as thymocytes mature further. In contrast, B7 engagement enhances both cell activation and death in parallel. Based on these data, we propose that the high level of ICAM-1 on cortical epithelial cells plays a special role in opening a window between TCR signaling for differentiation vs death, permitting efficient initiation of positive selection on epithelial ligands. In contrast, late CD28-dependent cosignaling on hemopoietic cells in the medulla would help enforce negative selection by augmenting the effects of TCR engagement by low levels of high affinity ligands.

Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways.

Heat shock proteins (HSPs) derived from tumors or virally infected cells can stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. After this membrane interaction, processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associated material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol.

Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo.

In most cells, transferrin receptor (TfR1)-mediated endocytosis is a major pathway for cellular iron uptake. We recently cloned the human transferrin receptor 2 (TfR2) gene, which encodes a second receptor for transferrin (Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., and Koeffler, H. P. (1999) J. Biol. Chem. 274, 20826-20832). In the present study, the regulation of TfR2 expression and function was investigated. A select Chinese hamster ovary (CHO)-TRVb cell line that does not express either TfR1 or TfR2 was stably transfected with either TfR1 or TfR2-alpha cDNA. TfR2-alpha-expressing cells had considerably lower affinity for holotransferrin when compared with TfR1-expressing CHO cells. Interestingly, in contrast to TfR1, expression of TfR2 mRNA in K562 cells was not up-regulated by desferrioxamine (DFO), a cell membrane-permeable iron chelator. In MG63 cells, expression of TfR2 mRNA was regulated in the cell cycle with the highest expression in late G(1) phase and no expression in G(0)/G(1). DFO reduced cell proliferation and DNA synthesis of CHO-TRVb control cells, whereas it had little effect on TfR2-alpha-expressing CHO cells when measured by clonogenic and cell cycle analysis. In addition, CHO cells that express TfR2-alpha developed into tumors in nude mice whereas CHO control cells did not. In conclusion, TfR2 expression may be regulated by the cell cycle rather than cellular iron status and may support cell growth both in vitro and in vivo.

The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate.

Signals elicited by binding of the T-cell antigen receptor and the CD4/CD8 co-receptor to major histocompatibility complex (MHC) molecules control the generation of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors that initially express both co-receptor proteins. These precursors have unique, clonally distributed T-cell receptors with unpredictable specificity for the self-MHC molecules involved in this differentiation process. However, the mature T cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC class I-binding) co-receptor that complements the MHC class-specificity of the T-cell receptor. How this matching of co-receptor-defined lineage and T-cell-receptor specificity is achieved remains unknown, as does whether signalling by the T-cell receptors, co-receptors and/or general cell-fate regulators such as Notch-1 contributes to initial lineage choice, to subsequent differentiation processes or to both. Here we show that the CD4 versus CD8 lineage fate of immature thymocytes is controlled by the co-receptor-influenced duration of initial T-cell receptor-dependent signalling. Notch-1 does not appear to be essential for this fate determination, but it is selectively required for CD8+ T-cell maturation after commitment directed by T-cell receptors. This indicates that the signals constraining CD4 versus CD8 lineage decisions are distinct from those that support subsequent differentiation events such as silencing of co-receptor loci.

The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli.

During their final differentiation or maturation, dendritic cells (DCs) redistribute their major histocompatibility complex (MHC) class II products from intracellular compartments to the plasma membrane. Using cells arrested in the immature state, we now find that DCs also regulate the initial intracellular formation of immunogenic MHC class II-peptide complexes. Immature DCs internalize the protein antigen, hen egg lysozyme (HEL), into late endosomes and lysosomes rich in MHC class II molecules. There, despite extensive colocalization of HEL protein and MHC class II products, MHC class II-peptide complexes do not form unless the DCs are exposed to inflammatory mediators such as tumor necrosis factor alpha, CD40 ligand, or lipoplolysaccharide. The control of T cell receptor (TCR) ligand formation was observed using the C4H3 monoclonal antibody to detect MHC class II-HEL peptide complexes by flow cytometry and confocal microscopy, and with HEL-specific 3A9 transgenic T cells to detect downregulation of the TCR upon MHC-peptide encounter. Even the binding of preprocessed HEL peptide to MHC class II is blocked in immature DCs, including the formation of C4H3 epitope in MHC class II compartments, suggesting an arrest to antigen presentation at the peptide-loading step, rather than an enhanced degradation of MHC class II-peptide complexes at the cell surface, as described in previous work. Therefore, the capacity of late endosomes and lysosomes to produce MHC class II-peptide complexes can be strictly controlled during DC differentiation, helping to coordinate antigen acquisition and inflammatory stimuli with formation of TCR ligands. The increased ability of maturing DCs to load MHC class II molecules with antigenic cargo contributes to the >100-fold enhancement of the subsequent primary immune response observed when immature and mature DCs are compared as immune adjuvants in culture and in mice.