Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease

BACKGROUND: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD). METHODS: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). RESULTS: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). CONCLUSIONS: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.

Interactions between dorsolateral and ventromedial prefrontal cortex underlie context-dependent stimulus valuation in goal-directed choice.

External circumstances and internal bodily states often change and require organisms to flexibly adapt valuation processes to select the optimal action in a given context. Here, we investigate the neurobiology of context-dependent valuation in 22 human subjects using functional magnetic resonance imaging. Subjects made binary choices between visual stimuli with three attributes (shape, color, and pattern) that were associated with monetary values. Context changes required subjects to deviate from the default shape valuation and to integrate a second attribute in order to comply with the goal to maximize rewards. Critically, this binary choice task did not involve any conflict between opposing monetary, temporal, or social preferences. We tested the hypothesis that interactions between regions of dorsolateral and ventromedial prefrontal cortex (dlPFC; vmPFC) implicated in self-control choices would also underlie the more general function of context-dependent valuation. Consistent with this idea, we found that the degree to which stimulus attributes were reflected in vmPFC activity varied as a function of context. In addition, activity in dlPFC increased when context changes required a reweighting of stimulus attribute values. Moreover, the strength of the functional connectivity between dlPFC and vmPFC was associated with the degree of context-specific attribute valuation in vmPFC at the time of choice. Our findings suggest that functional interactions between dlPFC and vmPFC are a key aspect of context-dependent valuation and that the role of this network during choices that require self-control to adjudicate between competing outcome preferences is a specific application of this more general neural mechanism.

Bone marrow-derived mesenchymal stromal cells improve vascular regeneration and reduce leukocyte-endothelium activation in critical ischemic murine skin in a dose-dependent manner

BACKGROUND AIMS Stem cells participate in vascular regeneration following critical ischemia. However, their angiogenic and remodeling properties, as well as their role in ischemia-related endothelial leukocyte activation, need to be further elucidated. Herein, we investigated the effect of bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a critically ischemic murine skin flap model. METHODS Groups received either 1 × 10(5), 5 × 10(5), or 1 × 10(6) BM-MSCs or cell-free conditioned medium (CM). Controls received sodium chloride. Intravital fluorescence microscopy was performed for morphological and quantitative assessment of micro-hemodynamic parameters over 12 days. RESULTS Tortuosity and diameter of conduit-arterioles were pronounced in the MSC groups (P < 0.01), whereas vasodilation was shifted to the end arteriolar level in the CM group (P < 0.01). These effects were accompanied by angiopoietin-2 expression. Functional capillary density and red blood cell velocity were enhanced in all treatment groups (P < 0.01). Although a significant reduction of rolling and sticking leukocytes was observed in the MSC groups with a reduction of diameter in postcapillary venules (P < 0.01), animals receiving CM exhibited a leukocyte-endothelium interaction similar to controls. This correlated with leukocyte common antigen expression in tissue sections (P < 0.01) and p38 mitogen-activated protein kinase expression from tissue samples. Cytokine analysis from BM-MSC culture medium revealed a 50% reduction of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-12, tumor necrosis factor-α, interferon-γ) and chemokines (keratinocyte chemoattractant, granulocyte colony-stimulating factor) under hypoxic conditions. DISCUSSION We demonstrated positive effects of BM-MSCs on vascular regeneration and modulation of endothelial leukocyte adhesion in critical ischemic skin. The improvements after MSC application were dose-dependent and superior to the use of CM alone.

Are shrubs really a sign of declining ecosystem function? Disentangling the myths and truths of woody encroachment in Australia

Since European settlement, there has been a dramatic increase in the density, cover and distribution of woody plants in former grassland and open woodland. There is a widespread belief that shrub encroachment is synonymous with declines in ecosystem functions, and often it is associated with landscape degradation or desertification. Indeed, this decline in ecosystem functioning is considered to be driven largely by the presence of the shrubs themselves. This prevailing paradigm has been the basis for an extensive program of shrub removal, based on the view that it is necessary to reinstate the original open woodland or grassland structure from which shrublands are thought to have been derived. We review existing scientific evidence, particularly focussed on eastern Australia, to question the notion that shrub encroachment leads to declines in ecosystem functions. We then summarise this scientific evidence into two conceptual models aimed at optimising landscape management to maximise the services provided by shrub-encroached areas. The first model seeks to reconcile the apparent conflicts between the patch- and landscape-level effects of shrubs. The second model identifies the ecosystem services derived from different stages of shrub encroachment. We also examined six ecosystem services provided by shrublands (biodiversity, soil C, hydrology, nutrient provision, grass growth and soil fertility) by using published and unpublished data. We demonstrated the following: (1) shrub effects on ecosystems are strongly scale-, species- and environment-dependent and, therefore, no standardised management should be applied to every case; (2) overgrazing dampens the generally positive effect of shrubs, leading to the misleading relationship between encroachment and degradation; (3) woody encroachment per se does not hinder any of the functions or services described above, rather it enhances many of them; (4) no single shrub-encroachment state (including grasslands without shrubs) will maximise all services; rather, the provision of ecosystem goods and services by shrublands requires a mixture of different states; and (5) there has been little rigorous assessment of the long-term effectiveness of removal and no evidence that this improves land condition in most cases. Our review provides the basis for an improved, scientifically based understanding and management of shrublands, so as to balance the competing goals of providing functional habitats, maintaining soil processes and sustaining pastoral livelihoods.

Decision-Making Processes in Voluntary Football Clubs in Relation to External Counselling

Introduction Recruiting and retaining volunteers who are prepared to make a long-term commitment is a major problem for Swiss sports clubs. With the inclusion of external counselling for the change and systematisation of volunteer management, sports clubs have a possibility to develop and defuse problems in spite of existing barriers and gaps in knowledge. To what extent is external counselling for personnel problems effective? It is often observed that standardised counselling inputs lead to varying consequences for sports clubs. It can be assumed that external impulses are interpreted and transformed differently into the workings of the club. However, this cannot be solely attributed to the situational or structural conditions of the clubs. It is also important to consider the underlying decision-making processes of a club. According to Luhmann’s organisational sociological considerations (2000), organisations (sports clubs) have to be viewed as social systems consisting of (communicated) decisions. This means that organisations are continually reproduced by decision-making processes. All other (observable) factors such as an organisation’s goals, recruiting strategies, support schemes for volunteers etc., have to be seen as an outcome of the operation of prior organisational decisions. Therefore: How do decision-making processes in sports clubs work in the context of the implementation of external counselling? Theoretical Framework An examination of the actual situation in sports clubs shows that decisions frequently appear to be shaped by inconsistency, unexpected outcomes, and randomness (Amis & Slack, 2003). Therefore, it must be emphasised that these decisions cannot be analysed according to any rational decision-making model. Their specific structural characteristics only permit a limited degree of rationality – bounded rationality. Non-profit organisations in particular are shaped by a specific mode of decisionmaking that Cohen, March, and Olsen (1972) have called the “garbage can model”. As sport clubs can also be conceived as “organised anarchies”, this model seems to offer an appropriate approach to understanding their practices and analysing their decision-making processes. The key concept in the garbage can model is the assumption that decision-making processes in organisations consist of four “streams”: (a) problems, (b) actors, (c) decision-making opportunities, and (d) solutions. Method Before presenting the method of the analysis of the decision-making processes in sports clubs, the external counselling will be described. The basis of the counselling is generated by a sports clubs’ capability to change. Due to the specific structural characteristics and organisational principles, change processes in sports clubs often merge with barriers and restrictions. These need to be considered when developing counselling guidelines for a successful planning and realisation of change processes. Furthermore, important aspects of personnel management in sports clubs and especially volunteer management must be implied in order to elaborate key elements for the counselling to recruit new volunteers (e.g., approach, expectations). A counselling of four system-counselling workshops was conceptualised by considering these specific characteristics. The decision-making processes in the sports clubs were analysed during the counselling and the implementation process. A case study is designed with the appropriate methodological approach for such explorative research. The approach adopted for these single case analyses was oriented toward the research program of behavioural decision-making theory (garbage can model). This posits that in-depth insights into organisational decision-making processes can only be gained through relevant case studies of existing organisational situations (Skille, 2013). Before, during and after the intervention, questionnaires and guided interviews were conducted with the project teams of the twelve par-ticipating football clubs to assess the different components of the “streams” in the context of external counselling. These interviews have been analysed using content analysis following guidelines as for-mulated by Mayring (2010). Results The findings show that decision-making processes in football clubs occur differently in the context of external counselling. Different initial positions and problems are the triggers for these decision-making processes. Furthermore, the implementation of the solutions and the external counselling is highly dependent on the commitment of certain people as central players within the decision-mak-ing process. The importance of these relationships is confirmed by previous findings in regard to decision-making and change processes in sports clubs. The decision-making processes in sports clubs can be theoretically analysed using behavioural decision-making theory and the “garbage can model”. Bounded rationality characterises all “streams” of the decision-making processes. Moreo-ver, the decision-making process of the football clubs can be well illustrated in the framework, and the interplay of the different dimensions illustrates the different decision-making practices within the football clubs. References Amis, J., & Slack, T. (2003). Analysing sports organisations: Theory and practice. In B. Houlihan (Eds.), Sport & Society (pp. 201–217). London, England: Sage. Cohen, M.D., March, J.G., & Olsen, J.P. (1972). A garbage can model of organisational choice. Ad-ministrative Science Quarterly, 17, 1-25. Luhmann, N. (2000). Organisation und Entscheidung. Opladen: Westdeutscher Verlag. Mayring, P. (2010). Qualitative Inhaltsanalyse. Grundlagen und Techniken. Weinheim: Beltz. Skille, E. Å. (2013). Case study research in sport management: A reflection upon the theory of science and an empirical example. In S. Söderman & H. Dolles (Eds.), Handbook of research on sport and business (pp. 161–175). Cheltenham, England: Edward Elgar.

In human basophils, IL-3 selectively induces RANKL expression that is modulated by IgER-dependent and IgER-independent stimuli

BACKGROUND Receptor activator of NF-κB ligand (RANKL) is expressed as either surface (hRANKL1, hRANKL2) or soluble (hRANKL3) form. RANKL is involved in multifaceted processes of immunoregulation and bone resorption such as they occur in rheumatoid arthritis (RA). Interestingly, activated basophils, which are effector cells in allergic inflammation, contribute to the progress of collagen-induced arthritis (CIA), a mouse model for RA. Here, we investigate under which conditions human basophils express RANKL. METHODS Among other stimuli, basophils were cultured with IL-3 alone. Alternatively, as a secondary stimulus, IgER-dependent or IgER-independent agents were added simultaneously either with IL-3 or after prolonged IL-3 culturing. Expression of RANKL protein and mRNA was analyzed by flow cytometry, ELISA, and real-time PCR. A coculture system was applied to investigate biological activity of basophil-derived RANKL. RESULTS We show that in human basophils, IL-3 but no other stimulus induces de novo expression of soluble and surface RANKL, of which the latter enhances survival of MoDC. Upon simultaneous stimulation, IgER cross-linking reduces surface RANKL expression, while IgER-independent stimuli have no effect. This is in contrast to consecutive stimulation, as triggering with both IgER-dependent and IgER-independent stimuli enhances RANKL expression, particularly in its soluble form. Real-time PCR analysis shows that RANKL expression is mainly regulated at the mRNA level. CONCLUSION This study identifies IL-3 as a potent inducer of RANKL expression in human basophils, suggesting them to interact with bone physiology and activation of immune cells. IgER-dependent and IgER-independent stimuli modulate the IL-3-mediated RANKL expression in a time- and stimulus-dependent fashion.

Tree Species Composition and Harvest Intensity Affect Herbivore Density and Leaf Damage on Beech, Fagus sylvatica, in Different Landscape Contexts

Most forests are exposed to anthropogenic management activities that affect tree species composition and natural ecosystem processes. Changes in ecosystem processes such as herbivory depend on management intensity, and on regional environmental conditions and species pools. Whereas influences of specific forest management measures have already been addressed for different herbivore taxa on a local scale, studies considering effects of different aspects of forest management across different regions are rare. We assessed the influence of tree species composition and intensity of harvesting activities on arthropod herbivores and herbivore-related damage to beech trees, Fagus sylvatica, in 48 forest plots in three regions of Germany. We found that herbivore abundance and damage to beech trees differed between regions and that – despite the regional differences - density of tree-associated arthropod taxa and herbivore damage were consistently affected by tree species composition and harvest intensity. Specifically, overall herbivore damage to beech trees increased with increasing dominance of beech trees – suggesting the action of associational resistance processes – and decreased with harvest intensity. The density of leaf chewers and mines was positively related to leaf damage, and several arthropod groups responded to beech dominance and harvest intensity. The distribution of damage patterns was consistent with a vertical shift of herbivores to higher crown layers during the season and with higher beech dominance. By linking quantitative data on arthropod herbivore abundance and herbivory with tree species composition and harvesting activity in a wide variety of beech forests, our study helps to better understand the influence of forest management on interactions between a naturally dominant deciduous forest tree and arthropod herbivores.

Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins.

Receptors of the Eph family and their ligands (ephrins) mediate developmental vascular assembly and direct axonal guidance. Migrating cell processes identify appropriate targets within migratory fields based on topographically displayed ephrin gradients. Here, EphB1 regulated cell attachment by discriminating the density at which ephrin-B1 was displayed on a reconstituted surface. EphB1-ephrin-B1 engagement did not promote cell attachment through mechanical tethering, but did activate integrin-mediated attachment. In endothelial cells, attachment to RGD peptides or fibrinogen was mediated through alphavbeta3 integrin. EphB1 transfection conferred ephrin-B1-responsive activation of alpha5beta1 integrin-mediated cell attachment in human embryonic kidney cells. Activation-competent but signaling-defective EphB1 point mutants failed to stimulate ephrin-B1 dependent attachment. These findings lead us to propose that EphB1 functions as a 'ligand density sensor' to signal integrin-mediated cell-matrix attachment.

Temperature Prediction Model for Bone Drilling Based on Density Distribution and In Vivo Experiments for Minimally Invasive Robotic Cochlear Implantation

Surgical robots have been proposed ex vivo to drill precise holes in the temporal bone for minimally invasive cochlear implantation. The main risk of the procedure is damage of the facial nerve due to mechanical interaction or due to temperature elevation during the drilling process. To evaluate the thermal risk of the drilling process, a simplified model is proposed which aims to enable an assessment of risk posed to the facial nerve for a given set of constant process parameters for different mastoid bone densities. The model uses the bone density distribution along the drilling trajectory in the mastoid bone to calculate a time dependent heat production function at the tip of the drill bit. Using a time dependent moving point source Green's function, the heat equation can be solved at a certain point in space so that the resulting temperatures can be calculated over time. The model was calibrated and initially verified with in vivo temperature data. The data was collected in minimally invasive robotic drilling of 12 holes in four different sheep. The sheep were anesthetized and the temperature elevations were measured with a thermocouple which was inserted in a previously drilled hole next to the planned drilling trajectory. Bone density distributions were extracted from pre-operative CT data by averaging Hounsfield values over the drill bit diameter. Post-operative [Formula: see text]CT data was used to verify the drilling accuracy of the trajectories. The comparison of measured and calculated temperatures shows a very good match for both heating and cooling phases. The average prediction error of the maximum temperature was less than 0.7 °C and the average root mean square error was approximately 0.5 °C. To analyze potential thermal damage, the model was used to calculate temperature profiles and cumulative equivalent minutes at 43 °C at a minimal distance to the facial nerve. For the selected drilling parameters, temperature elevation profiles and cumulative equivalent minutes suggest that thermal elevation of this minimally invasive cochlear implantation surgery may pose a risk to the facial nerve, especially in sclerotic or high density mastoid bones. Optimized drilling parameters need to be evaluated and the model could be used for future risk evaluation.

Reconciling two alternative mechanisms behind bi-decadal variability in the North Atlantic

Understanding the preferential timescales of variability in the North Atlantic, usually associated with the Atlantic meridional overturning circulation (AMOC), is essential for the prospects for decadal prediction. However, the wide variety of mechanisms proposed from the analysis of climate simulations, potentially dependent on the models themselves, has stimulated the debate of which processes take place in reality. One mechanism receiving increasing attention, identified both in idealized models and observations, is a westward propagation of subsurface buoyancy anomalies that impact the AMOC through a basin-scale intensification of the zonal density gradient, enhancing the northward transport via thermal wind balance. In this study, we revisit a control simulation from the Institut Pierre-Simon Laplace Coupled Model 5A (IPSL-CM5A), characterized by a strong AMOC periodicity at 20 years, previously explained by an upper ocean–atmosphere–sea ice coupled mode driving convection activity south of Iceland. Our study shows that this mechanism interacts constructively with the basin-wide propagation in the subsurface. This constructive feedback may explain why bi-decadal variability is so intense in this coupled model as compared to others.

Inhibition of photosynthesis by high temperature in oak (Quercus pubescens L.) leaves grown under natural conditions closely correlates with a reversible heat-dependent reduction of the activation state of ribulose-1,5-bisphosphate carboxylase/oxygenase

Inhibition of the net photosynthetic CO2 assimilation rate (Pn) by high temperature was examined in oak (Quercus pubescens L.) leaves grown under natural conditions. Combined measurements of gas exchange and chlorophyll (Chl) a fluorescence were employed to differentiate between inhibition originating from heat effects on components of the thylakoid membranes and that resulting from effects on photosynthetic carbon metabolism. Regardless of whether temperature was increased rapidly or gradually, Pn decreased with increasing leaf temperature and was more than 90% reduced at 45 °C as compared to 25 °C. Inhibition of Pn by heat stress did not result from reduced stomatal conductance (gs), as heat-induced reduction of gs was accompanied by an increase of the intercellular CO2 concentration (Ci). Chl a fluorescence measurements revealed that between 25 and 45 °C heat-dependent alterations of thylakoid-associated processes contributed only marginally, if at all, to the inhibition of Pn by heat stress, with photosystem II being remarkably well protected against thermal inactivation. The activation state of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) decreased from about 90% at 25 °C to less than 30% at 45 °C. Heat stress did not affect Rubisco per se, since full activity could be restored by incubation with CO2 and Mg2+. Western-blot analysis of leaf extracts disclosed the presence of two Rubisco activase polypeptides, but heat stress did not alter the profile of the activase bands. Inhibition of Pn at high leaf temperature could be markedly reduced by artificially increasing Ci. A high Ci also stimulated photosynthetic electron transport and resulted in reduced non-photochemical fluorescence quenching. Recovery experiments showed that heat-dependent inhibition of Pn was largely, if not fully, reversible. The present results demonstrate that in Q. pubescens leaves the thylakoid membranes in general and photosynthetic electron transport in particular were well protected against heat-induced perturbations and that inhibition of Pn by high temperature closely correlated with a reversible heat-dependent reduction of the Rubisco activation state.

What do brain network interactions tell about cognitive processes? How to seek causality?

Optimal adjustment of brain networks allows the biased processing of information in response to the demand of environments and is therefore prerequisite for adaptive behaviour. It is widely shown that a biased state of networks is associated with a particular cognitive process. However, those associations were identified by backward categorization of trials and cannot provide a causal association with cognitive processes. This problem still remains a big obstacle to advance the state of our field in particular human cognitive neuroscience. In my talk, I will present two approaches to address the causal relationships between brain network interactions and behaviour. Firstly, we combined connectivity analysis of fMRI data and a machine leaning method to predict inter-individual differences of behaviour and responsiveness to environmental demands. The connectivity-based classification approach outperforms local activation-based classification analysis, suggesting that interactions in brain networks carry information of instantaneous cognitive processes. Secondly, we have recently established a brand new method combining transcranial alternating current stimulation (tACS), transcranial magnetic stimulation (TMS), and EEG. We use the method to measure signal transmission between brain areas while introducing extrinsic oscillatory brain activity and to study causal association between oscillatory activity and behaviour. We show that phase-matched oscillatory activity creates the phase-dependent modulation of signal transmission between brain areas, while phase-shifted oscillatory activity blunts the phase-dependent modulation. The results suggest that phase coherence between brain areas plays a cardinal role in signal transmission in the brain networks. In sum, I argue that causal approaches will provide more concreate backbones to cognitive neuroscience.

Effects of team Knowledge and ecological constraints on decisional processes in customized football game scenarios

Several theories assume that successful team coordination is partly based on knowledge that helps anticipating individual contributions necessary in a situational task. It has been argued that a more ecological perspective needs to be considered in contexts evolving dynamically and unpredictably. In football, defensive plays are usually coordinated according to strategic concepts spanning all members and large areas of the playfield. On the other hand, fewer people are involved in offensive plays as these are less projectable and strongly constrained by ecological characteristics. The aim of this study is to test the effects of ecological constraints and player knowledge on decision making in offensive game scenarios. It is hypothesized that both knowledge about team members and situational constraints will influence decisional processes. Effects of situational constraints are expected to be of higher magnitude. Two teams playing in the fourth league of the Swiss Football Federation participate in the study. Forty customized game scenarios were developed based on the coaches’ information about player positions and game strategies. Each player was shown in ball possession four times. Participants were asked to take the perspective of the player on the ball and to choose a passing destination and a recipient. Participants then rated domain specific strengths (e.g., technical skills, game intelligence) of each of their teammates. Multilevel models for categorical dependent variables (team members) will be specified. Player knowledge (rated skills) and ecological constraints (operationalized as each players’ proximity and availability for ball reception) are included as predictor variables. Data are currently being collected. Results will yield effects of parameters that are stable across situations as well as of variable parameters that are bound to situational context. These will enable insight into the degree to which ecological constraints and more enduring team knowledge are involved in decisional processes aimed at coordinating interpersonal action.

Tissue Crowding Induces Caspase-Dependent Competition for Space.

Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied [1, 2, 3, 4 and 5], the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density [6]. Cell delamination was supposed to occur independently of caspase activation and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells [6]. Studying the elimination of cells in the midline region of the Drosophila pupal notum, we found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, we confirmed [ 6] that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways [ 7, 8 and 9]. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition [ 10 and 11]. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers [ 7, 8 and 9], that could promote tumor growth.

THE ROLE OF B CELLS IN THE T CELL DEPENDENT RELEASE OF HUMAN B CELL GROWTH FACTOR

Quiescent human B cells are postulated to go through activation and proliferation phases before undergoing differentiative phase for immunoglobulin secretion. The present studies address some of the aspects of activation and proliferation phase of normal human B cells. The definitions of signals responsible for B cell activation and proliferation resulted in the development of a highly specific, reproducible B cell growth factor (BCGF) assay. This BCGF bioassay utilizes activation by rabbit anti-human IgM-antibody. The functional specificity of this assay for measuring BCGF activity was demonstrated by the finding that target B cells proliferated but did not differentiate. The factor specificity was determined by specific absorption of BCGF by anti-IgM activated B cells. This assay was utilized for the studies of T-B cell collaboration and the essential function of monocytes in the production and/or release of B cell growth factor in a syngeneic in vitro system. It is apparent that highly purified T cells are poor producers of BCGF by themselves and require monocytes to secrete significant quantities of BCGF upon PHA stimulation. Macrophage soluble factor, Interleukin 1, is capable of replacing monocyte function for the release of BCGF by activated T cells. In our studies, B cells are incapable to function as accessory cells to replace monocyte function. Normal B cells are also not capable of producing BCGF under our experimental observations. However, the addition of these B cells at an optimum cell density (T:B ratio 1:1) doubles the monocyte dependent release of BCGF by syngeneic T cells. The augmentative role of B cells is expanded to understand the mechanism of BCGF release by T cells. It is observed from our studies that DR antigen of B cell surface is involved in the release of BCGF. The functional difference between DR of B cells and monocytes is observed as IL-1 could replace DR-treated monocytes whereas failed to replace DR-treated B cells for the release of BCGF by T cells. This functional difference may be attributed to the reported microheterogeneity in DR of B cells and monocytes. The addition of irradiated B cells increased the monocyte dependent T cell proliferation, suggesting the increase of T cell pool for BCGF release. In summary, the development of a biological assay specific for B cell growth factor led to the delineation of an interesting role of B cells in the release of its own growth factor by T cells. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of author.) UMI ^