Neural changes when actions change: Adaptation of strong and weak expectations

Repeated experiences with an event create the expectation that subsequent events will expose an analog structure. These spontaneous expectations rely on an internal model of the event that results from learning. But what happens when events change? Do experience-based internal models get adapted instantaneously, or is model adaptation a function of the solidity of, i.e., familiarity with, the corresponding internal model? The present fMRI study investigated the effects of model solidity on model adaptation in an action observation paradigm. Subjects were made acquainted with a set of action movies that displayed an altered script when encountered again in the scanning session. We found model adaptation to result in an attenuation of the premotor-parietal network for action observation. Model solidity was found to modulate activation in the parahippocampal gyrus and the anterior cerebellar lobules, where increased solidity correlated with activity increase. Finally, the comparison between early and late stages of learning indicated an effect of model solidity on adaptation rate. This contrast revealed the involvement of a fronto-mesial network of Brodmann area 10 and the ACC in those states of learning that were signified by high model solidity, no matter if the memorized original or the altered action model was the more solid component. Findings suggest that the revision of an internal model is dependent on its familiarity. Unwarranted adaptations, but also perseverations may thus be prevented

The giant planet orbiting the cataclysmic binary DP Leonis

Planets orbiting post-common envelope binaries provide fundamental information on planet formation and evolution, especially for the yet nearly unexplored class of circumbinary planets. We searched for such planets in \odp, an eclipsing short-period binary, which shows long-term eclipse-time variations. Using published, reanalysed, and new mid-eclipse times of the white dwarf in DP\,Leo, obtained between 1979 and 2010, we find agreement with the light-travel-time effect produced by a third body in an elliptical orbit. In particular, the measured binary period in 2009/2010 and the implied radial velocity coincide with the values predicted for the motion of the binary and the third body around the common center of mass. The orbital period, semi-major axis, and eccentricity of the third body are P_c = 28.0 +/- 2.0 yrs, a_c = 8.2 +/- 0.4 AU, and e_c = 0.39 +/- 0.13. Its mass of M_c sin(i_c) = 6.1 +/- 0.5 M_J qualifies it as a giant planet. It formed either as a first generation object in a protoplanetary disk around the original binary or as a second generation object in a disk formed in the common envelope shed by the progenitor of the white dwarf. Even a third generation origin in matter lost from the present accreting binary can not be entirely excluded. We searched for, but found no evidence for a fourth body.Comment: Accepted by A&

Observation of Collective Excitations of the Dilute 2D Electron System

We report inelastic light scattering measurements of dispersive spin and charge density excitations in dilute 2D electron systems reaching densities less than 10^{10} cm^{-2}. In the quantum Hall state at nu=2, roton critical points in the spin inter--Landau level mode show a pronounced softening as r_s is increased. Instead of a soft mode instability predicted by Hartree--Fock calculations for r_s ~ 3.3, we find evidence of multiple rotons in the dispersion of the softening spin excitations. Extrapolation of the data indicates the possibility of an instability for r_s >~ 11.Comment: Submitted to Physical Review Letter

Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions

CC chemokine receptor 2 is relevant for CD8-induced graft-versus- host disease but not for graft-versus-tumor activity

I Summary Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapy for a variety of malignant and non-malignant disorders of the hematopoietic system and for certain solid tumors. One of the major complications limiting the success and wider application of allogeneic HSCT is the occurrence of acute graft-versus-host disease (GVHD), which is a rapidly progressive illness with epithelial damage of gut, liver, skin, and lung, immunosuppression and cachexia. GVHD is mediated by alloreactive donor T cells contained in the graft and can be prevented by depletion of these T cells prior to transfer. However, alloreactive donor T cells also mediate the so-called graft-versus-tumor (GVT) effect, which is increasingly being recognized as an important component of the overall anti-tumor effect of an allogeneic HSCT. Therefore, a major focus of current research is to ameliorate GVHD without reducing GVT activity. Recent murine bone marrow transplantation studies suggest that interfering with T cell migration represents an attractive therapeutic approach towards this goal. In the present study, the role of the inflammatory chemokine receptor CCR2 for donor CD8 + T cell migration during GVHD was analyzed in well-established murine bone marrow transplantation models. It was found that recipients of CCR2-deficient (CCR2 -/-) CD8 + T cells develop significantly less GVHD morbidity and mortality than recipients of wild type CD8 + T cells and that this correlates with reduced target organ damage to the gut and liver. A competitive in vivo migration assay revealed that CCR2 -/-CD8 + T cells have an intrinsic migratory defect to the gut and liver, which was previously unknown. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and in vitro cytotoxicity of CCR2 -/-CD8 + T cells were intact. Importantly, the GVT effect of CCR2 -/-CD8 + T cells against murine P815 mastocytoma and A20 B cell lymphoma was preserved, which demonstrates that interference with T cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity. These data provide first evidence for a critical role of CCR2 for the control of CD8 + T cell migration in a pre-clinical disease model and establish the rationale for the use of CCR2 antagonists possibly in combination with other chemokine receptor antagonists as novel therapeutic tools in GVHD

Composition of human islet cell preparations for transplantation

To study the cellular composition of human islet cell isolates for transplantation, formalin-fixed and paraffin-embedded cell pellets were stained by the immunoperoxidase method with a panel of antibodies characterising endocrine, epithelial, soft tissue and haematolymphoid components. Immediately after separation, the isolates contained 30-80% islet cells, differing mainly in the content of islet and acinar cells, whereas the soft tissue, ductal/ductular and haematolymphoid elements comprised a relatively constant 10-20%. After 1 week in culture the islet cell content of less highly purified isolates (30-40% islets) dropped dramatically to 5%. The highly purified isolates (70-80% islets) showed only a minimal change in cellular composition; however, approximately two-thirds of islet cells were degranulated and did not stain for insulin. Haematolymphoid components were still present in all cultured isolates. We conclude that primarily mechanical purification methods and short-term culture are not sufficient to eliminate highly immunogenic cells. In addition, short-term culture is deleterious to the isolate if a significant number of acinar cells is still present after enrichment. © 1992 Springer-Verlag

Exosomes Derived from M. Bovis BCG Infected Macrophages Activate Antigen-Specific CD4+ and CD8+ T Cells In Vitro and In Vivo

Activation of both CD4+ and CD8+ T cells is required for an effective immune response to an M. tuberculosis infection. However, infected macrophages are poor antigen presenting cells and may be spatially separated from recruited T cells, thus limiting antigen presentation within a granuloma. Our previous studies showed that infected macrophages release from cells small membrane-bound vesicles called exosomes which contain mycobacterial lipid components and showed that these exosomes could stimulate a pro-inflammatory response in naïve macrophages. In the present study we demonstrate that exosomes stimulate both CD4+ and CD8+ splenic T cells isolated from mycobacteria-sensitized mice. Although the exosomes contain MHC I and II as well as costimulatory molecules, maximum stimulation of T cells required prior incubation of exosomes with antigen presenting cells. Exosomes isolated from M. bovis and M. tuberculosis infected macrophages also stimulated activation and maturation of mouse bone marrow-derived dendritic cells. Interestingly, intranasal administration of mice with exosomes isolated from M. bovis BCG infected macrophages induce the generation of memory CD4+ and CD8+ T cells. The isolated T cells also produced IFN-γ upon restimulation with BCG antigens. The release of exosomes from infected macrophages may overcome some of the defects in antigen presentation associated with mycobacterial infections and we suggest that exosomes may be a promising M. tuberculosis vaccine candidate

T-SPOT.TB responses during treatment of pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Immune responses to <it>Mycobacterium tuberculosis </it>antigens could serve as surrogate markers of treatment response.</p> <p>Methods</p> <p>Using the T-SPOT.<it>TB </it>assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-γ-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment.</p> <p>Results</p> <p>58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034).</p> <p>Conclusion</p> <p>IFN-γ-producing RD1-specific T cells, as measured in the T-SPOT.<it>TB </it>assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.</p

Isoniazid prophylaxis differently modulates T-cell responses to RD1-epitopes in contacts recently exposed to Mycobacterium tuberculosis: a pilot study

RATIONALE: Existing data on the effect of treatment of latent tuberculosis infection (LTBI) on T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens are contradictory. Differences in technical aspects of the assays used to detect this response and populations studied might explain some of these discrepancies. In an attempt to find surrogate markers of the effect of LTBI treatment, it would be important to determine whether, among contacts of patients with contagious tuberculosis, therapy for LTBI could cause changes in MTB-specific immune responses to a variety of RD1-antigens. METHODS AND RESULTS: In a longitudinal study, 44 tuberculin skin test(+ )recent contacts were followed over a 6-month period and divided according to previous exposure to MTB and LTBI treatment. The following tests which evaluate IFN-gamma responses to RD1 antigens were performed: QuantiFERON TB Gold, RD1 intact protein- and selected peptide-based assays. Among the 24 contacts without previous exposure that completed therapy, we showed a significant decrease of IFN-gamma response in all tests employed. The response to RD1 selected peptides was found to be more markedly decreased compared to that to other RD1 antigens. Conversely, no significant changes in the response to RD1 reagents were found in 9 treated subjects with a known previous exposure to MTB and in 11 untreated controls. CONCLUSION: These data suggest that the effect of INH prophylaxis on RD1-specific T-cell responses may be different based on the population of subjects enrolled (recent infection versus re-infection) and, to a minor extent, on the reagents used

Goettingen Minipigs (GMP): Comparison of Two Different Models for Inducing Diabetes

Purpose: Preclinical experiments on large animals are indispensable for evaluating the effectiveness of diabetes therapies. Miniature swine are well suited for such studies due to their physiological and pathophysiological responses. Methods: We compare two methods for inducing diabetes in Goettingen minipigs (GMP), in five with the beta cell toxin streptozotocin (STZ) and in five other GMP by total pancreatectomy (PE). Glucose homeostasis was assessed with the intravenous glucose-tolerance test (IVGTT) and continual monitoring of interstitial glucose levels. At conclusion of the observation period, the pancreata were examined histologically. Three non-diabetic GMP served as control group. Results: The IVGTT revealed markedly diabetic profiles in both GMP groups. STZ-GMP were found to harbor residual C-peptides and scattered insulin-positive cells in the pancreas. PE-GMP survived the total pancreatectomy only with intensive postoperative care. Conclusions: Although both methods reliably induced diabetes in GMP, the PE-GMP clearly had more health problems and required a greater expenditure of time and resources. The PE-GMP model, however, was better at eliminating endogenous insulin and C-peptide than the STZ-GMP model