T Cell Receptor (TCR) Antagonism without a Negative Signal: Evidence from T Cell Hybridomas Expressing Two Independent TCRs

Antagonist peptides inhibit T cell responses by an unknown mechanism. By coexpressing two independent T cell receptors (TCRs) on a single T cell hybridoma, we addressed the question of whether antagonist ligands induce a dominant-negative signal that inhibits the function of a second, independent TCR. The two receptors, Vα2Vβ5 and Vα2Vβ10, restricted by H-2Kb and specific for the octameric peptides SIINFEKL and SSIEFARL, respectively, were coexpressed on the same cell. Agonist stimulation demonstrated that the two receptors behaved independently with regard to antigen-induced TCR downregulation and intracellular biochemical signaling. The exposure of one TCR (Vα2Vβ5) to antagonist peptides could not inhibit a second independent TCR (Vα2Vβ10) from responding to its antigen. Thus, our data clearly demonstrate that these antagonist ligands do not generate a dominant-negative signal which affects the responsiveness of the entire cell. In addition, a kinetic analysis showed that even 12 h after engagement with their cognate antigen and 10 h after reaching a steady-state of TCR internalization, T cells were fully inhibited by the addition of antagonist peptides. The window of susceptibility to antagonist ligands correlated exactly with the time required for the responding T cells to commit to interleukin 2 production. The data support a model where antagonist ligands can competitively inhibit antigenic peptides from productively engaging the TCR. This competitive inhibition is effective during the entire commitment period, where sustained TCR engagement is essential for full T cell activation

Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress

Both the dorsomedial hypothalamic nucleus (DMH) and the paraventricular hypothalamic nucleus (PVN) have been implicated in the neural control of the cardiovascular response to stress. We used the GABAA agonist muscimol to inhibit neuronal activation and attempted to identify hypothalamic nuclei required for the cardiovascular response to air stress. Chronically instrumented rats received bilateral injections of either 80 pmol of muscimol or 100 nl of saline vehicle into the DMH, the PVN, or an intermediate area (including the rostral edge of the DMH and the region between the two nuclei) and were placed immediately in a restraining tube and subjected to 20 min of air stress. In all rats, air stress after vehicle injections caused marked increases in heart rate (137 +/- 6 beats/min) and blood pressure (26 +/- 2 mmHg). Microinjection of muscimol into the DMH suppressed the heart rate and blood pressure response by 85 and 68%, respectively. Identical microinjection of muscimol into the intermediate area between the DMH and the PVN attenuated the increases in heart rate by only 46% and in blood pressure by 52%. In contrast, similar injections into the vicinity of the PVN failed to alter the cardiovascular response to air stress. These findings demonstrate that muscimol-induced inhibition of neuronal activity in the region of the DMH blocks air stress-induced increases in heart rate and arterial pressure, whereas similar treatment in the area of the PVN has no effect

Mesoscopic spin confinement during acoustically induced transport

Long coherence lifetimes of electron spins transported using moving potential dots are shown to result from the mesoscopic confinement of the spin vector. The confinement dimensions required for spin control are governed by the characteristic spin-orbit length of the electron spins, which must be larger than the dimensions of the dot potential. We show that the coherence lifetime of the electron spins is independent of the local carrier densities within each potential dot and that the precession frequency, which is determined by the Dresselhaus contribution to the spin-orbit coupling, can be modified by varying the sample dimensions resulting in predictable changes in the spin-orbit length and, consequently, in the spin coherence lifetime.Comment: 10 pages, 2 figure

Fulminant neuroleptic malignant syndrome after perioperative withdrawal of antiParkinsonian medication

Neuroleptic malignant syndrome is a rare complication when using neuroleptic drugs. We report the case of a patient with severe Parkinson's disease who developed neuroleptic malignant syndrome after withdrawal of his antiParkinsonian medication for elective coronary artery bypass grafting. Sodium dantrolene may be a therapeutic option in severe case

A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Observation of second-harmonic generation induced by pure spin currents

Extensive efforts are currently being devoted to developing a new electronic technology, called spintronics, where the spin of electrons is explored to carry information. [1,2] Several techniques have been developed to generate pure spin currents in many materials and structures. [3-10] However, there is still no method available that can be used to directly detect pure spin currents, which carry no net charge current and no net magnetization. Currently, studies of pure spin currents rely on measuring the induced spin accumulation with optical techniques [5, 11-13] or spin-valve configurations. [14-17] However, the spin accumulation does not directly reflect the spatial distribution or temporal dynamics of the pure spin current, and therefore cannot monitor the pure spin current in a real-time and real-space fashion. This imposes severe constraints on research in this field. Here we demonstrate a second-order nonlinear optical effect of the pure spin current. We show that such a nonlinear optical effect, which has never been explored before, can be used for the non-invasive, non-destructive, and real-time imaging of pure spin currents. Since this detection scheme does not rely on optical resonances, it can be generally applied in a wide range of materials with different electronic bandstructures. Furthermore, the control of nonlinear optical properties of materials with pure spin currents may have potential applications in photonics integrated with spintronics.Comment: 19 pages, 3 figures, supplementary discussion adde

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients

Background: The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients. Methods: Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan–Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell’s concordance index (c-index). Results: An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13–3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07–3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added. Conclusion: An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients

Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer

Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients. Methods: Data from 371 consecutive PC patients, treated between 2004 and 2010 at a single centre, were evaluated retrospectively. The whole cohort was stratified into two groups according to the treatment modality. Group 1 comprised 261 patients with inoperable PC at diagnosis and group 2 comprised 110 patients with surgically resected PC. Cancer-specific survival (CSS) was assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of the NLR, the modified Glasgow prognostic score (mGPS) and the platelet-lymphocyte ratio univariate and multivariate Cox regression models were applied. Results: Multivariate analysis identified increased NLR as an independent prognostic factor for inoperable PC patients (hazard ratio (HR)=2.53, confidence interval (CI)=1.64–3.91, P<0.001) and surgically resected PC patients (HR=1.61, CI=1.02–2.53, P=0.039). In inoperable PC patients, the mGPS was associated with poor CSS only in univariate analysis (HR=1.44, CI=1.04–1.98). Conclusion: Risk prediction for cancer-related end points using NLR does add independent prognostic information to other well-established prognostic factors in patients with PC, regardless of the undergoing therapeutic modality. Thus, the NLR should be considered for future individual risk assessment in patients with PC