A chimeric T cell receptor with super-signaling properties

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-alphabeta chains result in the activation of distinct signal transduction pathways by the CD3-gammadeltaepsilon/zeta complex? To investigate which part of the TCR-beta chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-beta chain with the corresponding TCR-gamma chain domains. We show here that hybridoma cells expressing a chimeric TCR-beta chain (betaIII) containing intracellular and transmembrane TCR-gamma amino acids, together with a wild-type TCR-alpha (alphawt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-alphawt/betawt chains. This super-signaling phenotype of the betaIII chain was observed in two different TCRs. One specific for an alloantigen (I-A(bm12)) and one for an autoantigen (I-A(b)/MOG(35-55)). We found that this chimeric alphawt/betaIII TCR had normal association with CD3-gammadeltaepsilon and zeta chains. To investigate the effect of the chimeric betaIII chain in transgenic T cells, we made MOG(35-55)-specific TCR transgenic mice expressing either the alphawt/betawt or chimeric alphawt/betaIII TCR. Similar to what was observed in hybridoma cells, transgenic alphawt/betaIII T cells showed a super-signaling phenotype upon antigenic stimulation. Further studies may help us understand the effect of increased TCR signaling on autoimmunity and may lead to the identification of signaling molecules that can be targeted to stop the progression of autoimmune disorders such as multiple sclerosis.     

DRD4 exon 3 variants are not associated with symptomatology of major psychoses in a German population

We previously reported an association of DRD4 exon 3 long alleles with delusional symptomatology, independently from psychiatric diagnoses [Am. J. Med. Genet. 105 (2001) 283; Psychiatry Res. 80 (1998) 129]. The aim of this investigation was to replicate these results in an independent sample from Germany. We studied 394 subjects, affected by bipolar disorder (n = 32), schizoaffective disorder (n = 45), and schizophrenia (n = 317). All affected subjects were evaluated using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. DRD4 variants were not associated with symptomatology of major psychosis. Our present results, obtained in an independent German sample, did not confirm the association between DRD4 variants and delusional symptomatology. However it should be considered that the original sample included a much higher rate of mood disorders and this could partially explain the discrepancy.     

The Psychological Significance of Task-Induced Tonic Changes in Somatic and Autonomic Activity

Two experiments tested the view that task-induced autonomic-somatic gradient parallelism does exist and that the steeper the physiological gradients, over the course of a task, the more involved the subject and the greater the effort. Thirty-three male subjects performed easy and difficult versions of a continuous reaction time task. In both experiments the difficult task prompted steeper electromyographic (EMG) activity gradients than did the easy version. Scores on heart rate (HR) and skin conductance did not show clear gradients. However, task-dependent effort was positively related to the magnitude of the initial HR acceleration and to the steepness of the EMG gradient. The autonomic-somatic coupling hypothesis of Obrist did not explain the results. Instead, evidence for ventilatory-somatic parallelism was found.     

Respiratory Patterns as Predictors of Laughter

Earlier research on respiratory patterns indicates that they are sensitive to emotional processes. Abdominal and thoracic patterns were therefore used as predictors of laughter responses in 25 subjects participating in an entertainment situation. The abdominal respiratory body circumference changes (the abdominal amplitude) of the women predicted their laughter responses; the greater the abdominal amplitudes during the entertainment period, the more frequent and enduring were their laughter responses. No prediction was obtained by the respiratory patterns of men. The results suggest that respiratory patterns are sensitive indicators of laughter response habits in women only. The variability of tonus in the abdominal muscles was suggested to be of particular importance to the results, i. e. great variability yields frequent and enduring laughter responses in women.     

Origin and primary dispersal of the Mycobacterium tuberculosis Beijing genotype: clues from human phylogeography

We suggest that the evolution of the population structure of microbial pathogens is influenced by that of modern humans. Consequently, the timing of hallmark changes in bacterial genomes within the last 100,000 yr may be attempted by comparison with relevant human migrations. Here, we used a lineage within Mycobacterium tuberculosis, a Beijing genotype, as a model and compared its phylogeography with human demography and Y chromosome-based phylogeography. We hypothesize that two key events shaped the early history of the Beijing genotype: (1) its Upper Palaeolithic origin in the Homo sapiens sapiens K-M9 cluster in Central Asia, and (2) primary Neolithic dispersal of the secondary Beijing NTF::IS6110 lineage by Proto-Sino-Tibetan farmers within east Asia (human O-M214/M122 haplogroup). The independent introductions of the Beijing strains from east Asia to northern Eurasia and South Africa were likely historically recent, whereas their differential dissemination within these areas has been influenced by demographic and climatic factors.     

Substance P antagonists and mucociliary activity in rabbit

Summary Substance P (SP) is known to accelerate mucociliary (m.c.) activity in the rabbit maxillary sinus in vivo. The physiological significance of this finding was investigated by testing three putative SP antagonists. [Arg⁵, d-Trp^{7, 9}, Nle¹¹]SP_5–11 could not be used as an antagonist because it stimulated m.c. activity. [d-Arg¹, d-Trp^{7, 9}, Leu¹¹]SP had no effect on the m.c. activity changes induced by SP. [d-Pro², d-Trp^{7, 9}]SP was found to be an effective antagonist, 1 mg/kg of this drug reversibly inhibiting both the effects of 0.1 g/kg SP and the stimulating effect of 1.0 g/kg bradykinin and 30.0g/kg capsaicin; the stimulating effect of 0.5 g/kg methacholine was not inhibited. It is suggested that bradykinin and capsaicin stimulate m.c. activity at least partly by releasing SP.The results of this investigation also support the view that the accelerating effect of SP on m.c. activity reflects physiological SP-mediated protective mechanisms in the airways. It is concluded that [d-Pro², d-Trp^{7, 9}]SP is a useful pharmacological tool for studying the role of SP in the control of m.c. actvity in rabbits.     

Is reflection like soap? a critical narrative umbrella review of approaches to reflection in medical education research

Advances in Health Sciences Education - Reflection is a complex concept in medical education research. No consensus exists on what reflection exactly entails; thus far, cross-comparing empirical...     

Risk factors for Epstein–Barr virus reactivation after renal transplantation: Results of a large,multi-centre study

Epstein–Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.