CD40 Ligand and Autoantigen Are Involved in the Pathogenesis of Low-Grade B-Cell Lymphomas of Mucosa-Associated Lymphoid Tissue

Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology. Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR, and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade lymphomas throughout CDR1- CDR3 suggestive of positive selection through their antigen receptor. Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens. CD40L expression was found in the tumor marginal zone in substantial amounts. The in vitro proliferation response of all low-grade MALT-type lymphomas was dependent on anti-CD40- mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis

Descent of Equivalences and Character Bijections

Categorical equivalences between block algebras of finite groups—such as Morita and derived equivalences—are well known to induce character bijections which commute with the Galois groups of field extensions. This is the motivation for attempting to realise known Morita and derived equivalences over non-splitting fields. This article presents various results on the theme of descent to appropriate subfields and subrings. We start with the observation that perfect isometries induced by a virtual Morita equivalence induce isomorphisms of centres in non-split situations and explain connections with Navarro’s generalisation of the Alperin–McKay conjecture. We show that Rouquier’s splendid Rickard complex for blocks with cyclic defect groups descends to the non-split case. We also prove a descent theorem for Morita equivalences with endopermutation source

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Background: The Muscle-specific RING-finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo. Methods: MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real-time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass-spectrometry were used for mechanistic analyses. Results: DKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3-deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts. Conclusions: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo

Inhibition of IFN-γ-dependent antiviral airway epithelial defense by cigarette smoke

<p>Abstract</p> <p>Background</p> <p>Although individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood. Because airway epithelial cell responses to type II interferon (IFN) are critical in regulation of defense against many respiratory viral infections, we hypothesized that cigarette smoke has inhibitory effects on IFN-γ-dependent antiviral mechanisms in epithelial cells in the airway.</p> <p>Methods</p> <p>Primary human tracheobronchial epithelial cells were first treated with cigarette smoke extract (CSE) followed by exposure to both CSE and IFN-γ. Epithelial cell cytotoxicity and IFN-γ-induced signaling, gene expression, and antiviral effects against respiratory syncytial virus (RSV) were tested without and with CSE exposure.</p> <p>Results</p> <p>CSE inhibited IFN-γ-dependent gene expression in airway epithelial cells, and these effects were not due to cell loss or cytotoxicity. CSE markedly inhibited IFN-γ-induced Stat1 phosphorylation, indicating that CSE altered type II interferon signal transduction and providing a mechanism for CSE effects. A period of CSE exposure combined with an interval of epithelial cell exposure to both CSE and IFN-γ was required to inhibit IFN-γ-induced cell signaling. CSE also decreased the inhibitory effect of IFN-γ on RSV mRNA and protein expression, confirming effects on viral infection. CSE effects on IFN-γ-induced Stat1 activation, antiviral protein expression, and inhibition of RSV infection were decreased by glutathione augmentation of epithelial cells using N-acetylcysteine or glutathione monoethyl ester, providing one strategy to alter cigarette smoke effects.</p> <p>Conclusions</p> <p>The results indicate that CSE inhibits the antiviral effects of IFN-γ, thereby presenting one explanation for increased susceptibility to respiratory viral infection in individuals exposed to cigarette smoke.</p

Between the Vinča and Linearbandkeramik worlds: the diversity of practices and identities in the 54th–53rd centuries cal BC in south-west Hungary and beyond

Szederk&eacute;ny-Kukorica-dűlő is a large settlement in south-east Transdanubia, Hungary, excavated in advance of road construction, which is notable for its combination of pottery styles, variously including Vinča A, Raži&scaron;te and LBK, and longhouses of a kind otherwise familiar from the LBK world. Formal modelling of its date establishes that the site probably began in the later 54th century cal BC, lasting until the first decades of the 52nd century cal BC. Occupation, featuring longhouses, pits and graves, probably began at the same time on the east and west parts of the settlement, the central part starting a decade or two later; the western part was probably abandoned last. Vinča pottery is predominantly associated with the east and central parts of the site, and Raži&scaron;te pottery with the west. Formal modelling of the early history and diaspora of longhouses in the LBK world suggests their emergence in the Formative LBK of Transdanubia c. 5500 cal BC and then rapid diaspora in the middle of the 54th century cal BC, associated with the &lsquo;earliest&rsquo; (&auml;lteste) LBK. The adoption of longhouses at Szederk&eacute;ny thus appears to come a few generations after the start of the diaspora. Rather than explaining the mixture of things, practices and perhaps people at Szederk&eacute;ny by reference to problematic notions such as hybridity, we propose instead a more fluid and varied vocabulary including combination and amalgamation, relationships and performance in the flow of social life, and networks; this makes greater allowance for diversity and interleaving in a context of rapid change