Calcineurin sets the bandwidth for discrimination of signals during thymocyte development

At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.     

Rapid Manufacturing of Non-Assembly Complex Micro-Devices by Microstereolithography

This paper introduces a non-assembly manufacturing case with microstereolithography technology. The design and manufacturing process of a pneumatic thrust bearing is described, and a special tessellation method is developed to further improve the capability of the manufacturing system thus bigger products can also be easily manufactured. Implemented in a layer-by-layer fashion, stereolithography has been used for the rapid manufacturing of complex devices, and it avoids the expensive assembly process in the traditional manufacturing. This paper presents that microstereolithography can produce high-resolution products with intricate details, small openings, and smooth surfaces. The potential of the microstereolithograhy technique is explored for the rapid manufacturing of small and complex objects.     

A smart automated macroeconometric forecasting system

A smart, automated forecasting system is a kind of expert system for generating forecasts wholly or partly without human intervention. A pilot-scale system is reported in this paper. The interventions are made by a rulebase which describes the actual intervention procedures of the London Business School Centre for Economic Forecasting on one of the major macroeconometric forecasting models for the U.K. economy. The rulebase is sufficiently general as to be applicable to any forecasting model. One difference of the pilot model reported in this paper from conventional models is that policy behaviour is described entirely by rules rather than equations. This allows the use of thresholds, floors, ceilings, and discontinuities.     

Cytotoxic T-cell clones discriminate between A- and B-type Epstein-Barr virus transformants

Epstein-Barr virus (EBV) is the aetiological agent of infectious mononucleosis and is associated with Burkitt's lymphoma and nasopharyngeal carcinoma. The virus is harboured for life in all previously infected individuals and is apparently controlled by a population of EBV-specific memory T lymphocytes, specifically activated to recognize the functionally defined lymphocyte-detected membrane antigen. Two types (A and B) of EBV have been identified that show DNA sequence divergence within the BamH1 WYH region of the genome encoding the transformation-associated antigen, Epstein-Barr nuclear antigen 2 (EBNA 2) (ref. 4). To define the function of EBNA 2 in T-cell recognition, we have compared the ability of EBV-specific cytotoxic T-cell clones to distinguish between autologous B lymphocytes transformed by A- or B-type virus. We have now isolated both CD4 and CD8 cytotoxic T-cell clones that recognize autologous A-type but not B-type transformed lymphoblastoid cell lines, thus providing the first evidence that EBV-specific T-cell recognition can be mediated by EBNA 2. As this antigen is not expressed in Burkitt's lymphoma, this finding explains the failure of EBV-specific T-cell surveillance to eliminate the tumour.     

Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins

Several polypeptides are secreted into the medium of cells infected with vaccinia virus, a cytoplasmic DNA virus belonging to the poxvirus family. One of these, a polypeptide of relative molecular mass 19,000 is structurally related to epidermal growth factor and binds to epidermal growth factor receptor stimulating proliferation of uninfected cells in vitro and in vivo. Here, we show that a second, and much more abundant secretory polypeptide, is also encoded by vaccinia virus and is structurally related to the superfamily of complement control proteins. Members of this family can block complement-mediated induction of the inflammatory response, and engulfment, killing and lysis of bacteria and viruses.