Cervical spine: three-dimensional MR imaging with magnetization transfer prepulsed turbo field echo techniques

In 11 volunteers, magnetic resonance (MR) imaging of the cervical spine was performed with a magnetization transfer preparatory pulse (prepulsed), three-dimensional Fourier transform, turbo field echo sequence. The effects of flip angle, number of shots, phase-encoding profile order, and magnetization transfer prepulse offset frequency on cerebrospinal fluid-to-cord contrast were evaluated. The contrast was improved by lowering the flip angle, increasing the number of shots, and implementing a magnetization transfer prepulse and linear phase-encoding profile order. Maximum myelographic effect was achieved with the magnetization prepulse (500-Hz frequency offset), 3 degrees flip angle, six shots, and linear phase-encoding profile order.     

Identification of a truncated form of the CC chemokine CK beta-8 demonstrating greatly enhanced biological activity

A new CC chemokine, designated CKbeta-8 or myeloid progenitor inhibitor factor-1, was recently identified in a large scale sequencing effort and was cloned from a human aortic endothelial library. CKbeta-8 cDNA encodes a signal sequence of 21 amino acids, followed by a 99-amino acid predicted mature form. CKbeta-8 was expressed and purified from a baculovirus insect cell expression system, which resulted in the identification of different N-terminal variants of the secreted chemokine. The three major forms (containing amino acids 1-99, 24-99, and 25-99 of the secreted chemokine) showed a large variation in potency. CKbeta-8 activated both monocytes and eosinophils to mobilize intracellular calcium; however, the shortest form of CKbeta-8 (25-99) was >2 orders of magnitude more potent than the longest form. Cross-desensitization experiments in both monocytes and eosinophils suggested that the CCR1 receptor was probably the predominant receptor that mediates this chemokine's physiologic response. However, incomplete desensitization was encountered in both cell systems, suggesting involvement of an additional receptor(s). Interestingly, the short form of CKbeta-8 was the most potent chemotactic chemokine that we have ever evaluated in the monocyte system (EC50 = 54 pM). However, in contrast to its action on monocytes, CKbeta-8 was a very poor chemotactic factor for eosinophils.     

The role of I-Ag7 beta chain in peptide binding and antigen recognition by T cells

We examine here how the beta chain of the class II MHC molecule I-Ag7 influences T cell recognition. Three sets of T cell clones were identified. The first set recognizes peptides bound to I-Ag7, I-Ad and I-Ag7 mutant in which the allele-specific residues His and Ser at position 56 and 57 were changed to the Pro at residue 56 and to non-polymorphic Asp at residue 57. The second set responds to the antigen presented only by I-Ag7 and does not recognize the peptides bound to the other class II molecules. The third set is also specific for I-Ag7 as a result of the poor binding of the peptide to I-Ad and the mutant I-Ag7. These results indicate that positions 56 and 57 of the I-Ag7 class II MHC beta chain play a role in both T cell recognition of the MHC-peptide complex and peptide binding to MHC. These two different functions may be involved in I-Ag7-restricted beta cell antigen recognition by diabetogenic T cell clones.     

Autoreactivity of T cells from nonobese diabetic mice: an I-Ag7-dependent reaction

Mice bearing the I-Ag7 class II major histocompatibility complex molecules contain a high number of spontaneous autoreactive T cells, as estimated by limiting-dilution assays. We found this autoreactivity in various strains that bear the I-Ag7 molecule, such as the nonobese diabetic (NOD) mouse strain, which spontaneously develops autoimmune diabetes. However, NOD mice strains that do not express the I-Ag7 molecule, but instead express I-Ab, do not have a high incidence of autoreactive T cells. About 15% of the autoreactive T cells also recognize the I-Ag7 molecule expressed in the T2 line, which is defective in the processing of protein antigens. We interpret this to mean that some of the T cells may interact with class II molecules that are either devoid of peptides or contain a limited peptide content. We also find a high component of autoreactivity among antigen-specific T cell clones. These T cell clones proliferate specifically to protein antigens but also have a high level of reactivity to antigen-presenting cells not pulsed with antigen. Thus, the library of T cell receptors in NOD mice is skewed to autoreactivity, which we speculate is based on the weak peptide-binding properties of I-Ag7 molecules.     

Mapping the minimal murine T cell and B cell epitopes within a peptide vaccine candidate from the conserved region of the M protein of group A streptococcus

The highly conserved C-terminus of the M protein of group A streptococcus (GAS) is a promising vaccine candidate. An epitope within the conserved C-terminus of the M protein, peptide 145 (a 20-mer with the sequence: LRRDLDASREAKKQVEKALE), has been defined which is the target of opsonic antibodies in both humans and mice, and is recognized by the sera of most adults living in areas of high streptococcal exposure. However, due to potential cross-reactivity between T cells stimulated by this region of the M protein and host cardiac myosin, it is critical to define precisely the minimal protective epitopes within p145. Studies have shown that the immunodominant epitope expressed by p145 is conformational, occurring as an alpha-helical coiled-coil. To enable us to map the murine minimal B cell and T cell epitopes within p145, we have used a novel strategy that allowed us to present shorter sequences of p145 in a native-like conformation. The minimal B cell epitope was found to be contained within residues 7-20 of the p145 sequence, and we have shown that mice immunized with this region are able to generate antibodies that bind to and also opsonize the organism GAS. The T cell epitope is located at the N-terminal region of the p145 sequence, residues 3-14. We have managed, therefore, to define a vaccine candidate--a minimal opsonic B cell epitope within the p145 sequence--that does not incorporate a potentially deleterious T cell epitope.     

The organic grid: self-organizing computation on a peer-to-peer network

Desktop grids have been used to perform some of the largest computations in the world and have the potential to grow by several more orders of magnitude. However, current approaches to utilizing desktop resources require either centralized servers or extensive knowledge of the underlying system, limiting their scalability. We propose a new design for desktop grids that relies on a self-organizing, fully decentralized approach to the organization of the computation. Our approach, called the organic grid, is a radical departure from current approaches and is modeled after the way complex biological systems organize themselves. Similar to current desktop grids, a large computational task is broken down into sufficiently small subtasks. Each subtask is encapsulated into a mobile agent, which is then released on the grid and discovers computational resources using autonomous behavior. In the process of "colonization" of available resources, the judicious design of the agent behavior produces the emergence of crucial properties of the computation that can be tailored to specific classes of applications. We demonstrate this concept with a reduced-scale proof-of-concept implementation that executes a data-intensive independent-task application on a set of heterogeneous, geographically distributed machines. We present a detailed exploration of the design space of our system and a performance evaluation of our implementation using metrics appropriate for assessing self-organizing desktop grids.     

Synthesis of High-Performance Parallel Programs for a Class of ab Initio Quantum Chemistry Models

This paper provides an overview of a program synthesis system for a class of quantum chemistry computations. These computations are expressible as a set of tensor contractions and arise in electronic structure modeling. The input to the system is a a high-level specification of the computation, from which the system can synthesize high-performance parallel code tailored to the characteristics of the target architecture. Several components of the synthesis system are described, focusing on performance optimization issues that they address.     

Immunoregulatory events in the skin of patients with cutaneous T-cell lymphoma

BACKGROUND: Involved skin of patients with cutaneous T-cell lymphoma, mycosis fungoides type, contains an increased number of bone marrow-derived epidermal cells that express class II major histocompatibility complex molecules and an infiltrate of both activated non-malignant and malignant T cells. However, the mechanism by which the T cells achieve and maintain their activated state is uncertain. The aim of this article is, therefore, to review recent studies from the literature dealing with immunoregulatory events in patients with mycosis fungoides and Sézary syndrome. OBSERVATIONS: The nonmalignant T cells seem to be activated through the T-cell receptor by lesional epidermal CD1a+CD36+ macrophagelike cells that, on a cell per cell basis, are more potent antigen-presenting cells than normal CD1a+ Langerhans' cells present in uninvolved epidermis. In contrast, the malignant T cells have different activation requirements, because they can only be stimulated through antigen independent pathways, such as CDw60, CD28, and CD2. The malignant T cells produce T-helper (Th)-2 cytokines, and because interferon gamma (IFN-gamma)-producing Th1 cells are present in the early lesions of mycosis fungoides, nonmalignant tumor-infiltrating T cells may represent Th1 cells. Because Th1 cytokines counteract Th2 cytokines, tumor-infiltrating T cells may potentially have the capacity to downregulate the growth of the malignant cells. CONCLUSION: The balance between progression vs remission in mycosis fungoides is related to complex interactions between the malignant T cells, nonmalignant T cells, and hyperstimulative antigen-presenting cells present within the skin.     

Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis

The human squamous cell carcinoma antigens (SCCA) 1 and 2 are tandemly arrayed genes that encode two high-molecular-weight serine proteinase inhibitors (serpins). Although these proteins are 92% identical, differences in their reactive site loops suggest that they inhibit different types of proteinases. Our previous studies show that SCCA2 inhibits chymotrypsin-like serine proteinases [Schick et al. (1997) J. Biol. Chem. 272, 1849-1855]. We now show that, unlike SCCA2, SCCA1 lacks inhibitory activity against any of the more common types of serine proteinases but is a potent cross-class inhibitor of the archetypal lysosomal cysteine proteinases cathepsins K, L, and S. Kinetic analysis revealed that SCCA1 interacted with cathepsins K, L, and S at 1:1 stoichiometry and with second-order rate constants >/= 1 x 10(5) M-1 s-1. These rate constants were comparable to those obtained with the prototypical physiological cysteine proteinase inhibitor, cystatin C. Also relative to cystatin C, SCCA1 was a more potent inhibitor of cathepsin K-mediated elastolytic activity by forming longer lived inhibitor-proteinase complexes. The t1/2 of SCCA1-cathepsin S complexes was >1155 min, whereas that of cystatin C-cathepsin complexes was 55 min. Cleavage between the Gly and Ser residues of the reactive site loop and detection of a stable SCCA1-cathepsin S complex by sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggested that the serpin interacted with the cysteine proteinase in a manner similar to that observed for typical serpin-serine proteinase interactions. These data suggest that, contingent upon their reactive site loop sequences, mammalian serpins, in general, utilize their dynamic tertiary structure to trap proteinases from more than one mechanistic class and that SCCA1, in particular, may be involved in a novel inhibitory pathway aimed at regulating a powerful array of lysosomal cysteine proteinases.     

Reliability testing of the dermatology index of disease severity (DIDS). An index for staging the severity of cutaneous inflammatory disease

OBJECTIVES: To describe a new severity of illness index for inflammatory skin disease called the Dermatology Index of Disease Severity (DIDS), and to show its preliminary use and reliability in staging disease in patients with psoriasis and dermatitis. DESIGN: Interobserver rating study using the DIDS with as many as 10 observers independently rating the same patient at a single point in time. SETTING: Ambulatory care clinics at an academic medical center with patients from various socioeconomic backgrounds. PATIENTS: Thirty-four patients with psoriasis and 15 patients with dermatitis were included in the study. MAIN OUTCOME MEASURES: The severity of illness for each patient was rated as 1 of 5 stages: 0, no evidence of clinical disease; I, limited disease; II, mild disease; III, moderate disease; and IV, severe disease. The degree of interobserver concordance was measured by the Cohen kappa statistic. RESULTS: All 5 stages were represented in the study of patients with psoriasis. The overall kappa statistic was 0.76, which is defined as substantial interobserver concordance. The use of the instrument in dermatitis showed good consensus in staging, where the kappa statistic was 0.41. CONCLUSION: We introduce an easy and efficient instrument for staging the severity of illness in inflammatory cutaneous diseases. The reliability of the DIDS is demonstrated in patients with psoriasis and in patients with dermatitis.