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Although numerous mechanisms for promoting software reuse have been proposed and implemented over the years, most have focused on the reuse of implementation code. There is much conjecture and some empirical evidence, however, that the most effective forms of reuse are generally found at more abstract levels of software design. We discuss software reuse at the architectural level of design. Specifically, we argue that the concept of "architectural style" is useful for supporting the classification, storage, and retrieval of reusable architectural design elements. We briefly describe the Aesop system's Software Shelf (D. Garlan et al., 1994), a tool that assists designers in selecting appropriate design elements and patterns based on stylistic information and design constraints.

Molecular testing of thyroid specimens has increased dramatically over the last decade and has become an important adjunct to cytopathology for the management of patients with thyroid nodules. Current applications include tumor subtyping, tumor prognosis, and risk stratification of specific subtypes of thyroid nodules. Among these applications, the latter has shown the most significant clinical utility and adoption. Specifically, this application involves the molecular analysis of thyroid fine needle aspiration (FNA) specimens from indeterminate nodules that are not clearly benign or malignant cytologically and carry an elevated risk of malignancy (ROM) relative to cytologically benign nodules. Because of this unacceptably high ROM, patients with indeterminate nodules frequently undergo diagnostic surgery although approximately 75 % of the nodules are found to be histologically benign upon surgical pathology review. The goal of molecular testing of these indeterminate nodules, which comprise approximately 15–30 % of all cases, is to reclassify them into lower or higher risk groups, permitting conservative management and unnecessary surgery in the lower risk group while increasing the chance of malignancy and potentially guiding surgical management in the higher risk group. The aim of this chapter is to provide an overview of the current and future uses of molecular testing of thyroid cytopathology specimens with a focus on molecular evaluation of those with indeterminate cytopathology.

Although the assumption of utility-maximizing consumers has been challenged for decades, empirical applications of alternative choice rules are still very new. We add to this growing body of literature by proposing a model based on the idea of a “satisficing” decision maker. In contrast to previous models (including recent models implementing alternative choice rules), satisficing depends on the order in which alternatives are evaluated. We therefore conduct a visual conjoint experiment to collect search and choice data. We model search and product evaluation jointly and allow for interdependence between them. The choice rule incorporates a conjunctive rule for the evaluations and, contrary to most previous models, does not rely on compensatory trade-offs at all. The results strongly support the proposed model. For instance, we find that search is indeed influenced by product evaluations. More importantly, the model results strongly support the satisficing stopping rule. Finally, we perform a holdout prediction task and find that the proposed model outperforms a standard multinomial logit model.

The North Korean nuclear weapons test on October 9, 2006 made front-page news. Condemnation was nearly universal. Diplomatic activity was frantic. Within a week the UN Security Council passed Resol...

T cell receptor (TCR) δ and α variable region genes are assembled from germ-line gene segments located in a single chromosomal locus in which TCRδ segments are situated between TCRα segments. The TCRα enhancer (Eα) located at the 3′ end of the TCRα/δ locus functions over a long chromosomal distance to promote TCRα rearrangement and maximal TCRδ expression; whereas the TCRδ enhancer (Eδ) is located among the TCRδ segments and functions with additional element(s) to mediate TCRδ rearrangement. We used gene-targeted mutation to evaluate whether the identity of Eα and the position of Eδ are critical for the developmental stage-specific assembly of TCR δ and α variable region genes. Specific replacement of Eα with Eδ, the core Eα element (EαC), or the Ig heavy chain intronic enhancer (iEμ), all of which promote accessibility in the context of transgenic V(D)J recombination substrates, did not promote a significant level of TCRα rearrangement beyond that observed in the absence of Eα. Therefore, the identity and full complement of Eα-binding sites are critical for promoting accessibility within the TCRα locus. In the absence of the endogenous Eδ element, specific replacement of Eα with Eδ also did not promote TCRδ rearrangement. However, deletion of intervening TCRα/δ locus sequences to restore the inserted Eδ to its normal chromosomal position relative to 5′ sequences rescued TCRδ rearrangement. Therefore, unlike Eα, Eδ lacks ability to function over the large intervening TCRα locus and/or Eδ function requires proximity to additional upstream element(s) to promote TCRδ accessibility.

Splenic B lineage cells expressing recombination activation genes (RAG(+)) in mice immunized with 4-hydroxy-3-nitrophenyl-acetyl coupled to chicken gamma-globulin (NP-CGG) and the adjuvant aluminum-hydroxide (alum) have been proposed to be mature B cells that reexpress RAG after an antigen encounter in the germinal center (GC), a notion supported by findings of RAG expression in peripheral B lymphocyte populations activated in vitro. However, recent studies indicate that these cells might be immature B cells that have not yet extinguished RAG expression. Here, we employ RAG2-green fluorescent protein (GFP) fusion gene knock-in mice to show that RAG(+) B lineage cells do appear in the spleen after the administration of alum alone, and that their appearance is independent of T cell interactions via the CD40 pathway. Moreover, splenic RAG(+) B lineage cells were detectable in immunized RAG2-deficient mice adoptively transferred with bone marrow (BM) cells, but not with spleen cells from RAG(+) mice. Although splenic RAG(+) B cells express surface markers associated with GC B cells, we also find the same basic markers on progenitor/precursor BM B cells. Finally, we did not detect RAG gene expression after the in vitro stimulation of splenic RAG(-) mature B cells with mitogens (lipopolysaccharide and anti-CD40) and cytokines (interleukin [IL]-4 and IL-7). Together, our studies indicate that RAG(+) B lineage cells from BM accumulate in the spleen after immunization, and that this accumulation is not the result of an antigen-specific response.

T cell receptor (TCR) beta chain allelic exclusion occurs at the thymocyte CD4- 8- (double-negative, or DN) to CD4+ 8+ (double-positive, or DP) transition, concurrently with differentiation and cellular expansion, and is imposed by a negative feedback loop in which a product of the first rearranged TCRbeta allele arrests further recombination in the TCRbeta locus. All of the major events associated with the development of DP cells can be induced by the introduction of TCRbeta or activated Lck transgenes. Here, we present evidence that the signaling pathways that promote thymocyte differentiation and expansion of RAG-deficient DN cells but not those that suppress rearrangements of endogenous TCRbeta genes in normal DN cells are engaged by activated Ras. We propose that TCRbeta allelic exclusion is mediated by effector pathways downstream of Lck but independent of Ras.

We have used gene-targeted mutation to assess the role of the T cell receptor δ (TCRδ) enhancer (Eδ) in αβ and γδ T cell development. Mice lacking Eδ exhibited no defects in αβ T cell development but had a severe reduction in thymic and peripheral γδ T cells and decreased VDJδ rearrangements. Simultaneous deletion of both Eδ and the TCRα enhancer (Eα) demonstrated that residual TCRδ rearrangements were not driven by Eα, implicating additional elements in TCRδ locus accessibility. Surprisingly, while deletion of Eδ severely impaired germline TCRδ expression in double-negative thymocytes, absence of Eδ did not affect expression of mature δ transcripts in γδ T cells. We conclude that Eδ has an important role in TCRδ locus regulation at early, but not late, stages of γδ T cell development.

T-cell development is a complex and ordered process that is regulated in part by the progressive assembly and expression of antigen receptor genes. T cells can be divided into two lineages based on expression of either an alpha beta or gamma delta T-cell antigen receptor (TCR). The genes that encode the TCR beta and gamma chains lie in distinct loci, whereas the genes that encode the TCR alpha and delta chains lie in a single locus (TCR alpha/delta locus). Assembly of TCR variable region genes is mediated by a site-specific recombination process that is common among all lymphocytes. Despite the common nature of this process, recombination of TCR genes is tightly regulated within the context of the developing T cell. TCR beta, gamma and delta variable region genes are assembled prior to TCR alpha variable region genes. Furthermore, assembly of TCR beta variable region genes is regulated within the context of allelic exclusion. The regulation of rearrangement and expression of genes within the TCR alpha/delta locus presents a complicated problem. TCR alpha and delta variable region genes are assembled at different stages of T-cell development, and fully assembled TCR alpha and delta variable region genes must be expressed in distinct lineages of T cells, alpha beta and gamma delta, respectively. We have developed several experimental approaches to assess the role of cis-acting elements in regulating recombination and expression of TCR genes. Here we describe these approaches and discuss our analyses of the regulation of accessibility of the TCR beta and TCR alpha/delta loci during T-cell development.

Architectural styles, object-oriented design and design patterns all hold promise as approaches that simplify software design and reuse by capturing and exploiting system design knowledge. This article explores the capabilities and roles of the various approaches, their strengths and their limitations.

We generated mice harboring germline mutations in which the enhancer element located 9 kb 3′ of the immunoglobulin κ light chain gene (3′E κ ) was replaced either by a single loxP site (3′E κ Δ) or by a neomycin resistance gene (3′E κ N). Mice homozygous for the 3′E κ Δ mutation had substantially reduced numbers of κ-expressing B cells and increased numbers of λ-expressing B cells accompanied by decreased κ versus λ gene rearrangement. In these mutant mice, κ expression was reduced in resting B cells, but was normal in activated B cells. The homozygous 3′E κ N mutation resulted in a similar but more pronounced phenotype. Both mutations acted in cis . These studies show that the 3′E κ is critical for establishing the normal κ/λ ratio, but is not absolutely essential for κ gene rearrangement or, surprisingly, for normal κ expression in activated B cells. These studies also imply the existence of additional regulatory elements that have overlapping function with the 3′E κ element.

Numerous architectural description languages (ADLs) have been developed, each providing complementary capabilities for architectural development and analysis. Unfortunately, each ADL and supporting toolset operates in isolation, making it difficult to integrate those tools and share architectural descriptions. Acme is being developed as a joint effort of the software architecture research community as a common interchange format for architecture design tools. Acme provides a structural framework for characterizing architectures, together with annotation facilities for additional ADL-specific information. This scheme permits subsets of ADL tools to share architectural information that is jointly understood, while tolerating the presence of information that falls outside their common vocabulary. In this paper we describe Acme's key features, rationale, and technical innovations.

RAG1 and RAG2 are the lymphocyte-specific components of the V(D)J recombinase. In vitro analyses of RAG function have relied on soluble, highly truncated "core" RAG proteins. To identify potential functions for noncore regions and assess functionality of core RAG1 in vivo, we generated core RAG1 knockin (RAG1(c/c)) mice. Significant B and T cell numbers are generated in RAG1(c/c) mice, showing that core RAG1, despite missing approximately 40% of the RAG1 sequence, retains significant in vivo function. However, lymphocyte development and the overall level of V(D)J recombination are impaired at the progenitor stage in RAG1(c/c) mice. Correspondingly, there are reduced numbers of peripheral RAG1(c/c) B and T lymphocytes. Whereas normal B lymphocytes undergo rearrangement of both JH loci, substantial levels of germline JH loci persist in mature B cells of RAG1(c/c) mice, demonstrating that DJH rearrangement on both IgH alleles is not required for developmental progression to the stage of VH to DJH recombination. Whereas VH to DJH rearrangements occur, albeit at reduced levels, on the nonselected alleles of RAG1(c/c) B cells that have undergone D to JH rearrangements, we do not detect VH to DH rearrangements in RAG1(c/c) B cells that retain germline JH alleles. We discuss the potential implications of these findings for noncore RAG1 functions and for the ordered assembly of VH, DH, and JH segments.

T cell receptor (TCR) delta and alpha variable region genes are assembled from germ-line gene segments located in a single chromosomal locus in which TCR delta segments are situated between TCR alpha segments. The TCR alpha enhancer (E alpha) located at the 3' end of the TCR alpha/delta locus functions over a long chromosomal distance to promote TCR alpha rearrangement and maximal TCR delta expression; whereas the TCR delta enhancer (E delta) is located among the TCR delta segments and functions with additional element(s) to mediate TCR delta rearrangement. We used gene-targeted mutation to evaluate whether the identity of E alpha and the position of E delta are critical for the developmental stage-specific assembly of TCR delta and alpha variable region genes. Specific replacement of E alpha with E delta, the core E alpha element (E alpha C), or the Ig heavy chain intronic enhancer (iE mu), all of which promote accessibility in the context of transgenic V(D)J recombination substrates, did not promote a significant level of TCR alpha rearrangement beyond that observed in the absence of E alpha. Therefore, the identity and full complement of E alpha-binding sites are critical for promoting accessibility within the TCR alpha locus. In the absence of the endogenous E delta element, specific replacement of E alpha with E delta also did not promote TCR delta rearrangement. However, deletion of intervening TCR alpha/delta locus sequences to restore the inserted E delta to its normal chromosomal position relative to 5' sequences rescued TCR delta rearrangement. Therefore, unlike E alpha, E delta lacks ability to function over the large intervening TCR alpha locus and or E delta function requires proximity to additional upstream element(s) to promote TCR delta accessibility.

The recombination-activating gene (RAG)1 and RAG2 proteins comprise the lymphocyte-specific components of the V(D)J recombinase and are required for the assembly of antigen-receptor variable-region genes. A mutant truncated RAG2 protein (“core” RAG2) lacking the C-terminal 144 amino acids, together with core RAG1, is able to mediate the basic biochemical steps required for V(D)J recombinationin vitroand in transfected cell lines. Here we examine the effect of replacing the endogenousRAG2locus in mice with coreRAG2. These mice generate substantial numbers of B and T cells, demonstrating that the core RAG2 protein retains significantin vivofunction. However, core RAG2 mice display a reduction in the total number of B and T cells, reflecting impaired lymphocyte development at the progenitor stage associated with reduced chromosomal V(D)J recombination. We discuss potential roles of the RAG2 C terminus in mediating rearrangement of endogenous antigen-receptor loci.

The engineering and application aspects of centrifugal blowers, ie, high pressure, low volume air delivery, and axial fans, low pressure, high volume air delivery are presented. The types of centrifugal blowers and their uses, typical installation practice, noise, and performance is discussed. Performance curves are defined. Air delivery is effected by blade designs as well as application, especially in the petrochemical field, is detailed including selection, noise prediction, and fan vibration problems. Various means of air flow control from damper, controllable pitch fans to variable speed drives are discussed, and a list of primary U.S. and world manufacturers is given. Keywords: Fans; Blowers; Centrifugal fans; Fan laws; Performance; Design; Noise; Vibration; Types; Characteristics; Fan selection; Capacity control

We generated mice in which a functional RAG2:GFP fusion gene is knocked in to the endogenous RAG2 locus. In bone marrow and thymus, RAG2:GFP expression occurs in appropriate stages of developing B and T cells as well as in immature bone marrow IgM+ B cells. RAG2:GFP also is expressed in IgD+ B cells following cross-linking of IgM on immature IgM+IgD+ B cells generated in vitro. RAG2:GFP expression is undetectable in most immature splenic B cells; however, in young RAG2:GFP mice, there are substantial numbers of splenic RAG2:GFP+ cells that mostly resemble pre–B cells. The latter population decreases in size with age but reappears following immunization of older RAG2:GFP mice. We discuss the implications of these findings for current models of receptor assembly and diversification.

The generation of a productive "in-frame" T cell receptor beta (TCR beta), immunoglobulin (Ig) heavy (H) or Ig light (L) chain variable region gene can result in the cessation of rearrangement of the alternate allele, a process referred to as allelic exclusion. This process ensures that most alphabeta T cells express a single TCR beta chain and most B cells express single IgH and IgL chains. Assembly of TCR alpha and TCR gamma chain variable region genes exhibit allelic inclusion and alphabeta and gammadelta T cells can express two TCR alpha or TCR gamma chains, respectively. However, it was not known whether assembly of TCR delta variable regions genes is regulated in the context of allelic exclusion. To address this issue, we have analyzed TCR delta rearrangements in a panel of mouse splenic gammadelta T cell hybridomas. We find that, similar to TCR alpha and gamma variable region genes, assembly of TCR delta variable region genes exhibits properties of allelic inclusion. These findings are discussed in the context of gammadelta T cell development and regulation of rearrangement of TCR delta genes.

The World Wide Web (WWW) has recently become a very popular facility for the dissemination of information. As a result of this popularity, it is experiencing rapidly increasing traffic load. Single machine servers cannot keep pace with the ever greater load being placed upon them. To alleviate this problem, we have implemented a distributed Web server group. The server group can effectively balance request load amongst its members (within about 10% of optimal), and client response time is no worse than in the single server case. Client response time was not improved because the measured client traffic consumed all available network throughput. The distributed operation of the server groups is completely transparent to standard Web clients. (AN)

Fossomatic, a fully automatic, fluoro-optoelectronic somatic cell counter, was evaluated in 6 laboratories. One set of 6 duplicate milk samples, fresh and preserved, was read with instruments as routinely calibrated to each laboratory’s direct microscopic somatic cell counts (DMSCCs), i.e., local standard. A second set was read after standardizing the instrument to a 3-sample common standard (DMSCC) shipped to each collaborator. Cell levels of the unknowns ranged from 371 to 2301 thousand (th)/ml by DMSCC, with an s per sample of 14.8% and s of a level mean of 1.8%. Fossomatic values averaged 1014 compared to 1031 th cells/ml by DMSCC, had homogeneous variance for duplicates within laboratories (s = 4.0%), and had an error per observation of 6.2%. The linear coefficient of 0.9966±0.0039 (for fresh milk and common standard) for the Fossomatic values regressed on DMSCC gave an excellent and unbiased estimate of the cell concentration in a milk sample. A small bias was evident in only 5 of 24 linear regressions (fresh or preserved within each standard) where slopes differed significantly from 1. All 5 were on values derived from a local standard with maximum biases of +18% and —28% (at a 1 million level). Preserved milk had slightly lower (P < 0.01) cell concentrations than fresh milk but only by 3.6% at 1 million. Although condition X level was significant (P < 0.01), the 6 cell levels differed by a magnitude of only 27— 45 th cells/ml. Between-laboratory variation (the component was 4.6%) and laboratory X level interaction were both significant, but their contributions to error were small. The spread in laboratories at any cell level was about 12% and the error of estimate for a sample sent to 2 laboratories was 6.8%. Although interactions were significant with this precise method, they were not of such a magnitude as to invalidate cell count estimates in practice. The Fossomatic method has been adopted as official first action.

Laboratory tests of Bacillus thuringiensis var. kurstaki (strain HD-1) against Platynota idaeusalis reared on a semisynthetic diet showed that the LC50 values for neonates and 9-day-old larvae showed no significant difference in susceptibility; however, 14-day-old larvae were significantly more susceptible than neonates or 9-day-old larvae. There was no evidence of any interaction between 14-day-old larvae reared on the semisynthetic diets with and without formaldehyde and B. thuringiensis toxicity at any assessment reading. Likewise the toxicity of B. thuringiensis to 14-day-old larvae reared on apple leaves did not differ from the B. thuringiensis toxicity of 14-day-old larvae reared on semisynthetic diets with and without formaldehyde.

The new television broadcasting center for the Los Angeles area incorporates many new engineering developments to improve technical quality, increase reliability and simplify operation. Equipment includes a digital computer, for automatic control of switching of audio and video program material, and highly stable vidicon film cameras which require a minimum of operating adjustment. The facilities employ many innovations in plant layout, system design and installation practices. The video and audio facilities are described and the philosophy which led to the designs is set forth, with emphasis on the methods and features which are new.

An alternative analysis of a study on the phototactic behavior of a bark beetle leads to two conclusions that differ from those of the original author. We find (1) that the beetles behaved in a normal manner and (2) that they could be selected for their positive response to uv. light.

THE pH of chicken flesh like that of other animal carcasses changes during rigor mortis and the ultimate pH is normally reached shortly after slaughter (Bate-Smith and Bendall, 1949; de Fremery and Pool, 1960; and Dodge and Peters, 1960). Mountney et al. (1964) reported that the application of HCl to the surface of chicken carcasses inhibited microbial growth. Literature dealing with pH changes of the chicken carcass surface per se has not been found by the authors. The purpose of the present study was to ascertain pH changes of the surface of chicken carcasses after rigor mortis and determine the effects of some environmental conditions on pH changes of the chicken carcass surface. EXPERIMENTAL General. Carcass surface pH was determined by thoroughly rinsing a carcass sample with sterile distilled water and the pH of the rinse water determined. Preliminary work showed that pH determination could be made by placing electrodes…

During vagus nerve stimulation the heart rate was maintained at a constant level by an electric pacemaker. Under these conditions no changes were found in ventricular function curves, myocardial oxygen consumption and coronary blood flow. Acetylcholine infusion, with heart rate maintained constant, caused decreased myocardial contractility and coronary and peripheral vasodilation.