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Decisions about cell survival or death are central components of adaptive immunity and occur at several levels in immune system development and function. The Bcl-2 family of homologous proteins plays an important role in these decisions in lymphoid cells. Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death. We sought to gain insight into the role of A1 in immune system development and function. A murine A1-a transgene was expressed under the control of the Eμ enhancer, and mice with A1 overexpression in B- and T-cell lineages were derived. Thymocytes and early B cells in Eμ-A1 mice showed extended survival. B-lineage development was altered, with expansion of the pro–B cell subset at the expense of pre–B cells, suggesting an impairment of the pro– to pre–B-cell transition. This early B-cell phenotype resembled Eμ–Bcl-xL mice but did not preferentially rescue cells with completed V(D)J rearrangements of the immunoglobulin heavy chain. In contrast to Eμ–Bcl-2 transgenes, A1 expression in pro–B cells did not rescue pre–B-cell development in SCID mice. These studies indicate that A1 protects lymphocytes from apoptosis in vitro but that it has lineage- and stage-specific effects on lymphoid development. Comparison with the effects of Bcl-2 and Bcl-xL expressed under similar control elements supports the model that antiapoptotic Bcl-2 homologs interact differentially with intracellular pathways affecting development and apoptosis in lymphoid cells.

The rat (Rattus norvegicus) is an important experimental model for many human diseases including arthritis, diabetes, and other autoimmune and chronic inflammatory diseases. The rat genetic linkage map, however, is less well developed than those of mouse and human. Integrated rat genetic linkage maps have been previously reported by Pravenec et al. (1996, Mamm. Genome 7: 117-127) (500 markers mapped in one cross), Bihoreau et al. (1997, Genome Res. 7: 434-440) (767 markers mapped in three crosses), Wei et al. (1998, Mamm. Genome 9: 1002-1007) (562 markers mapped in two crosses), Brown et al. (1998, Mamm. Genome 9: 521-530) (678 markers mapped in four crosses), and Nordquist et al. (1999, Rat Genome 5: 15-20) (330 markers mapped in two crosses). The densest linkage map combined with a radiation hybrid map, reported by Steen et al. (1999, Genome Res. 9: AP1-AP8), includes 4736 markers mapped in two crosses. Here, we present an integrated linkage map with 1137 markers. We have constructed this map by genotyping F2 progeny of five crosses: F344/NHsd x LEW/NHsd (673 markers), DA/Bkl x F344/NHsd (531 markers), BN/SsN x LEW/N (714 markers), DA/Bkl x BN/SsNHsd (194 markers), and DA/Bkl x ACI/SegHsd (245 markers). These inbred rat strains vary in susceptibility/resistance to multiple autoimmune diseases and are used extensively for many types of investigation. The integrated map includes 360 loci mapped in three or more crosses. The map contains 196 new SSLP markers developed by our group, as well as many SSLP markers developed by other groups. Two hundred forty genes are incorporated in the map. This integrated map should allow comparison of rat genetic maps from different groups and thereby facilitate genetic studies of rat autoimmune and related disease models.

Tumor cell lines are an indispensable tool for cancer research. However, among cell lines of the same pathological group, heterogeneity has been detected in gene expression, gene mutation, and cellular response to various treatments. In this study, we systematically investigated the extent of heterogeneity of gene expression in three glioblastoma cell lines using cDNA array technology in which the expression of 588 cellular genes is studied simultaneously. Comparison of the expression profiles revealed substantial qualitative and quantitative heterogeneity. Among the 588 genes, 197 genes were expressed in all three lines and 56 genes were not expressed in any of the three lines; total of 222 genes were expressed in only two of the three cell lines, and 113 genes were expressed in only one of the three cell lines. These results provide molecular evidence that cell lines of the same pathological origin can be highly heterogeneous.

The effectiveness of chemotherapy for human cancers is limited by pharmacokinetic parameters such as variation in metabolism and is determined by the cellular response. In this work, we aimed to gain a more holistic understanding of the molecular basis of glioma response to the DNA-alkylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by using a systematic approach: we investigated the expression of 588 genes with various cellular functions in a BCNU-resistant glioblastoma cell line and a BCNU-sensitive subline before and after treatment with BCNU. Our gene expression profiling revealed major differences in gene expression between these two cell lines, especially after treatment with BCNU. One striking example was that BCNU decreased the expression of six DNA-repair genes in sensitive but not in resistant cells. In sensitive cells, BCNU treatment resulted in the induction of two MAP kinase genes; this finding suggests that the specific response to BCNU in sensitive cells may involve the Jun kinase signal transduction pathway. After BCNU treatment, marked induction of tumor necrosis factor was detected only in sensitive cells, suggesting that tumor necrosis factor is a mediator of BCNU-induced cell death. Bcl-2 family members were not altered by BCNU in sensitive cells, suggesting that BCNU-induced cell death may be independent of the bcl-2 pathway. Results of the present study demonstrate that gene expression profiling may facilitate identification of cellular pathways associated with specific responses to chemotherapeutic agents and contribute to an understanding of the molecular basis of drug action.

There is increasing recognition that the internationalisation of family-firms is becoming an important area of research. Despite the growth of this research area, studies of the internationalisation of family-firms remains limited. Current research in the area has tended to focus on family-firms in largely Western contexts and the economic and familial factors behind their internationalisation. Furthermore, little is known about the internationalisation pathways of family-firms in differing institutional context and the socio-cultural factors that facilitate the features which lie behind it. This study aims to make a start in researching this gap in our understanding. We do this by looking at four case studies of family-firms from Singapore. Based on our findings, we classified firms into one of three internationalisation pathways – traditional, born global and born again global – and we highlight some important differences between the socio-cultural factors that facilitate their internationalisation pathways.

It is of fundamental importance for biological scientists to assess cellular energetics. Under aerobic conditions, the tricarboxylic acid cycle (TCA cycle) is coupled with the mitochondrial electron cascade pathway to provide the cell with energy. The nicotinamide adenine dinucleotide-conjugated pair (NAD and NADH) is the coenzyme in numerous important biomedical reactions which include several important dehydrogenase reactions in the TCA cycle. Based on Le Chatelier's principle, NADH will accumulate when this energy production mechanism is impaired. The relative amounts of NAD and NADH in a cell are defined as the redox state of the cell (Williamson et.al. 1967) which provides a valuable index of cellular energetics. The sum of the amounts of NAD and NADH in a cell may be assumed to be constant during a finite time; therefore, a reliable means of measuring the NADH concentration would provide us with a useful indicator of tissue viability. Traditionally, the quantities of NADH and NAD may be measured by chemical assay methods. We can avoid these tediois analyses by exploiting the significant difference between the ultraviolet absorption spectra of this redox pair. However, because of the opacity of biological samples and the interference of other biochemicals that also absorb ultraviolet radiation, measurement of NADH and NAD+ concentrations in vivo by absorption spectroscopy is not feasible.© (1991) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

This paper is an attempt to analyse the interface between and among innovation, technology, knowledge and intellectual property in today's global internet society. The purpose of this paper is twofold. We analyse the role of measurement and intangibility in the standard-making process of intellectual property, especially differences in intellectual property across regions of the world. Secondly, we emphasise the importance of measurement costs, and intangibility of value in technology management, and knowledge in organisations, institutions and society in the 21st century. Such factors have been relatively under researched in technology and innovation management research.

The previous issue of the AT&T Technical Journal on information technology (IT) focused on best practices in IT design and development, addressing both project management and technical areas. Reuse technologies and applications are discussed in this issue.

In the foreword to this issue of the AT&T Technical Journal, Dan Stanzione reiterates the need for sharing best practices across the company, especially in the area of software development. Software is the key integrating element in information technology (IT). Although definitions abound, IT is used here to describe the set of technologies employed in the design, development, and deployment of information systems.

This paper discusses how the nature of electronic commerce affects strategic decision making. First, some features of electronic commerce are identified that distinguish it from traditional business - new markets, knowledge-based competition, speed of change and increasing returns. Next, how each of these features affects strategic decision making is demonstrated. Finally, how the process has changed following the internet stock market crash and may continue to change in the future is discussed.

Novel Integration of HIV within the X-Linked Lymphoproliferative Disease Candidate Gene in Pediatric Malignancies

Purpose: Children infected with HIV (human immunodeficiency virus) are at risk for developing cancers ranging from hematologic malignancies including lymphomas to sarcomas such as leiomyosarcoma. Recently, our laboratory has shown that a subset of adult HIV-associated malignancies contains an integrated-form of HIV and may play a direct role in causing cancer. The current study was undertaken to determine if an integrated form of HIV exists in the same types of tumors in children.

A variant of the revised simplex method is given for solving capacitated network flow problems with additional linear constraints. The mathematical development, computer implementation and computational experience are presented. The algorithm described uses a working basis of size equal to the number of additional linear constraints for pivoting, pricing, and inversion, which for large networks, can result in a substantial reduction of computation over a standard linear programming approach.

Telecommunications network loading problems focus on routing traffic through networks so as to satisfy the demand forecast between all pairs of nodes. The objective is to minimize the total routing costs subject to satisfying capacity constraints associated with the individual links. This paper presents a nonlinear programming formulation for the multiperiod network loading problem, a problem that appears in many guises throughout network planning. Such problems are also known in the operations research literature as (multiperiod) multicommodity network flow problems. The resulting optimization problem has a very large number of variables and constraints. We describe the implementation of a nonlinear optimization algorithm, the Frank-Wolfe method with PARTAN extension and projective gradient acceleration, on a parallel vector processor for solving these large dynamic network loading problems. Our computational experience shows that our algorithm solves large, realistic loading problems very efficiently and is serving as a valuable tool for telecommunications network planning.

A directed acyclic graph (dag) can be used to represent an arithmetic expression consisting of sequences of binary operations on arguments. The Sethi-Ullman algorithm (Journal of the ACM, Vol. 17 No. 4, pp. 715-728) generates optimal object code for a machine with N≧1 registers and unlimited memory capacity when the dag is a binary tree. We first describe a dag labeling algorithm which gives the minimum number of registers required to evaluate any node without any stores. We then define a subclass of dags, the 1-load binary dags, employing a tree-like grammar, and modify the Sethi-Ullman algorithm to include this subclass but only when N = 2 registers. The proof of optimality relies on the use of syntax directed translation schemas. Modification of the algorithm to include all dags, or to allow N > 2 registers, appears difficult.

Continuum Probe Designertrade by Acoustic Ideas Inc. is a tool that can help design an optimized phased array ultrasonic transducer for a given inspection task. One component of Continuum Probe Designertrade can calculate the cost of a probe for a given geometry, and the fmincon function in the MATLABreg optimization toolbox has been used to find the optimal probe geometry. However, the search space of probe geometries is very noisy, and the inconsistent performance of fmincon in this noisy search space has interfered with the deployment of Continuum Probe Designertrade as a commercial product. An evolution strategy has been developed that includes "smart" start points and coordinated parallel runs. Compared to fmincon, the developed evolution strategy finds solutions that require an average of 61.4% fewer elements. Since control instrumentation can only handle a limited number of independent channels, the evolution strategy designs are also more than five times more likely to be implementable. These improvements that have been achieved by the evolution strategy will play an important role in the commercial deployment of Continuum Probe Designertrade.