bluuebunny/crossref_metadata_2025 huggingface dataset:
High-level design verification of microprocessors via error modeling
Authors: Campenhout D. Van , Al-Asaad H. , Hayes J. P. , Mudge T. , Brown R. B.
Published: July 2002

A design verification methodology for microprocessor hardware based on modeling design errors and generating simulation vectors for the modeled errors via physical fault testing techniques is presented. We have systematically collected design error data from a number of microprocessor design projects. The error data is used to derive error models suitable for design verification testing. A class of basic error models is identified and shown to yield tests that provide good coverage of common error types. To improve coverage for more complex errors, a new class of conditional error models is introduced. An experiment to evaluate the effectiveness of our methodology is presented. Single actual design errors are injected into a correct design, and it is determined if the methodology will generate a test that detects the actual errors. The experiment has been conducted for two microprocessor designs and the results indicate that very high coverage of actual design errors can be obtained with test sets that are complete for a small number of synthetic error models.
Towards a theory of cost management for digital libraries and electronic commerce
Authors: Sistla A. Prasad , Wolfson Ouri , Yesha Yelena , Sloan Robert
Published: July 2002

One of the features that distinguishes digital libraries from traditional databases is new cost models for client access to intellectual property. Clients will pay for accessing data items in digital libraries, and we believe that optimizing these costs will be as important as optimizing performance in traditional databases. In this article we discuss cost models and protocols for accessing digital libraries, with the objective of determining the minimum cost protocol for each model. We expect that in the future information appliances will come equipped with a cost optimizer, in the same way that computers today come with a built-in operating system. This article makes the initial steps towards a thery and practice of intellectual property cost management.
A test package for Sturm-Liouville solvers
Authors: Pryce J. D.
Published: July 2002

The author and colleagues have produced a collection of 60 test problems which offer a realistic performance test of the currently available automatic codes for eigenvalues of the classical Sturm-Liouville problem. We describe a Fortran implementation and the considerations that went into its design. A novel feature is that (almost) all the code defining one problem is textually contiguous in the Fortran text, unlike for example the DETEST package for ODE initial-value solvers where the definition of a problem is spread over several routines. The described implementation forms the infrastructure of the SLDRVER interactive package which supports exploration of a set of Sturm-Liouville problems with the four SL-solvers SLEIGN, SLEDGE, SL02F, and SLEIGN2. A “standard” set of 60 problems is provided, but it is simple to replace this by another one.
A hierarchy-aware approach to faceted classification of objected-oriented components
Authors: Damiani E. , Fugini M. G. , Bellettini C.
Published: July 2002

This article presents a hierarchy-aware classification schema for obje ct-oriented code, where software components are classified according to their
behavioral characteristics
, such as provided services, employed algorithms, and needed data. In the case of reusable application frameworks, these characteristics are constructured from their
model
, i.e., from the description of the abstract classes specifying both the framework structure and purpose. In conventional object libraries, the characteristics are extracted semiautomatically from class interfaces. Characteristics are term pairs, weighted to represent “how well” they describe component behavior. The set of characteristics associated with a given component forms its
software descriptor
. A descriptor base is presented where descriptors are organized on the basis of structured relationships, such as similarity and composition. The classification is supported by a thesaurus acting as a language-independent unified lexicon. The descriptor base is conceived for developers who, besides conventionally browsing the descriptors hierarchy, can query the system, specifying a set of desired functionalities and getting a ranked set of adaptable candidates. User feedback is taken into account in order to progressively ameliorate the quality of the descriptors according to the views of the user community. Feedback is made dependent of the user typology through a
user profile
. Experimental results in terms of recall and precision of the retrieval mechanism against a sample code base are reported.
Performance analysis of linear hashing with partial expansions
Authors: Larson Per-Åke
Published: July 2002

Linear hashing with partial expansions is a new file organization primarily intended for files which grow and shrink dynamically. This paper presents a mathematical analysis of the expected performance of the new scheme. The following measures are considered: length of successful and unsuccessful searches, accesses required to insert or delete a record, and the size of the overflow area. The performance is cyclical. For all performance measures, the necessary formulas are derived for computing the expected performance at any point of a cycle and the average over a cycle. Furthermore, the expected worst case in connection with searching is analyzed. The overall performance depends on several file parameters. The numerical results show that for many realistic parameter combinations the performance is expected to be extremely good. Even the longest search is expected to be of quite reasonable length.
Algorithms for Parallel-Search Memories
Authors: Falkoff A. D.
Published: July 2002

The underlying logical structure of parallel-search memories is described; the characteristic operation of three major types is displayed in the execution of searches based on equality; and algorithms are presented for searches based on other specifications including maximum, miniTnum, greater than, less than, nearest to, between limits, and ordering (sorting). It is shown that there is a hierarchy of dependency among these algorithms, that they appear in pairs with each member of a pair belonging to one or the other of two distinct classes, and that every type of search can be executed within each class.
The Generation of Optimal Code for Arithmetic Expressions
Authors: Sethi Ravi , Ullman J. D.
Published: July 2002

The problem of evaluating arithmetic expressions on a machine with
N
≥ 1 general purpose registers is considered. It is initially assumed that no algebraic laws apply to the operators and operands in the expression. An algorithm for evaluation of expressions under this assumption is proposed, and it is shown to take the shortest possible number of instructions. It is then assumed that certain operators are commutative or both commutative and associative. In this case a procedure is given for finding an expression equivalent to a given one and having the shortest possible evaluation sequence. It is then shown that the algorithms presented here also minimize the number of storage references in the evaluation.
Code Generation for a One-Register Machine
Authors: Bruno John , Sethi Ravi
Published: July 2002

The majority of computers that have been built have performed all computations in devices called accumulators, or registers. In this paper, it is shown that the problem of generating minimal-length code for such machines is hard in a precise sense; specifically it is shown that the problem is NP-complete. The result is true even when the programs being translated are arithmetic expressions. Admittedly, the expressions in question can become complicated.
Queuing Network Models with State-Dependent Routing
Authors: Towsley Don
Published: July 2002

A model of a closed queuing network within which customer routing between queues may depend on the state of the network is presented. The routing functions allowed may be rational functions of the queue lengths of various downstream queues which reside within special subnetworks called p-subnetworks. If a network with no state-dependent routing has a product-form joint equilibrium distribution of the queue lengths, then the introduction of these routing functions will preserve the product form of the equilibrium distribution. An example to illustrate the applicability of the model to the problem of analyzing a load balancing strategy is presented. It is also indicated how the parametric analysis of a network with routing functions can be simplified through the analysis of a simpler “equivalent” network.
Response Time Analysis of Multiprocessor Computers for Database Support
Authors: Shultz Roger K. , Zingg Roy J.
Published: July 2002

Comparison of three multiprocessor computer architectures for database support is made possible through evaluation of response time expressions. These expressions are derived by parameterizing algorithms performed by each machine to execute a relational algebra query. Parameters represent properties of the database and components of the machines. Studies of particular parameter values exhibit response times for conventional machine technology, for low selectivity, high duplicate occurrence, and parallel disk access, increasing the number of processors, and improving communication and processing technology.
Dynamic state traversal for sequential circuit test generation
Authors: Hsiao Michael S. , Rudnick Elizabeth M. , Patel Janak H.
Published: July 2002

A new method for state justification is proposed for sequential circuit test generation. The
linear
list of states dynamically obtained during the derivation of test vectors is used to guide the search during state justification. State-transfer sequences that drive the circuit from the current state to the target state may already be known. Otherwise, genetic engineering of existing state-transfer sequences is required. In both cases, genetic-algorithm-based techniques are used to generate valid state justification sequences for the circuit in the presence of the target fault. This approach achieves extremely high fault coverages, and thus outperforms previous deterministic and simulation-based techniques.
High-level library mapping for memories
Authors: Jha Pradip K. , Dutt Nikil D.
Published: July 2002

We present high-level library mapping, a technique that synthesizes a source memory module from a library of target memory modules. In this paper, we define the problem of high-level library mapping for memories, identify and solve the three subproblems associated with this task, and finally combine these solutions into a suite of two memory mapping algorithms. Experimental results on a number of memory-intensive designs demonstrate that our memory mapping approach generates a wide variety of cost-effective designs, often counter-intuitive ones, based on a user-given cost function, the target library, and the mapping algorithm used.
Adaptive exact-fit storage management
Authors: Oldehoeft Rodney R. , Allan Stephen J.
Published: July 2002

Tested against extremes in the characteristics of arrival patterns to dynamic allocation software, the working-set approach outperforms the FIFO method except in the case of completely random request patterns—where the working-set method performs as well as the FIFO method.
Sorting
Authors: Martin W. A.
Published: July 2002

The bibliography appearing at the end of this article lists 37 sorting algorithms and 100 books and papers on sorting published in the last 20 years. The basic ideas presented here have been abstracted from this body of work, and the best algorithms known are given as examples. As the algorithms are explained, references to related algorithms and mathematical or experimental analyses are given. Suggestions are then made for choosing the algorithm best suited to a given situation.
Balancing binary trees by internal path reduction
Authors: Gonnet Gaston H.
Published: July 2002

We present an algorithm for balancing binary search trees. In this algorithm single or double rotations are performed when they decrease the internal path of the total tree. It is shown that the worst internal path on such trees is never more than 5 percent worse than optimal and that its height is never more than 44 percent taller than optimal. This compares favorably with the
AVL
trees whose internal path may be 28 percent worse than optimal and the same 44 percent worst height, and with the weight-balanced trees which may be 15 and 100 percent worse than optimal, respectively. On the other hand, the number of rotations during a single insertion/deletion can be O(n), although the amortized worst-case number of rotations is O(log n) per update.
Minimal perfect hash functions made simple
Authors: Cichelli Richard J.
Published: July 2002

A method is presented for computing machine independent, minimal perfect hash functions of the form: hash value ← key length + the associated value of the key's first character + the associated value of the key's last character. Such functions allow single probe retrieval from minimally sized tables of identifier lists. Application areas include table lookup for reserved words in compilers and filtering high frequency words in natural language processing. Functions for Pascal's reserved words, Pascal's predefined identifiers, frequently occurring English words, and month abbreviations are presented as examples.
Disk scheduling
Authors: Hofri Micha
Published: July 2002

We report on a rather extensive simulation effort directed at evaluating the merits of two scheduling strategies, FCFS and SSTF, for moving-arm disks under stationary request arrival process. For First-Come-First-Served (FCFS) scheduling, analytic results for the mean waiting time are also given (in a closed form). If the objective of a schedule is to minimize the mean waiting time (or queue size) and its variance, the results seem to confirm the overall superiority of Shortest-Seek-Time-First (SSTF), particularly for medium and heavy traffic. This holds also when the input is highly correlated or addresses the cylinders nonuniformly. These results contradict some statements published in recent years. The domain of policies where SSTF is optimal is considered. The simulation methodology is described in some detail.
A model for automating file and program design in business application systems
Authors: Alter Steven
Published: July 2002

This paper discusses a model for finding an efficient implementation of a business application system whose logical specifications have been determined in advance. The model views file and program design as a problem of systematically coordinating the configurations of datasets and computations. It uses a straightforward search technique to determine aggregations of computations, aggregations of datasets, device, organization, and key order for each dataset, key order for each computation, and access method for each dataset-computation pair. Although computational results are presented for a sample problem involving 54 computations and 49 datasets, the main point of the paper is that the underlying model works computationally and is simple enough to be adapted to many file design situations.
A time- and space-efficient garbage compaction algorithm
Authors: Morris F. Lockwood
Published: July 2002

Given an area of storage containing scattered, marked nodes of differing sizes, one may wish to rearrange them into a compact mass at one end of the area while revising all pointers to marked nodes to show their new locations. An algorithm is described here which accomplishes this task in linear time relative to the size of the storage area, and in a space of the order of one bit for each pointer. The algorithm operates by reversibly encoding the situation (that a collection of locations point to a single location) by a linear list, emanating from the pointed-to location, passing through the pointing locations, and terminating with the pointed-to location's transplanted contents.
Optimal space allocation on disk storage devices
Authors: Morgan Howard Lee
Published: July 2002

When the amount of space required for file storage exceeds the amount which can be kept online, decisions must be made as to which files are to be permanently resident and which mountable. These decisions will affect the number of mount requests issued to the operators. This is often a bottleneck in a computing facility, and reducing the number of mounts thus decreases turnaround time. An optimization model for the assignment of files to disk packs, and packs to either resident or nonresident status is presented. Heuristics are suggested for those cases in which it is Inefficient to compute the actual optimum.
On the distributions of significant digits and roundoff errors
Authors: Tsao Nai-Kuan
Published: July 2002

Generalized logarithmic law is derived for the distribution of the first
t
significant digits of a random digital integer. This result is then used to determine the distribution of the roundoff errors in floating-point operations, which is a mixture of uniform and reciprocal distributions.
A PL/1 program to assist the comparative linguist
Authors: Frantz Donald G.
Published: July 2002

A practical PL/1 program is described which can assist comparative linguists to determine the regular sound correspondences between genetically related languages. The investigator must arrange data for input by aligning pairs of suspected cognates. The program tabulates the correspondences, and uses list processing techniques to sort and count them. Each pair of words is then assigned a relative value that is a function of the total frequency in the data of each correspondence found in that pair of words. The output is a list of all correspondence types with their frequency of occurrence in the data, and a separate listing of each correspondence with all wordpairs showing that correspondence (unless their relative value is below an arbitrarily chosen cutoff point). The article explains the usefulness, as well as the limitations, of the program, and illustrates its use with a small portion of hypothetical data.
Automatic data compression
Authors: Marron B. A. , de Maine P. A. D.
Published: July 2002

The “information explosion” noted in recent years makes it essential that storage requirements for all information be kept to a minimum. A fully automatic and rapid three-part compressor which can be used with “
any
” body of information to greatly reduce slow external storage requirements and to increase the rate of information transmission through a computer is described in this paper. The system will also automatically decode the compressed information on an item-by-item basis when it is required.

The three component compressors, which can be used separately to accomplish their specific tasks, are discussed: NUPAK for the automatic compression of numerical data, ANPAK for the automatic compression of “
any
” information, and IOPAK for further compression of information to be stored on tape or cards.
Collaborative Virtual Design Environments
Authors: Ragusa James M. , Bochenek Grace M.
Published: July 2002

Computer-generated animated and enhanced movies and training simulations are now commonplace because of an exponential increase in cost-effective computer power and software robustness. Today, pilots and astronauts routinely train and practice normal and emergency scenarios much as they would in a real vehicle in an operational environment. As entertainment-seeking consumers, we regularly find ourselves viewing movies, TV, and games containing imaginary dinosaurs, aircraft dogfights, monsters, and voyages to other planets and galaxies.
The virtual mesh
Authors: Alonso L. , Cuny F. , Jean S. Petit , Paul J.-C. , Lazard S. , Wies E.
Published: July 2002

In this article, we introduce a general-purpose method for computing radiosity on scenes made of parametric surfaces with arbitrary trimming curves. In contrast with past approaches that require a tessellation of the input surfaces (be it made up of triangles or patches with simple trimming curves) or some form of geometric approximation, our method takes full advantage of the rich and compact mathematical representation of objects. At its core lies the
virtual mesh
, an abstraction of the input geometry that allows complex shapes to be illuminated as if they were simple primitives. The virtual mesh is a collection of normalized square domains to which the input surfaces are mapped while preserving their energy properties. Radiosity values are then computed on these supports before being lifted back to the original surfaces. To demonstrate the power of our method, we describe a high-order wavelet radiosity implementation that uses the virtual mesh. Examples of objects and environments, designed for interactive applications or virtual reality, are presented. They prove that, by exactly integrating curved surfaces in the resolution process, the virtual mesh allows complex scenes to be rendered more quickly, more accurately, and much more naturally than with previously known methods.
An authorization model for a public key management service
Authors: Samarati Pierangela , Reiter Michael K. , Jajodia Sushil
Published: July 2002

Public key management has received considerable attention from both the research and commercial communities as a useful primitive for secure electronic commerce and secure communication. While the mechanics of certifying and revoking public keys and escrowing and recovering private keys have been widely explored, less attention has been paid to access control frameworks for regulating access to stored keys by different parties. In this article we propose such a framework for a key management service that supports public key registration, lookup, and revocation, and private key escrow, protected use (e.g., to decrypt selected messages), and recovery. We propose an access control model using a policy based on principal, ownership, and authority relationships on keys. The model allows owners to grant to others (and revoke) privileges to execute various actions on their keys. The simple authorization language is very expressive, enabling the specification of authorizations for composite subjects that can be fully specified (ground) or partially specified, thus making the authorizations applicable to all subjects satisfying some conditions. We illustrate how the access control policy and the authorizations can easily be expressed through a simple and restricted, hence efficiently computable, form of logic language.
Internet time out
Authors: Denning Peter
Published: July 2002

Technology won't solve information overload. New commitment management practices will.
Consistency maintenance in real-time collaborative graphics editing systems
Authors: Sun Chengzheng , Chen David
Published: July 2002

Real-time collaborative graphics editing systems allow a group of users to view and edit the same graphics document at the same time from geographically dispersed sites connected by communication networks. Consistency maintenance in the face of concurrent accesses to shared objects is one of the core issues in the design of these types of systems. In this article, we propose an object-level multiversioning approach to consistency maintenance in real-time collaborative graphic editors. This approach is novel in achieving intention preservation and convergence, in preserving the work concurrently produced by multiple users in the face of conflict, and in minimizing the number of object versions for conflict resolution. Major technical contributions of this work include a formal specification of a unique combined effect for an arbitrary group of conflict and compatible operations, a distributed algorithm for incremental creation of multiple object versions, a consistent object identification scheme for multiple object versions, and a convergent layering scheme for overlapping objects. All algorithms and schemes presented in this article have been implemented in an Internet-based GRACE (graphics collaborative editing) system.
File access performance of diskless workstations
Authors: Lazowska Edward D. , Zahorjan John , Cheriton David R. , Zwaenepoel Willy
Published: July 2002

This paper studies the performance of single-user workstations that access files remotely over a local area network. From the environmental, economic, and administrative points of view, workstations that are diskless or that have limited secondary storage are desirable at the present time. Even with changing technology, access to shared data will continue to be important. It is likely that some performance penalty must be paid for remote rather than local file access. Our objectives are to assess this penalty and to explore a number of design alternatives that can serve to minimize it.

Our approach is to use the results of measurement experiments to parameterize queuing network performance models. These models then are used to assess performance under load and to evahrate design alternatives. The major conclusions of our study are: (1) A system of diskless workstations with a shared file server can have satisfactory performance. By this, we mean performance comparable to that of a local disk in the lightly loaded case, and the ability to support substantial numbers of client workstations without significant degradation. As with any shared facility, good design is necessary to minimize queuing delays under high load. (2) The key to efficiency is protocols that allow volume transfers at every interface (e.g., between client and server, and between disk and memory at the server) and at every level (e.g., between client and server at the level of logical request/response and at the level of local area network packet size). However, the benefits of volume transfers are limited to moderate sizes (8-16 kbytes) by several factors. (3) From a performance point of view, augmenting the capabilities of the shared file server may be more cost effective than augmenting the capabilities of the client workstations. (4) Network contention should not be a performance problem for a lo-Mbit network and 100 active workstations in a software development environment.
Dynamic file migration in distributed computer systems
Authors: Gavish Bezalel , Liu Sheng Olivia R.
Published: July 2002

The importance of file migration is increasing because of its potential to improve the performance of distributed office, manufacturing and hospital information systems. To encourage research in the file migration problem, the authors summarize accomplishments of researchers of the problem, provide a detailed comparison of file migration and dynamic file allocation problems, and identify important areas of research to support the development of effective file migration policies.
Integrating network optimization capabilities into a high-level modeling language
Authors: Zenios Stavros A.
Published: July 2002

Research in network optimization has reached the stage where large-scale problems-linear or non-linear, pure or generalized-are solved very efficiently with minimal computing resources. Representing such problems for solution on the computer, however, remains a rather cumbersome task. Taking advantage of developments in high-level modeling languages, we design and implement integrated systems to facilitate the representation and solution of network problems. Such systems integrate the flexibility and robustness of modeling languages with the efficiency of network optimizers.

We describe two alternative modes for this integration, which can be achieved for linear and nonlinear problems alike. The use of the resulting systems is demonstrated with the solution of large-scale problems from diverse applications and with the implementation of network decomposition algorithms.
Higher-order Horn clauses
Authors: Nadathur Gopalan , Miller Dale
Published: July 2002

A generalization of Horn clauses to a higher-order logic is described and examined as a basis for logic programming. In qualitative terms, these higher-order Horn clauses are obtained from the first-order ones by replacing first-order terms with simply typed λ-terms and by permitting quantification over all occurrences of function symbols and some occurrences of predicate symbols. Several proof-theoretic results concerning these extended clauses are presented. One result shows that although the substitutions for predicate variables can be quite complex in general, the substitutions necessary in the context of higher-order Horn clauses are tightly constrained. This observation is used to show that these higher-order formulas can specify computations in a fashion similar to first-order Horn clauses. A complete theorem-proving procedure is also described for the extension. This procedure is obtained by interweaving higher-order unification with backchaining and goal reductions, and constitutes a higher-order generalization of SLD-resolution. These results have a practical realization in the higher-order logic programming language called λProlog.
THE PCAST ENERGY STUDIES: Toward a National Consensus on Energy Research, Development, Demonstration, and Deployment Policy
Authors: Holdren John P. , Baldwin Samuel F.
Published: July 2002

▪ Abstract  During the period 1995–1999, the President's Committee of Advisors on Science and Technology (PCAST) produced three major energy studies, at President Clinton's request. The panels that conducted these studies were broadly constituted from the academic, industrial, and NGO (nongovernmental organization) sectors, and their recommendations were unanimous. These efforts (a) helped lay the foundation for several major energy initiatives of the second Clinton term, including the Climate Change Technology Initiative, the Nuclear Energy Research Initiative, and the International Clean Energy Initiative; (b) helped launch energy R&D activities on methane hydrates and geological sequestration of carbon dioxide; and (c) strengthened related activities, such as the Partnership for a New Generation of Vehicles, the Partnership for Advancing Technologies in Housing, the fossil power Vision-21 Program, and the National Bioenergy Initiative. Federal budgets for research, development, demonstration, and deployment of advanced energy technologies have increased substantially over the past four years, but they still fall short of PCAST's recommendations; and a number of the PCAST recommendations on matters other than budget have yet to be fully implemented. The PCAST energy studies demonstrate the possibility of forging consensus around key energy issues and provide a foundation on which, it is hoped, the continuing pursuit of a coherent national policy on energy innovation will be able to build.
FLUID MECHANICS FOR SAILING VESSEL DESIGN
Authors: Milgram Jerome H.
Published: July 2002

▪ Abstract  The design of sailing vessels is an ancient art that places an ever-increasing reliance on modern engineering sciences. Fluid mechanics shares the forefront of this reliance along with structural mechanics. This review focuses on the application of fluid mechanics in modern sailing vessel design. It is now common practice to predict sailing performance with what are called velocity prediction computer programs. The validity of the predictions is crucially dependent on accurate modeling of the air and water forces on the vessel. This article reviews existing methods of force modeling that include theory, experimentation, and numerical fluid mechanics and aerodynamics. The accuracy and reliability of the numerical methods are considered on the basis of experimental results and full-scale performance in areas for which the information is available.
LINEAR AND NONLINEAR MODELS OF ANISOTROPIC TURBULENCE
Authors: Cambon Claude , Scott Julian F.
Published: July 2002

▪ Abstract  Because of mean distortion, most turbulent flows are anisotropic. Two-point descriptions, forming the heart of this review of anisotropic models, capture the continuum of anisotropically structured turbulent scales and, moreover, allow exact treatment of the linear terms representing mean distortion, only needing closure assumptions for the nonlinear part of the model. The rapid-distortion limit, in which nonlinear terms are neglected, is the main subject of Section 2, while Section 3 introduces nonlinearity. It is shown that, even with significant nonlinearity, many features of turbulence can, at least qualitatively, be understood using linear theory alone, e.g. the directionality of velocity fluctuations and correlation lengths induced by strong mean shear near a wall or straining by duct flow, whereas some, e.g. wave resonances in rotating turbulence, involve a subtle combination of linear and nonlinear terms. The importance of linear effects is reflected in the triadic models of Section 3, which contain no approximations of the linear terms and whose anisotropic nonlinear closures are heavily dependent on linear theory. Despite being fundamentally less satisfactory (because they involve additional ad hoc hypotheses to compensate for the lack of two-point information), one-point models dominate industrial calculations because they are robust, well-established, and computationally relatively cheap. Although there are too many spectral degrees of freedom for a one-point model to reproduce two-point results in all circumstances, two-point theories—in particular RDT—have been exploited to develop new one-point models, as discussed in Section 4. Given the significant limitation of classical two-point models to homogeneous turbulence, some inhomogeneous extensions are described in Section 5.
CHASING THE CANCER DEMON
Authors: Knudson Alfred G.
Published: July 2002

▪ Abstract  Boveri's idea that somatic mutations are at the root of cancer found its first specific support with the investigation of leukemia and Burkitt's lymphoma, and the discovery of the mechanism of oncogene activation by balanced translocation. The study of retinoblastoma later led to the cloning of the first antioncogene, or tumor suppressor gene, and to understanding the mechanisms by which the wild-type genes lose activity. Only a small subset of cancer involves simple mechanisms. A category of hereditary disorders called the phakomatoses provide a perspective on the chain of oncogenic events in such cancers because of two-hit precursor lesions that have a low probability of malignant transformation. The common carcinomas are much more complex and are typically genetically unstable, owing either to mutational instability or chromosomal instability.
Signal Transduction Mediated by the T Cell Antigen Receptor: The Role of Adapter Proteins
Authors: Samelson Lawrence E.
Published: July 2002

Engagement of the T cell antigen receptor (TCR) leads to a complex series of molecular changes at the plasma membrane, in the cytoplasm, and at the nucleus that lead ultimately to T cell effector function. Activation at the TCR of a set of protein tyrosine kinases (PTKs) is an early event in this process. This chapter reviews some of the critical substrates of these PTKs, the adapter proteins that, following phosphorylation on tyrosine residues, serve as binding sites for many of the critical effector enzymes and other adapter proteins required for T cell activation. The role of these adapters in binding various proteins, the interaction of adapters with plasma membrane microdomains, and the function of adapter proteins in control of the cytoskeleton are discussed.
THROMBOPOIETIN: UNDERSTANDING AND MANIPULATING PLATELET PRODUCTION
Authors: Kaushansky, MD K.
Published: July 2002

▪ Abstract  Until recently, platelet production was the least understood aspect of blood cell development. This gap in our understanding resulted from the scarcity of megakaryocytes, the marrow precursor of blood platelets, and from confusion surrounding the cytokines and hormones that support their development. The recent cloning and characterization of thrombopoietin (TPO) has profoundly changed our udnerstanding of platelet production. Using in vitro assay systems, several groups have shown that TPO supports the proliferation of megakaryocytic progenitor cells and their differentiation into mature platelet-producing cells. Moreover, and somewhat surprisingly, TPO also acts in synergy with other pluripotent cytokines on the hematopoietic stem cell to augment development of erythroid and myeloid progenitors. These in vitro effects correlate well with the in vivo biology of the hormone. When administered to normal animals, TPO expands the numbers of hematopoietic progenitors of all lineages and greatly accelerates platelet production. Moreover, when TPO or its receptor is genetically eliminated, progenitor cell levels of all lineages are reduced, and platelet production is profoundly impaired. In animals administered cytoreductive therapy, the use of TPO is associated with accelerated hematopoietic recovery, not only of megakaryocytes and platelets, but also of erythrocytes and leukocytes. It, thus, is hoped that TPO may play an important role in reducing the myelosuppressive complications of naturally occurring and iatrogenic states of marrow failure.
BONE DISEASE IN MODERATE RENAL FAILURE: Cause, Nature, and Prevention
Authors: Bushinsky, MD David A.
Published: July 2002

▪ Abstract  There are two primary types of bone disorders observed in patients with end-stage renal disease: a high-turnover osteodystrophy characterized by osteitis fibrosa, and a low-turnover osteodystrophy characterized initially by osteomalacia and, more recently, by adynamic or aplastic bone disease. This article reviews the clinical presentation, pathogenesis, and laboratory findings of patients with these two disorders. It discusses the important roles of phosphorus binding, vitamin D administration, and correction of acidosis in prevention and treatment of bone disease in patients with moderate renal insufficiency.
GETTING STARTED: Regulating the Initiation of DNA Replication in Yeast
Authors: Toone W. Mark , Aerne Birgit L. , Morgan Brian A. , Johnston and Leland H.
Published: July 2002

▪ Abstract  Initiation of DNA replication in yeast appears to operate through a two-step process. The first step occurs at the end of mitosis in the previous cell cycle, where, following the decrease in B cyclin-dependent kinase activity, an extended protein complex called the prereplicative complex (pre-RC) forms over the origin of replication. This complex is dependent on the association of the Cdc6 protein with the Origin Recognition Complex (ORC) and appears concomitantly with the nuclear entry of members of the Mcm family of proteins. The second step is dependent upon the cell passing through a G1 decision point called Start. If the environmental conditions are favorable, and the cells reach a critical size, then there is a rise in G1 cyclin-dependent kinase activity, which leads to the activation of downstream protein kinases; the protein kinases are, in turn, required for triggering initiation from the preformed initiation complexes. These protein kinases, Dbf4-Cdc7 and Clb5/6(B-cyclin)-Cdc28, are thought to phosphorylate targets within the pre-RC. The subsequent rise in B cyclin protein kinase activity following Start not only triggers origin firing, but also inhibits the formation of new pre-RCs, which ensures that there is only one S phase in each cell cycle. The destruction of B-cyclin protein kinase activity at the end of the cell cycle potentiates the formation of new pre-RCs—resetting origins for the next S phase.

  “… Or say that the end precedes the beginning.”                       TS Eliot
MASS MEASUREMENT FAR FROM STABILITY
Authors: Mittig W. , Lépine-Szily A. , Orr N. A.
Published: July 2002

▪ Abstract  The measurement of nuclear masses far from stability provides a fundamental test for our understanding of nuclear structure. Over the last decade new experimental techniques for the production and measurement of the masses of exotic nuclei have been developed. Predictions of nuclear models, however, exhibit significant disaccord as one progresses away from β stability. As a result, nuclear masses remain a field of experimental and theoretical challenge.
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, NIH: A Short History
Authors: Gillette James R.
Published: July 2002

The Laboratory of Chemical Pharmacology (LCP) began in 1950 as the Section of Pharmacology within the National Heart Institute, the National Institutes of Health. Its first chief was Bernard B. Brodie, considered by many to be one of the fathers of modern pharmacology. Since its inception, LCP has made many significant contributions to the fields of pharmacology and toxicology. LCP was among the first to study (a) the effects of drugs on the turnover of serotonin and norepineprine in brain and other tissues, (b) the absorption of drugs from the gastrointestinal tract and their passage across the blood-brain barrier, (c) the oxidation and reduction of drugs and other foreign compounds by liver microsomal enzymes (later known as the cytochrome P450 enzymes) and inhibitors and inducers of these enzymes, (d) the formation of toxic chemically reactive metabolites of drugs and other foreign compounds, and (e) mechanisms of immunological responses. Approximately 300 scientists worked in LCP during its existence, and they and their collaborators published more than 1,300 papers. This is a short history of the people who worked in it and of their contributions to biomedical sciences.
Protein Tyrosine Phosphatases: Structure and Function, Substrate Specificity, and Inhibitor Development
Authors: Zhang Zhong-Yin
Published: July 2002

Protein tyrosine phosphatases (PTPs) are signaling enzymes that control a diverse array of cellular processes. Malfunction of PTP activity is associated with a number of human disorders. Recent genetic and biochemical studies indicate that PTPs represent a novel platform for drug discovery. Detailed knowledge of PTP substrate specificity and the wealth of structural data on PTPs provide a solid foundation for rational PTP inhibitor design. This review summarizes a correlation of PTP structure and function from mutagenesis experiments. The molecular basis for PTP1B and MKP3 substrate recognition is discussed. A powerful strategy is presented for creating specific and high-affinity bidentate PTP inhibitors that simultaneously bind both the active site and a unique adjacent site. Finally, recent advances in the development of potent and selective inhibitors for PTP1B and Cdc25 are described.
AKAP Mediated Signal Transduction
Authors: Michel Jennifer J. Carlisle , Scott John D.
Published: July 2002

Compartmentalization of cyclic AMP-dependent protein kinase (PKA) is achieved through association with A-kinase anchoring proteins (AKAPs). AKAPs are a group of structurally diverse proteins with the common function of binding to the regulatory subunit of PKA and confining the holoenzyme to discrete locations within the cell. This mode of regulation ensures that PKA is exposed to isolated cAMP gradients, which allows for efficient catalytic activation and accurate substrate selection. Several AKAPs coordinate multiple members of signaling cascades, effectively assembling upstream activators and downstream effectors within the same macromolecular complex. Consequently, AKAPs may serve as points of integration for numerous signaling pathways. This review details the most recent advances in our understanding of the various biological functions dependent upon AKAP-anchored signaling complexes.
LOCALIZED INTRACELLULAR CALCIUM SIGNALING IN MUSCLE: Calcium Sparks and Calcium Quarks
Authors: Niggli Ernst
Published: July 2002

▪ Abstract  Subcellularly localized Ca2+ signals in cardiac and skeletal muscle have recently been identified as elementary Ca2+ signaling events. The signals, termed Ca2+ sparks and Ca2+ quarks, represent openings of Ca2+ release channels located in the membrane of the sarcoplasmic reticulum (SR). In cardiac muscle, the revolutionary discovery of Ca2+ sparks has allowed the development of a fundamentally different concept for the amplification of Ca2+ signals by Ca2+-induced Ca2+ release. In such a system, a graded amplification of the triggering Ca2+ signal entering the myocyte via L-type Ca2+ channels is accomplished by a recruitment process whereby individual SR Ca2+ release units are locally controlled by L-type Ca2+ channels. In skeletal muscle, the initial SR Ca2+ release is governed by voltage-sensors but subsequently activates additional Ca2+ sparks by Ca2+-induced Ca2+ release from the SR. Results from studies on elementary Ca2+ release events will improve our knowledge of muscle Ca2+ signaling at all levels of complexity, from the molecule to normal cellular function, and from the regulation of cardiac and skeletal muscle force to the pathophysiology of excitation-contraction coupling.
CATEGORICAL DATA ANALYSIS
Authors: Wickens Thomas D.
Published: July 2002

▪ Abstract  This chapter reviews recent developments in the analysis of categorical and contingency-table data. The first portion examines developments in model testing and selection. The second portion examines work on models for the structure of dependence. These include log-linear parameter models, models for latent classes, models for missing observations, numerical-scale-based association and correlation models (such as correspondence analysis), the treatment of ordered categories, and models for marginal distributions.
FROM MEASURING TO IMPROVING PUBLIC HEALTH PRACTICE
Authors: Turnock Bernard J. , Handler Arden S.
Published: July 2002

▪ Abstract  Efforts to measure public health practice have taken on various forms and focused on different aspects of the system of public health practice over the past century. Before 1990, measurement was primarily based on a series of self-assessment instruments initiated under the auspices of the Committee on Administrative Practice of the American Public Health Association. These instruments emphasized measurement of immediate results of local public health services although they also provided information on local resources and capacity to perform. Following the Institute of Medicine's report in 1988, efforts began to focus on performance related to public health's core functions. These more recent assessments suggest that the system of public health practice must be improved to achieve the targets of effectiveness established for the year 2000. Ultimately, a comprehensive national surveillance system for public health practice will need to both measure and examine the relationships among inputs (resources, capacity, etc), core function–related processes, outputs (services) as well as outcomes.
Bidirectional Contextual Resolution
Authors: Pulman Stephen G.
Published: July 2002

This paper describes a formalism and implementation for the interpretation and generation of sentences containing context-dependent constructs like determiners, pronouns, focus, and ellipsis. A variant of quasi-logical form is used as an under specified meaning representation, related to resolved logical forms via conditional equivalences. These equivalences define the interpretation of contextually dependent constructs with respect to a given context. Higher-order unification and abduction are used in relating expressions to contexts. The conditional equivalences can be used unchanged in both the interpretation and the generation direction.