bluuebunny/crossref_metadata_2025 huggingface dataset:
Ott
Authors: Sewell Peter , Nardelli Francesco Zappa , Owens Scott , Peskine Gilles , Ridge Thomas , Sarkar Susmit , Strniša Rok
Published: October 2007

It is rare to give a semantic definition of a full-scale programming language, despite the many potential benefits. Partly this is because the available
metalanguages
for expressing semantics - usually either L
a
T
E
X for informal mathematics, or the formal mathematics of a proof assistant - make it much harder than necessary to work with large definitions.

We present a metalanguage specifically designed for this problem, and a tool, ott, that sanity-checks such definitions and compiles them into proof assistant code for Coq, HOL, Isabelle, and (in progress) Twelf, together with L
a
T
E
X code for production-quality typesetting, and OCaml boilerplate. The main innovations are:(1) metalanguage design to make definitions concise, and easy to read and edit;(2) an expressive but intuitive metalanguage for specifying binding structures; and (3) compilation to proof assistant code.

This has been tested in substantial case studies, including modular specifications of calculi from the TAPL text, a Lightweight Java with Java JSR 277/294 module system proposals, and a large fragment of OCaml (around 306 rules), with machine proofs of various soundness results. Our aim with this work is to enable a phase change: making it feasible to work routinely, without heroic effort, with rigorous semantic definitions of realistic languages.
Extensible pattern matching via a lightweight language extension
Authors: Syme Don , Neverov Gregory , Margetson James
Published: October 2007

Pattern matching of algebraic data types (ADTs) is a standard feature in typed functional programming languages, but it is well known that it interacts poorly with abstraction. While several partial solutions to this problem have been proposed, few have been implemented or used. This paper describes an extension to the .NET language F# called
active patterns
, which supports pattern matching over abstract representations of generic heterogeneous data such as XML and term structures, including where these are represented via object models in other .NET languages. Our design is the first to incorporate both ad hoc pattern matching functions for partial decompositions and "views" for total decompositions, and yet remains a simple and lightweight extension. We give a description of the language extension along with numerous motivating examples. Finally we describe how this feature would interact with other reasonable and related language extensions: existential types quantified at data discrimination tags, GADTs, and monadic generalizations of pattern matching.
Bidirectionalization transformation based on automatic derivation of view complement functions
Authors: Matsuda Kazutaka , Hu Zhenjiang , Nakano Keisuke , Hamana Makoto , Takeichi Masato
Published: October 2007

Bidirectional transformation
is a pair of transformations: a
view function
and a
backward transformation
. A view function maps one data structure called source onto another called view. The corresponding backward transformation reflects changes in the view to the source. Its practically useful applications include replicated data synchronization, presentation-oriented editor development, tracing software development, and view updating in the database community. However, developing a bidirectional transformation is hard, because one has to give two mappings that satisfy the bidirectional properties for system consistency.

In this paper, we propose a new framework for bidirectionalization that can automatically generate a useful backward transformation from a view function while guaranteeing that the two transformations satisfy the bidirectional properties. Our framework is based on two known approaches to bidirectionalization, namely the constant complement approach from the database community and the combinator approach from the programming language community, but it has three new features: (1) unlike the constant complement approach, it can deal with transformations between algebraic data structures rather than just tables; (2) unlike the combinator approach, in which primitive bidirectional transformations have to be explicitly given, it can derive them automatically; (3) it generates a view update checker to validate updates on views, which has not been well addressed so far. The new framework has been implemented and the experimental results show that our framework has promise.
Inductive reasoning about effectful data types
Authors: Filinski Andrzej , Støvring Kristian
Published: October 2007

We present a pair of reasoning principles,
definition
and
proof
by
rigid induction
, which can be seen as proper generalizations of lazy-datatype induction to monadic effects other than partiality. We further show how these principles can be integrated into logical-relations arguments, and obtain as a particular instance a general and principled proof that the success-stream and failure-continuation models of backtracking are equivalent. As another application, we present a monadic model of general search trees, not necessarily traversed depth-first. The results are applicable to both lazy and eager languages, and we emphasize this by presenting most examples in both Haskell and SML.
A type directed translation of MLF to system F
Authors: Leijen Daan
Published: October 2007

The MLF type system by Le Botlan and Rémy is a natural extension of Hindley-Milner type inference that supports full first-class polymorphism, where types can be of higher-rank and impredicatively instantiated. Even though MLF is theoretically very attractive, it has not seen widespread adoption. We believe that this partly because it is unclear how the rich language of MLF types relate to standard System F types. In this article we give the first type directed translation of MLF terms to System F terms. Based on insight gained from this translation, we also define "Rigid MLF" (MLF
=
), a restriction of MLF where all bound values have a System F type. The expressiveness of MLF
=
is the same as that of boxy types, but MLF
=
needs fewer annotations and we give a detailed comparison between them.
McErlang
Authors: Fredlund Lars-Åke , Svensson Hans
Published: October 2007

We present a model checker for verifying distributed programs written in the Erlang programming language. Providing a model checker for Erlang is especially rewarding since the language is by now being seen as a very capable platform for developing industrial strength distributed applications with excellent failure tolerance characteristics. In contrast to most other Erlang verification attempts, we provide support for a very substantial part of the language. The model checker has full Erlang data type support, support for general process communication, node semantics (inter-process behave subtly different from intra-process communication), fault detection and fault tolerance through process linking, and can verify programs written using the OTP Erlang component library (used by most modern Erlang programs).

As the model checking tool is itself implemented in Erlang we benefit from the advantages that a (dynamically typed) functional programming language offers: easy prototyping and experimentation with new verification algorithms, rich executable models that use complex data structures directly programmed in Erlang, the ability to treat executable models interchangeably as programs (to be executed directly by the Erlang interpreter) and data, and not least the possibility to cleanly structure and to cleanly combine various verification sub-tasks. In the paper we discuss the design of the tool and provide early indications on its performance.
Experience report
Authors: Sims Steve , DuVarney Daniel C.
Published: October 2007

Reactis
is a commercially successful testing and validation tool which is implemented almost entirely in Standard ML. Our experience using a functional language to develop a commercial product has led us to the conclusion that while functional languages have some disadvantages, in the case of Reactis the benefits of a functional language substantially outweigh the drawbacks.
iTasks
Authors: Plasmeijer Rinus , Achten Peter , Koopman Pieter
Published: October 2007

In this paper we introduce the iTask system: a set of combinators to specify
work flows
in a pure functional language at a very high level of abstraction. Work flow systems are automated systems in which
tasks
are coordinated that have to be executed by humans and computers. The combinators that we propose support work flow patterns commonly found in commercial work flow systems. Compared with most of these commercial systems, the iTask system offers several advantages: tasks are statically typed, tasks can be higher order, the combinators are fully compositional, dynamic and recursive work flows can be specified, and last but not least, the specification is used to generate an executable web-based multi-user work flow application. With the iTask system, useful work flows can be defined which cannot be expressed in other systems: work can be interrupted
and
subsequently directed to other workers for further processing.

The implementation is special as well. It is based on the Clean iData toolkit which makes it possible to create fully dynamic, interactive, thin client web applications. Thanks to the generic programming techniques used in the iData toolkit, the programming effort is reduced significantly: state handling, form rendering, user interaction, and storage management is handled automatically. The iTask system allows a task to be regarded as a special kind of persistent redex being reduced by the application user via task completion. The combinators control the order in which these redexes are made available to the application user. The system rewrites the persistent task redexes in a similar way as functions are rewritten in lazy functional languages.
Experience report
Authors: Welsh Noel , Gurnell David
Published: October 2007

Over the past year Untyped has developed some 40'000 lines of Scheme code for a variety of web-based applications, which receive over 10'000 hits a day. This is, to our knowledge, the largest web-based application deployment of PLT Scheme. Our experiences developing with PLT Scheme show that deficiencies in the existing infrastructure can be easily overcome, and we can exploit advanced language features to improve productivity. We conclude that PLT Scheme makes an excellent platform for developing web-based applications, and is competitive with more mainstream choices.
Functional pearl
Authors: Herman David
Published: October 2007

Filinski showed that callcc and a single mutable reference cell are sufficient to express the delimited control operators shift and reset. However, this implementation interacts poorly with dynamic bindings like exception handlers. We present a variation on Filinski's encoding of delimited continuations that behaves appropriately in the presence of exceptions and give an implementation in Standard ML of New Jersey. We prove the encoding correct with respect to the semantics of delimited dynamic binding.
Adding delimited and composable control to a production programming environment
Authors: Flatt Matthew , Yu Gang , Findler Robert Bruce , Felleisen Matthias
Published: October 2007

Operators for delimiting control and for capturing composable continuations litter the landscape of theoretical programming language research. Numerous papers explain their advantages, how the operators explain each other (or don't), and other aspects of the operators' existence. Production programming languages, however, do not support these operators, partly because their relationship to existing and demonstrably useful constructs - such as exceptions and dynamic binding - remains relatively unexplored.

In this paper, we report on our effort of translating the theory of delimited and composable control into a viable implementation for a production system. The report shows how this effort involved a substantial design element, including work with a formal model, as well as significant practical exploration and engineering.

The resulting version of PLT Scheme incorporates the expressive combination of delimited and composable control alongside dynamic-wind, dynamic binding, and exception handling. None of the additional operators subvert the intended benefits of existing control operators, so that programmers can freely mix and match control operators.
Type-safe higher-order channels in ML-like languages
Authors: Park Sungwoo
Published: October 2007

As a means of transmitting not only data but also code encapsulated within functions, higher-order channels provide an advanced form of task parallelism in parallel computations. In the presence of mutable references, however, they pose a safety problem because references may be transmitted to remote threads where they are no longer valid.

This paper presents an ML-like parallel language with
type-safe
higher-order channels. By type safety, we mean that no value written to a channel contains references, or equivalently, that no reference escapes via a channel from the thread where it is created. The type system uses a typing judgment that is capable of deciding whether the value to which a term evaluates contains references or not. The use of such a typing judgment also makes it easy to achieve another desirable feature of channels,
channel locality
, that associates every channel with a unique thread for serving all values addressed to it.

Our type system permits mutable references in sequential computations and also ensures that mutable references never interfere with parallel computations. Thus it provides both flexibility in sequential programming and ease of implementing parallel computations.
Evaluating high-level distributed language constructs
Authors: Nyström Jan , Trinder Phil , King David
Published: October 2007

The paper investigates the impact of high level distributed programming language constructs on the engineering of realistic software components. Based on reengineering two non-trivial telecoms components, we compare two high-level distributed functional languages, Erlang and GdH, with conventional distributed technologies C++/CORBA and C++/UDP.

We investigate several aspects of high-level distributed languages including the impact on code size of high-level constructs. We identify three language constructs that primarily contribute to the reduction in application size and quantify their impact. We provide the first evidence based on analysis of a substantial system to support the widely-held supposition that high-level constructs reduce programming effort associated with specifying distributed coordination. We investigate whether a language with sophisticated high-level fault tolerance can produce suitably robust components, and both measure and analyse the additional programming effort needed to introduce robustness. Finally, we investigate some implications of a range of type systems for engineering distributed software.
Experience report
Authors: Frenzel Leif
Published: October 2007

This paper summarizes experiences from an open source project that builds a free Haskell IDE based on Eclipse (an open source IDE platform). Eclipse is extensible and has proved to be a good basis for IDEs for several programming languages. Difficulties arise mainly because it is written in Java and requires extensions to be written in Java. This made it hard to reuse existing development tools implemented in Haskell, and turned out to be a considerable obstacle to finding contributors. Several approaches to resolve these issues are described and their advantages and disadvantages discussed.
User-friendly functional programming for web mashups
Authors: Ennals Rob , Gay David
Published: October 2007

MashMaker is a web-based tool that makes it easy for a normal user to create web mashups by browsing around, without needing to type, or plan in advance what they want to do.

Like a web browser, Mashmaker allows users to create mashups by browsing, rather than writing code, and allows users to bookmark interesting things they find, forming new widgets - reusable mashup fragments. Like a spreadsheet, MashMaker mixes program and data and allows ad-hoc unstructured editing of programs.

MashMaker is also a modern functional programming language with non-side effecting expressions, higher order functions, and lazy evaluation. MashMaker programs can be manipulated either textually, or through an interactive tree representation, in which a program is presented together with the values it produces.

In order to cope with this unusual domain, MashMaker contains a number of deviations from normal function languages. The most notable of these is that, in order to allow the programmer to write programs directly on their data, all data is stored in a single tree, and evaluation of an expression always takes place at a specific point in this tree, which also functions as its scope.
A generic usage analysis with subeffect qualifiers
Authors: Hage Jurriaan , Holdermans Stefan , Middelkoop Arie
Published: October 2007

Sharing analysis and uniqueness typing are static analyses that aim at determining which of a program's objects are to be used at most once. There are many commonalities between these two forms of usage analysis. We make their connection precise by developing an expressive generic analysis that can be instantiated to both sharing analysis and uniqueness typing. The resulting system, which combines parametric polymorphism with effect subsumption, is specified within the general framework of qualified types, so that readily available tools and techniques can be used for the development of implementations and metatheory.
Feedback directed implicit parallelism
Authors: Harris Tim , Singh Satnam
Published: October 2007

In this paper we present an automated way of using spare CPU resources within a shared memory multi-processor or multi-core machine. Our approach is (
i
) to profile the execution of a program, (
ii
) from this to identify pieces of work which are promising sources of parallelism, (
iii
) recompile the program with this work being performed speculatively via a work-stealing system and then (
iv
) to detect at run-time any attempt to perform operations that would reveal the presence of speculation.

We assess the practicality of the approach through an implementation based on GHC 6.6 along with a limit study based on the execution profiles we gathered. We support the full Concurrent Haskell language compiled with traditional optimizations and including I/O operations and synchronization as well as pure computation. We use 20 of the larger programs from the 'nofib' benchmark suite. The limit study shows that programs vary a lot in the parallelism we can identify: some have none, 16 have a potential 2x speed-up, 4 have 32x. In practice, on a 4-core processor, we get 10-80% speed-ups on 7 programs. This is mainly achieved at the addition of a second core rather than beyond this.

This approach is therefore not a replacement for manual parallelization, but rather a way of squeezing extra performance out of the threads of an already-parallel program or out of a program that has not yet been parallelized.
Lazy call-by-value evaluation
Authors: Braßel Bernd , Hanus Michael , Fischer Sebastian , Huch Frank , Vidal Germán
Published: October 2007

Designing debugging tools for lazy functional programming languages is a complex task which is often solved by expensive tracing of lazy computations. We present a new approach in which the information collected as a trace is reduced considerably (kilobytes instead of megabytes). The idea is to collect a kind of step information for a call-by-value interpreter, which can then efficiently reconstruct the computation for debugging/viewing tools, like declarative debugging. We show the correctness of the approach, discuss a proof-of-concept implementation with a declarative debugger as back end and present some benchmarks comparing our new approach with the Haskell debugger Hat.
Faster laziness using dynamic pointer tagging
Authors: Marlow Simon , Yakushev Alexey Rodriguez , Peyton Jones Simon
Published: October 2007

In the light of evidence that Haskell programs compiled by GHC exhibit large numbers of mispredicted branches on modern processors, we re-examine the "tagless" aspect of the STG-machine that GHC uses as its evaluation model.

We propose two tagging strategies: a simple strategy called semi-tagging that seeks to avoid one common source of unpredictable indirect jumps, and a more complex strategy called dynamic pointer-tagging that uses the spare low bits in a pointer to encode information about the pointed-to object. Both of these strategies have been implemented and exhaustively measured in the context of a production compiler, GHC, and the paper contains detailed descriptions of the implementations. Our measurements demonstrate significant performance improvements (14% for dynamic pointer-tagging with only a 2% increase in code size), and we further demonstrate that much of the improvement can be attributed to the elimination of mispredicted branch instructions.

As part of our investigations we also discovered that one optimisation in the STG-machine, vectored-returns, is no longer worthwhile and we explain why.
A type system for recursive modules
Authors: Dreyer Derek
Published: October 2007

There has been much work in recent years on extending ML with recursive modules. One of the most difficult problems in the development of such an extension is the
double vision
problem, which concerns the interaction of recursion and data abstraction. In previous work, I defined a type system called RTG, which solves the double vision problem at the level of a System-F-style core calculus. In this paper, I scale the ideas and techniques of RTG to the level of a recursive ML-style module calculus called RMC, thus establishing that no tradeoff between data abstraction and recursive modules is necessary. First, I describe RMC's typing rules for recursive modules informally and discuss some of the design questions that arose in developing them. Then, I present the formal semantics of RMC, which is interesting in its own right. The formalization synthesizes aspects of both the Definition and the Harper-Stone interpretation of Standard ML, and includes a novel two-pass algorithm for recursive module typechecking in which the coherence of the two passes is emphasized by their representation in terms of the same set of inference rules.
Stream fusion
Authors: Coutts Duncan , Leshchinskiy Roman , Stewart Don
Published: October 2007

This paper presents an automatic deforestation system,
stream fusion
, based on equational transformations, that fuses a wider range of functions than existing short-cut fusion systems. In particular, stream fusion is able to fuse zips, left folds and functions over nested lists, including list comprehensions. A distinguishing feature of the framework is its simplicity: by transforming list functions to expose their structure, intermediate values are eliminated by general purpose compiler optimisations.

We have reimplemented the Haskell standard List library on top of our framework, providing stream fusion for Haskell lists. By allowing a wider range of functions to fuse, we see an increase in the number of occurrences of fusion in typical Haskell programs. We present benchmarks documenting time and space improvements.
Call-pattern specialisation for Haskell programs
Authors: Peyton Jones Simon
Published: October 2007

User-defined data types, pattern-matching, and recursion are ubiquitous features of Haskell programs. Sometimes a function is called with arguments that are statically known to be in constructor form, so that the work of pattern-matching is wasted. Even worse, the argument is sometimes freshly-allocated, only to be immediately decomposed by the function.

In this paper we describe a simple, modular transformation that specialises recursive functions according to their argument "shapes". We describe our implementation of this transformation in the Glasgow Haskell Compiler, and give measurements that demonstrate substantial performance improvements: a worthwhile 10% on average, with a factor of 10 in particular cases.
Data storage, the next generation
Authors: Weiss Aaron
Published: October 2007

"You can't have everything," quipped comedian Steven Wright. "Where would you put it?" Although some astronomers say that the universe is actually expanding, most of us are already running out of free space for our stuff. That is, unless your stuff is digital. Data storage, unlike your attic, has been expanding for decades.
Virtually yours
Authors: Greiner Lynn
Published: October 2007

These days, it's virtually impossible to read virtually any IT publication without seeing references to---you guessed it---virtualization.
Oh where, oh where could my broadband be?
Authors: Fowler Dennis
Published: October 2007

Almost a decade ago I began my tenure as NetNews columnist by looking with great enthusiasm at the various broadband technologies under development. I waxed lyrical about DSL and cable, rhapsodized about satellites, and sang paeans of praise to broadband via power lines.
Muscle-specific overexpression of the type 1 IGF receptor results in myoblast-independent muscle hypertrophy via PI3K, and not calcineurin, signaling
Authors: Quinn LeBris S. , Anderson Barbara G. , Plymate Stephen R.
Published: October 2007

The insulin-like growth factors (IGF-I and IGF-II), working through the type 1 IGF receptor (IGF-1R), are key mediators of skeletal muscle fiber growth and hypertrophy. These processes are largely dependent on stimulation of proliferation and differentiation of muscle precursor cells, termed myoblasts. It has not been rigorously determined whether the IGFs can also mediate skeletal muscle hypertrophy in a myoblast-independent fashion. Similarly, although the phosphatidylinositol 3-kinase (PI3K) and calcineurin signaling pathways have been implicated in skeletal muscle hypertrophy, these pathways are also involved in skeletal myoblast differentiation. To determine whether the IGFs can stimulate skeletal muscle hypertrophy in a myoblast-independent fashion, we developed and validated a retroviral expression vector that mediated overexpression of the human IGF-1R in rat L6 skeletal myotubes (immature muscle fibers), but not in myoblasts. L6 myotubes transduced with this vector accumulated significantly higher amounts of myofibrillar proteins, in a ligand- and receptor-dependent manner, than controls and demonstrated significantly increased rates of protein synthesis. Stimulation of myotube hypertrophy was independent of myoblast contributions, inasmuch as these cultures did not exhibit increased levels of myoblast proliferation or differentiation. Experiments with PI3K and calcineurin inhibitors indicated that myoblast-independent myotube hypertrophy was mediated by PI3K, but not calcineurin, signaling. This study demonstrates that IGF can mediate skeletal muscle hypertrophy in a myoblast-independent fashion and suggests that muscle-specific overexpression of the IGF-1R or stimulation of its signaling pathways could be used to develop strategies to ameliorate muscle wasting without stimulating proliferative pathways leading to carcinogenesis or other pathological sequelae.
Antecedent short-term central nervous system administration of estrogen and progesterone alters counterregulatory responses to hypoglycemia in conscious male rats
Authors: Sandoval Darleen A. , Gong Bin , Davis Stephen N.
Published: October 2007

The aim of this study was to test the hypothesis that antecedent short-term administration of estradiol or progesterone into the central nervous system (CNS) reduces levels of neuroendocrine counterregulatory hormones during subsequent hypoglycemia. Conscious unrestrained male Sprague-Dawley rats were studied during randomized 2-day experiments. Day 1 consisted of an 8-h lateral ventricle infusion of estradiol (1 μg/μl; n = 9), progesterone (1 μg/μl; n = 9), or saline (0.2 μl/min; n = 10). On day 2, a 2-h hyperinsulinemic (30 pmol·kg−1·min−1) hypoglycemic (2.9 ± 0.2 mM) clamp was performed on all rats. Central administration of estradiol on day 1 resulted in significantly lower plasma epinephrine levels during hypoglycemia compared with saline, whereas central administration of progesterone resulted in increased levels of plasma norepinephrine and decreased levels of corticosterone both at baseline and during hypoglycemia. Glucagon responses during hypoglycemia were unaffected by prior administration of estradiol or progesterone. Endogenous glucose production following day 1 estradiol was significantly lower during day 2 hypoglycemia, and consequently, the glucose infusion rate to maintain the glycemia was significantly greater after estradiol administration compared with saline. These data suggest that 1) CNS administration of both female reproductive hormones can have rapid effects in modulating levels of counterregulatory hormones during subsequent hypoglycemia in conscious male rats, 2) forebrain administration of reproductive hormones can significantly reduce pituitary adrenal and sympathetic nervous system drive during hypoglycemia, 3) reproductive steroid hormones produce differential effects on sympathetic nervous system activity during hypoglycemia, and 4) reduction of epinephrine resulted in significantly blunted metabolic counterregulatory responses during hypoglycemia.
Detrimental metabolic effects of combining long-term cigarette smoke exposure and high-fat diet in mice
Authors: Chen Hui , Hansen Michelle J. , Jones Jessica E. , Vlahos Ross , Anderson Gary P. , Morris Margaret J.
Published: October 2007

Obesity and cigarette smoking are both important risk factors for insulin resistance, cardiovascular disease, and cancer. Smoking reduces appetite, which makes many people reluctant to quit. Few studies have documented the metabolic impact of combined smoke exposure (se) and high-fat-diet (HFD). Neuropeptide Y (NPY) is a powerful hypothalamic feeding stimulator that promotes obesity. We investigated how chronic se affects caloric intake, adiposity, plasma hormones, inflammatory mediators, and hypothalamic NPY peptide in animals fed a palatable HFD. Balb/c mice (5 wk old, male) were exposed to smoke (2 cigarettes, twice/day, 6 days/wk, for 7 wk) with or without HFD. Sham-exposed mice were handled similarly without se. Plasma leptin, hypothalamic NPY, and adipose triglyceride lipase (ATGL) mRNA were measured. HFD induced a 2.3-fold increase in caloric intake, increased adiposity, and glucose in both sham and se cohorts. Smoke exposure decreased caloric intake by 23%, with reduced body weight in both dietary groups. Fat mass and glucose were reduced only by se in the chow-fed animals. ATGL mRNA was reduced by HFD in se animals. Total hypothalamic NPY was reduced by HFD, but only in sham-exposed animals; se increased arcuate NPY. We conclude that although se ameliorated hyperphagia and reversed the weight gain associated with HFD, it failed to reverse fat accumulation and hyperglycemia. The reduced ATGL mRNA expression induced by combined HFD and se may contribute to fat retention. Our data support a powerful health message that smoking in the presence of an unhealthy Western diet increases metabolic disorders and fat accumulation.
Cardiotrophin-1 is expressed in adipose tissue and upregulated in the metabolic syndrome
Authors: Natal Cristina , Fortuño María Antonia , Restituto Patricia , Bazán Antonio , Colina Immaculada , Díez Javier , Varo Nerea
Published: October 2007

Adipose tissue is a target for cardiotrophin-1 (CT-1), a cytokine member of the IL-6 family of cytokines that is involved in cardiac growth and dysfunction. However, it is unknown whether adipocytes are a source of CT-1 and whether CT-1 is overexpressed in diseases characterized by increased fat depots [i.e., the metabolic syndrome (MS)]. Thus this work aimed 1) to test whether adipose tissue expresses CT-1 and whether CT-1 expression can be modulated and 2) to compare serum CT-1 levels in subjects with and without MS diagnosed by National Cholesterol Education Program Adult Treatment Panel III criteria. Gene and protein expression of CT-1 was determined by real-time RT-PCR, ELISA, and Western blotting. CT-1 expression progressively increased, along with differentiation time from preadipocyte to mature adipocyte in 3T3-L1 cells. CT-1 expression was enhanced by glucose in a dose-dependent manner in these cells. mRNA and protein CT-1 expression was also demonstrated in human adipose biopsies. Immunostaining showed positive staining in adipocytes. Finally, increased CT-1 serum levels were observed in patients with MS compared with control subjects (127 ± 9 vs. 106 ± 4 ng/ml, P < 0.05). Circulating levels of CT-1 were associated with glucose levels ( r = 0.2, P < 0.05). Taken together, our data suggest that adipose tissue can be recognized as a source of CT-1, which could account for the high circulating levels of CT-1 in patients with MS.
Histamine-Induced Excitatory Responses in Mouse Ventromedial Hypothalamic Neurons: Ionic Mechanisms and Estrogenic Regulation
Authors: Zhou Jin , Lee Anna W. , Devidze Nino , Zhang Qiuyu , Kow Lee-Ming , Pfaff Donald W.
Published: October 2007

Histamine is capable of modulating CNS arousal states by regulating neuronal excitability. In the current study, histamine action in the ventromedial hypothalamus (VMH), its related ionic mechanisms, and its possible facilitation by estrogen were investigated using whole cell patch-clamp recording in brain slices from ovariectomized female mice. Under current clamp, a bath application of histamine (20 μM) caused membrane depolarization, associated with an increased membrane resistance. In some cells, the depolarization was accompanied by action potentials. Histamine application also significantly reduced the latency of action potential evoked by current steps. Histamine-induced depolarization was not affected by either tetrodotoxin or Cd2+. However, after blocking K+ channels with tetraethylammonium, 4-aminopyridine, and Cs+, depolarization was significantly decreased. Under voltage clamp, histamine-induced depolarization was associated with an inward current. The current–voltage relationship revealed that this inward current reversed near EK. The histamine effect was mimicked by a histamine receptor 1 (H1) agonist, but not a histamine receptor 2 (H2) agonist. An H1 antagonist, but not H2 antagonist, abolished histamine responses. When ovariectomized mice were treated with estradiol benzoate (E2), histamine-induced depolarization was significantly enhanced with an increased percentage of cells showing action potential firing. These results suggest that histamine depolarized VMH neurons by attenuating a K+ leakage current and this effect was mediated by H1 receptor. E2 facilitated histamine-induced excitation of VMH neurons. This histamine effect may present a potential mechanism by which estrogens modulate the impact of generalized CNS arousal on a sexual arousal–related neuronal group.
Neurophysiology of Prehension. III. Representation of Object Features in Posterior Parietal Cortex of the Macaque Monkey
Authors: Gardner Esther P. , Babu K. Srinivasa , Ghosh Soumya , Sherwood Adam , Chen Jessie
Published: October 2007

Neurons in posterior parietal cortex (PPC) may serve both proprioceptive and exteroceptive functions during prehension, signaling hand actions and object properties. To assess these roles, we used digital video recordings to analyze responses of 83 hand-manipulation neurons in area 5 as monkeys grasped and lifted objects that differed in shape (round and rectangular), size (large and small spheres), and location (identical rectangular blocks placed lateral and medial to the shoulder). The task contained seven stages—approach, contact, grasp, lift, hold, lower, relax—plus a pretrial interval. The four test objects evoked similar spike trains and mean rate profiles that rose significantly above baseline from approach through lift, with peak activity at contact. Although representation by the spike train of specific hand actions was stronger than distinctions between grasped objects, 34% of these neurons showed statistically significant effects of object properties or hand postures on firing rates. Somatosensory input from the hand played an important role as firing rates diverged most prominently on contact as grasp was secured. The small sphere—grasped with the most flexed hand posture—evoked the highest firing rates in 43% of the population. Twenty-one percent distinguished spheres that differed in size and weight, and 14% discriminated spheres from rectangular blocks. Location in the workspace modulated response amplitude as objects placed across the midline evoked higher firing rates than positions lateral to the shoulder. We conclude that area 5 neurons, like those in area AIP, integrate object features, hand actions, and grasp postures during prehension.
Dissociable Mechanisms of Cognitive Control in Prefrontal and Premotor Cortex
Authors: Chambers Christopher D. , Bellgrove Mark A. , Gould Ian C. , English Therese , Garavan Hugh , McNaught Elizabeth , Kamke Marc , Mattingley Jason B.
Published: October 2007

Intelligent behavior depends on the ability to suppress inappropriate actions and resolve interference between competing responses. Recent clinical and neuroimaging evidence has demonstrated the involvement of prefrontal, parietal, and premotor areas during behaviors that emphasize conflict and inhibition. It remains unclear, however, whether discrete subregions within this network are crucial for overseeing more specific inhibitory demands. Here we probed the functional specialization of human prefrontal cortex by combining repetitive transcranial magnetic stimulation (rTMS) with integrated behavioral measures of response inhibition (stop-signal task) and response competition (flanker task). Participants undertook a combined stop-signal/flanker task after rTMS of the inferior frontal gyrus (IFG) or dorsal premotor cortex (dPM) in each hemisphere. Stimulation of the right IFG impaired stop-signal inhibition under conditions of heightened response competition but did not influence the ability to suppress a competing response. In contrast, stimulation of the right dPM facilitated execution but had no effect on inhibition. Neither of these results was observed during rTMS of corresponding left-hemisphere regions. Overall, our findings are consistent with existing evidence that the right IFG is crucial for inhibitory control. The observed double dissociation of neurodisruptive effects between the right IFG and right dPM further implies that response inhibition and execution rely on distinct neural processes despite activating a common cortical network.
Functional and evolutionary relationships of troponin C
Authors: Gillis Todd E. , Marshall Christian R. , Tibbits Glen F.
Published: October 2007

Striated muscle contraction is initiated when, following membrane depolarization, Ca2+binds to the low-affinity Ca2+binding sites of troponin C (TnC). The Ca2+activation of this protein results in a rearrangement of the components (troponin I, troponin T, and tropomyosin) of the thin filament, resulting in increased interaction between actin and myosin and the formation of cross bridges. The functional properties of this protein are therefore critical in determining the active properties of striated muscle. To date there are 61 known TnCs that have been cloned from 41 vertebrate and invertebrate species. In vertebrate species there are also distinct fast skeletal muscle and cardiac TnC proteins. While there is relatively high conservation of the amino acid sequence of TnC homologs between species and tissue types, there is wide variation in the functional properties of these proteins. To date there has been extensive study of the structure and function of this protein and how differences in these translate into the functional properties of muscles. The purpose of this work is to integrate these studies of TnC with phylogenetic analysis to investigate how changes in the sequence and function of this protein, integrate with the evolution of striated muscle.
Characterization and functional divergence of the α1-adrenoceptor gene family: insights from rainbow trout (Oncorhynchus mykiss)
Authors: Chen Xi , Perry Steve F. , Aris-Brosou Stéphane , Selva Corrado , Moon Thomas W.
Published: October 2007

Presently, three α1-adrenoceptor (AR) types are recognized in vertebrates: α1A-, α1B-, and α1D-ARs. These α1-subtypes have distinct pharmacology and molecular profiles, play crucial roles in metabolic and vascular control, and are the targets for numerous pharmaceuticals, especially those affecting blood pressure and vascular resistance. To better understand the functional divergence within the α1-AR gene family, we sequenced these α1-AR paralogs in the rainbow trout and performed an extensive phylogenetic analysis. We show that these AR genes evolved by duplication events just before the origin of the jawed vertebrates. Our computational analyses suggest that the differences between the three α1-AR subtypes may affect their tissue specificity, ligand specificity, and possibly signal transduction processes and desensitization. We also show that, within each subtype, differences exist between fish and mammalian receptors, both at the transcriptional and at the physiological level. These differences, however, suggest that the role of α1-ARs in fish is more complex than previously thought. Our integrated analysis of the α1-AR gene family suggests that these receptors evolved these distinct features very early within vertebrates.
Discovery and Pharmacologic Characterization of CP-724,714, a Selective ErbB2 Tyrosine Kinase Inhibitor
Authors: Jani Jitesh P. , Finn Richard S. , Campbell Mary , Coleman Kevin G. , Connell Richard D. , Currier Nicolas , Emerson Erling O. , Floyd Eugenia , Harriman Shawn , Kath John C. , Morris Joel , Moyer James D. , Pustilnik Leslie R. , Rafidi Kristina , Ralston Sherry , Rossi Ann Marie K. , Steyn Stefanus J. , Wagner Larry , Winter Steven M. , Bhattacharya Samit K.
Published: October 2007

Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal–regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects. [Cancer Res 2007;67(20):9887–93]
Proteasome Inhibition Up-regulates p53 and Apoptosis-Inducing Factor in Chondrocytes Causing Severe Growth Retardation in Mice
Authors: Zaman Farasat , Menendez-Benito Victoria , Eriksson Emma , Chagin Andrei S. , Takigawa Masaharu , Fadeel Bengt , Dantuma Nico P. , Chrysis Dionisios , Sävendahl Lars
Published: October 2007

Proteasome inhibitors (PI), a novel class of anticancer drugs, are relatively well tolerated and have recently been introduced into the clinic for the treatment of multiple myeloma. The tumor selectivity and low toxicity of PIs are surprising, given the crucial role of the ubiquitin/proteasome system in a multitude of cellular processes. Here, we show that systemic administration of PIs specifically impairs the ubiquitin/proteasome system in growth plate chondrocytes. Importantly, young mice displayed severe growth retardation during treatment as well as 45 days after the cessation of treatment with clinically relevant amounts of MG262 (0.2 μmol/kg body weight/injection) or bortezomib (1.0 mg/kg body weight/injection). Dysfunction of the ubiquitin/proteasome system was accompanied by the induction of apoptosis of stem-like and proliferative chondrocytes in the growth plate. These results were recapitulated in cultured fetal rat metatarsal bones and chondrocytic cell lines (rat, human). Apoptosis was associated with up-regulation of the proapoptotic molecules, p53 and apoptosis-inducing factor (AIF), both in vitro and in vivo. In addition to the observation that AIF is expressed in the growth plate, we also provide evidence that AIF serves as a direct target protein for ubiquitin, thus explaining its prominent up-regulation upon proteasome inhibition. Suppression of p53 or AIF expression with small interfering RNAs partly rescued chondrocytes from proteasome inhibition–induced apoptosis (35% and 41%, respectively). Our observations show that proteasome inhibition may selectively target essential cell populations in the growth plate causing significant growth failure. These findings could have important implications for the use of proteasome inhibitors in the treatment of childhood cancer. [Cancer Res 2007;67(20):10078–86]
Interleukin-4 Cytotoxin Therapy Synergizes with Gemcitabine in a Mouse Model of Pancreatic Ductal Adenocarcinoma
Authors: Shimamura Takeshi , Royal Richard E. , Kioi Mitomu , Nakajima Atsushi , Husain Syed R. , Puri Raj K.
Published: October 2007

Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (IL-4R), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from >0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50 >1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein–transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA. [Cancer Res 2007;67(20):9903–12]