bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy
Authors: Domingo Pere , Cabeza M. Carmen , Pruvost Alain , Torres Ferran , Salazar Juliana , del Mar Gutierrez M. , Mateo M. Gracia , Fontanet Angels , Fernandez Irene , Domingo Joan C. , Villarroya Francesc , Vidal Francesc , Baiget Montserrat 
Published: February 2011

ABSTRACTThe antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T-TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjustedpost hoccomparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol/106cells (interquartile range [IQR] = 8.12 to 13.87 fmol/106cells) in patients with a high-expression TS genotype (2/3G, 3C/3G, and 3G/3G), whereas in those with a low-expression TS genotype (2/2, 2/3C, and 3C/3C), they were 21.40 fmol/106cells (IQR = 18.90 to 27.0 fmol/106cells) (P< 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable;P= 0.0023). The low-expression TS genotype was associated with the development of HIV/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0;P= 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS.
Further Characterization of
Bacillus subtilis
Antibiotic Biosensors and Their Use for Antibacterial Mode-of-Action Studies
Authors: Mariner Katherine R. , Ooi Nicola , Roebuck Deborah , O'Neill Alex J. , Chopra Ian 
Published: February 2011

ABSTRACT

We further examined the usefulness of previously reported
Bacillus subtilis
biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.
Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice
Authors: Shibata Sayaka , Gillespie J. Robert , Kelley Angela M. , Napuli Alberto J. , Zhang Zhongsheng , Kovzun Kuzma V. , Pefley Ranae M. , Lam Jocelyn , Zucker Frank H. , Van Voorhis Wesley C. , Merritt Ethan A. , Hol Wim G. J. , Verlinde Christophe L. M. J. , Fan Erkang , Buckner Frederick S. 
Published: February 2011

ABSTRACT

Human African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS of
Trypanosoma brucei
demonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on the
T. brucei
MetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms of
T. brucei
cultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition and
T. brucei
growth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 μM, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of the
T. brucei
MetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors.
Chromosome-Encoded AmpC and CTX-M Extended-Spectrum β-Lactamases in Clinical Isolates of
Proteus mirabilis
from Korea
Authors: Song Wonkeun , Kim Juwon , Bae Il Kwon , Jeong Seok Hoon , Seo Young Hee , Shin Jong Hee , Jang Sook Jin , Uh Young , Shin Jeong Hwan , Lee Mi-Kyung , Lee Kyungwon 
Published: February 2011

ABSTRACT

Among 222
Proteus mirabilis
clinical isolates collected from 17 hospitals in Korea in 2008, 28 (12.6%) and 8 (3.6%) isolates exhibited extended-spectrum β-lactamase (ESBL) and AmpC phenotypes, respectively. The most common type of ESBL gene identified by PCR and sequencing experiments was
bla
CTX-M-14a
(
n
= 12). The
bla
CTX-M-90
(
n
= 4),
bla
CTX-M-15
(
n
= 3),
bla
CTX-M-12
(
n
= 3),
bla
CTX-M-2
(
n
= 2),
bla
CTX-M-14b
(
n
= 1),
bla
TEM-52
(
n
= 5), and
bla
SHV-12
(
n
= 1) genes were also detected. Eight isolates carried an AmpC β-lactamase gene, such as
bla
CMY-2
(
n
= 6) or
bla
DHA-1
(
n
= 2). All
bla
genes encoding CTX-M-1- and CTX-M-9-type enzymes and all
bla
CMY-2
genes were preceded by IS
Ecp1
-like elements. The
bla
CTX-M-2
gene found in two isolates was located on a complex class 1 integron. The
bla
DHA-1
gene was preceded by a transcriptional regulator gene and was followed by phage shock protein genes. The
bla
CTX-M
genes were located on the chromosome in 21 isolates. A plasmid location for the
bla
CTX-M
gene was found in only four isolates: the
bla
CTX-M-14a
gene was located on ∼150-kbp IncA/C plasmids in three isolates and on a ∼50-kbp IncN plasmid in one isolate. The
bla
TEM-52
gene was located on ∼50-kbp IncN plasmids in all five isolates. The AmpC β-lactamase genes were located on the chromosome in seven of eight isolates; one isolate carried the
bla
CMY-2
gene on a ∼150-kbp IncA/C plasmid. Our results show that a chromosomal location of CTX-M ESBL and AmpC β-lactamase genes in
P. mirabilis
is no longer an unusual phenomenon in hospital environments.
An Autotransporter Protein fromOrientia tsutsugamushiMediates Adherence to Nonphagocytic Host Cells
Authors: Ha Na-Young , Cho Nam-Hyuk , Kim Yeon-Sook , Choi Myung-Sik , Kim Ik-Sang 
Published: February 2011

ABSTRACTOrientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen whose mechanism of cellular adhesion and invasion is poorly characterized. Bioinformatic analyses of twoO. tsutsugamushigenomes revealed the presence of a group of genes that encode autotransporter proteins. In this study, we identified 10 autotransporter gene products and categorized them into five groups of orthologs (ScaA to ScaE) based on their sequence similarities. Sequence homology was highest between members of ScaC group, suggesting the functional conservation of bacterium-host interactions. ScaC was actively expressed on the surface ofO. tsutsugamushiand induced antibody responses in scrub typhus patients. Experiments using microbeads conjugated to recombinant ScaC or a surrogateEscherichia coliexpression system showed that ScaC was sufficient to mediate attachment to, but not invasion of, nonphagocytic mammalian cells. In addition, preincubation of host cells with recombinant ScaC significantly inhibited their interaction withO. tsutsugamushi. Finally, fibronectin was identified as a potential receptor for ScaC by using yeast two-hybrid screening, and this was confirmed using a glutathioneS-transferase (GST) pulldown assay. Taken together, these results demonstrate that ScaC is involved in the interaction ofO. tsutsugamushiwith mammalian host cells and suggest that ScaC may play a critical role in bacterial pathogenesis.
ON THE FILTERING PROPERTIES OF THE EMPIRICAL MODE DECOMPOSITION
Authors: WU ZHAOHUA , HUANG NORDEN E. 
Published: February 2011

The empirical mode decomposition (EMD) based time-frequency analysis has been used in many scientific and engineering fields. The mathematical expression of EMD in the time-frequency-energy domain appears to be a generalization of the Fourier transform (FT), which leads to the speculation that the latter may be a special case of the former. On the other hand, the EMD is also known to behave like a dyadic filter bank when used to decompose white noise. These two observations seem to contradict each other. In this paper, we study the filtering properties of EMD, as its sifting number changes. Based on numerical results of the decompositions using EMD of a delta function and white noise, we conjecture that, as the (pre-assigned and fixed) sifting number is changed from a small number to infinity, the EMD corresponds to filter banks with a filtering ratio that changes accordingly from 2 (dyadic) to 1; the filter window does not narrow accordingly, as the sifting number increases. It is also demonstrated that the components of a delta function resulted from EMD with any prescribed sifting number can be rescaled to a single shape, a result similar to that from wavelet decomposition, although the shape changes, as the sifting number changes. These results will lead to further understandings of the relations of EMD to wavelet decomposition and FT.
Matters of design
Authors: Hong Jason 
Published: February 2011

http://cacm.acm.org/blogs/blog-cacm

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

twitter

Follow us on Twitter at http://twitter.com/blogCACM
Jason Hong considers how software companies could effectively incorporate first-rate design into their products.
Functional pearl
Authors: Vytiniotis Dimitrios , Kennedy Andrew J. 
Published: February 2011

We show how the binary encoding and decoding of typed data and typed programs can be understood, programmed, and verified with the help of question-answer games. The encoding of a value is determined by the yes/no answers to a sequence of questions about that value; conversely, decoding is the interpretation of binary data as answers to the same question scheme.
We introduce a general framework for writing and verifying game-based codecs. We present games for structured, recursive, polymorphic, and indexed types, building up to a representation of well-typed terms in the simply-typed λ-calculus. The framework makes novel use of isomorphisms between types in the definition of games. The definition of isomorphisms together with additional simple properties make it easy to prove that codecs derived from games never encode two distinct values using the same code, never decode two codes to the same value, and interpret any bit sequence as a valid code for a value or as a prefix of a valid code.
TeachScheme!
Authors: Felleisen Matthias 
Published: February 2011

In 1995, my team and I decided to create an outreach project that would use our research on functional programming to change the K-12 computer science curriculum. We had two different goals in mind. On the one hand, our curriculum should rely on mathematics to teach programming, and it d exploit programming to teach mathematics. All students - not just those who major in computer science - should benefit. On the other hand, our course should demonstrate that introductory programming can focus on program design, not just a specific syntax. We also wished to create a smooth path from a design-oriented introductory course all the way to courses on large software projects.
My talk presents a checkpoint of our project, starting with our major scientific goal, a comprehensive theory of program design. Our work on this theory progresses through the development of program design courses for all age groups. At this point, we offer curricular materials for middle schools, high schools, three college-level freshman courses, and a junior-level course on constructing large components. We regularly use these materials to train K-12 teachers, after-school volunteers, and college faculty; thus far, we have reached hundreds of instructors, who in turn have dealt with thousands of students in their classrooms.
A fresh look at programming with names and binders
Authors: Pouillard Nicolas , Pottier François 
Published: February 2011

A wide range of computer programs, including compilers and theorem provers, manipulate data structures that involve names and binding. However, the design of programming idioms which allow performing these manipulations in a safe and natural style has, to a large extent, remained elusive.
In this paper, we present a novel approach to the problem. Our proposal can be viewed either as a programming language design or as a library: in fact, it is currently implemented within Agda. It provides a safe and expressive means of programming with names and binders. It is abstract enough to support multiple concrete implementations: we present one in nominal style and one in de Bruijn style. We use logical relations to prove that "well-typed programs do not mix names with different scope". We exhibit an adequate encoding of Pitts-style nominal terms into our system.
Fortifying macros
Authors: Culpepper Ryan , Felleisen Matthias 
Published: February 2011

Existing macro systems force programmers to make a choice between clarity of specification and robustness. If they choose clarity, they must forgo validating significant parts of the specification and thus produce low-quality language extensions. If they choose robustness, they must write in a style that mingles the implementation with the specification and therefore obscures the latter.
This paper introduces a new language for writing macros. With the new macro system, programmers naturally write robust language extensions using easy-to-understand specifications. The system translates these specifications into validators that detect misuses - including violations of context-sensitive constraints - and automatically synthesize appropriate feedback, eliminating the need for ad hoc validation code.
Functional parallel algorithms
Authors: Blelloch Guy E. 
Published: February 2011

Functional programming presents several important advantages in the design, analysis and implementation of parallel algorithms:

It discourages iteration and encourages decomposition.

It supports persistence and hence easy speculation.

It encourages higher-order aggregate operations.

It is well suited for defining cost models tied to the programming language rather than the machine.

Implementations can avoid false sharing.

Implementations can use cheaper weak consistency models.

And most importantly, it supports safe deterministic parallelism.

In fact functional programming supports a level of abstraction in which parallel algorithms are often as easy to design and analyze as sequential algorithms. The recent widespread advent of parallel machines therefore presents a great opportunity for functional programming languages. However, any changes will require significant education at all levels and involvement of the functional programming community.
In this talk I will discuss an approach to designing and analyzing parallel algorithms in a strict functional and fully deterministic setting. Key ideas include a cost model defined in term of analyzing work and span, the use of divide-and-conquer and contraction, the need for arrays (immutable) to achieve asymptotic efficiency, and the power of (deterministic) randomized algorithms. These are all ideas I believe can be taught at any level.
Regular, shape-polymorphic, parallel arrays in Haskell
Authors: Keller Gabriele , Chakravarty Manuel M.T. , Leshchinskiy Roman , Peyton Jones Simon , Lippmeier Ben 
Published: February 2011

We present a novel approach to regular, multi-dimensional arrays in Haskell. The main highlights of our approach are that it (1) is purely functional, (2) supports reuse through shape polymorphism, (3) avoids unnecessary intermediate structures rather than relying on subsequent loop fusion, and (4) supports transparent parallelisation.
We show how to embed two forms of shape polymorphism into Haskell's type system using type classes and type families. In particular, we discuss the generalisation of regular array transformations to arrays of higher rank, and introduce a type-safe specification of array slices.
We discuss the runtime performance of our approach for three standard array algorithms. We achieve absolute performance comparable to handwritten C code. At the same time, our implementation scales well up to 8 processor cores.
A certified framework for compiling and executing garbage-collected languages
Authors: McCreight Andrew , Chevalier Tim , Tolmach Andrew 
Published: February 2011

We describe the design, implementation, and use of a machine-certified framework for correct compilation and execution of programs in garbage-collected languages. Our framework extends Leroy's Coq-certified Compcert compiler and Cminor intermediate language. We add: (i) a new intermediate language, GCminor, that includes primitives for allocating memory in a garbage-collected heap and for specifying GC roots; (ii) a precise, low-level specification for a Cminor library for garbage collection; and (iii) a proven semantics-preserving translation from GCminor to Cminor plus the GC library. GCminor neatly encapsulates the interface between mutator and collector code, while remaining simple and flexible enough to be used with a wide variety of source languages and collector styles. Front ends targeting GCminor can be implemented using any compiler technology and any desired degree of verification, including full semantics preservation, type preservation, or informal trust.
As an example application of our framework, we describe a compiler for Haskell that translates the Glasgow Haskell Compiler's Core intermediate language to GCminor. To support a simple but useful memory safety argument for this compiler, the front end uses a novel combination of type preservation and runtime checks, which is of independent interest.
VeriML
Authors: Stampoulis Antonis , Shao Zhong 
Published: February 2011

Modern proof assistants such as Coq and Isabelle provide high degrees of expressiveness and assurance because they support formal reasoning in higher-order logic and supply explicit machine-checkable proof objects. Unfortunately, large scale proof development in these proof assistants is still an extremely difficult and time-consuming task. One major weakness of these proof assistants is the lack of a single language where users can develop complex tactics and decision procedures using a rich programming model and in a typeful manner. This limits the scalability of the proof development process, as users avoid developing domain-specific tactics and decision procedures.
In this paper, we present VeriML - a novel language design that couples a type-safe effectful computational language with first-class support for manipulating logical terms such as propositions and proofs. The main idea behind our design is to integrate a rich logical framework - similar to the one supported by Coq - inside a computational language inspired by ML. The language design is such that the added features are orthogonal to the rest of the computational language, and also do not require significant additions to the logic language, so soundness is guaranteed. We have built a prototype implementation of VeriML including both its type-checker and an interpreter. We demonstrate the effectiveness of our design by showing a number of type-safe tactics and decision procedures written in VeriML.
A domain-specific approach to architecturing error handling in pervasive computing
Authors: Mercadal Julien , Enard Quentin , Consel Charles , Loriant Nicolas 
Published: February 2011

The challenging nature of error handling constantly escalates as a growing number of environments consists of networked devices and software components. In these environments, errors cover a uniquely large spectrum of situations related to each layer ranging from hardware to distributed platforms, to software components. Handling errors becomes a daunting task for programmers, whose outcome is unpredictable. Scaling up error handling requires to raise the level of abstraction beyond the code level and the try-catch construct, approaching error handling at the software architecture level.
We propose a novel approach that relies on an Architecture Description Language (ADL), which is extended with error-handling declarations. To further raise the level of abstraction, our approach revolves around a domain-specific architectural pattern commonly used in pervasive computing. Error handling is decomposed into components dedicated to platform-wide, error-recovery strategies. At the application level, descriptions of functional components include declarations dedicated to error handling.
We have implemented a compiler for an ADL extended with error-handling declarations. It produces customized programming frameworks that drive and support the programming of error handling. Our approach has been validated with a variety of applications for building automation.
Do I use the wrong definition?
Authors: Shi Yao , Park Soyeon , Yin Zuoning , Lu Shan , Zhou Yuanyuan , Chen Wenguang , Zheng Weimin 
Published: February 2011

Software bugs, such as concurrency, memory and semantic bugs, can significantly affect system reliability. Although much effort has been made to address this problem, there are still many bugs that cannot be detected, especially concurrency bugs due to the complexity of concurrent programs. Effective approaches for detecting these common bugs are therefore highly desired.
This paper presents an invariant-based bug detection tool, DefUse, which can detect not only concurrency bugs (including the previously under-studied order violation bugs), but also memory and semantic bugs. Based on the observation that many bugs appear as violations to programmers' data flow intentions, we introduce three different types of definition-use invariants that commonly exist in both sequential and concurrent programs. We also design an algorithm to automatically extract such invariants from programs, which are then used to detect bugs. Moreover, DefUse uses various techniques to prune false positives and rank error reports.

We evaluated DefUse using
sixteen
real-world applications with twenty real-world concurrency and sequential bugs. Our results show that DefUse can effectively detect 19 of these bugs, including 2 new bugs that were never reported before, with only a few false positives. Our training sensitivity results show that, with the benefit of the pruning and ranking algorithms, DefUse is accurate even with insufficient training.