bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen-Presenting Dendritic Cells Rescue CD4-Depleted CCR2−/−Mice from LethalHistoplasma capsulatumInfection
Authors: Szymczak Wendy A. , Deepe George S. 
Published: March 2010

ABSTRACTExcessive production of interleukin-4 impairs clearance of the fungal pathogenHistoplasma capsulatumin mice lacking the chemokine receptor CCR2. An increase in the interleukin-4 level is associated with decreased recruitment of dendritic cells to lungs; therefore, we investigated the possibility that these cells influence interleukin-4 production. Adoptive transfer of wild-type or CCR2−/−bone marrow-derived dendritic cells loaded with heat-killed yeast cells to infected CCR2−/−mice suppressed interkeukin-4 transcription. Surprisingly, transfer of cells did not reduce the fungal burden despite the fact that it limited interleukin-4 transcription. Yeast cell-loaded bone marrow-derived dendritic cell-mediated regulation of interleukin-4 transcription was dependent on major histocompatibility complex II antigen presentation to CD4+T cells. We previously showed that CD4+T cells were a source of interleukin-4 in infected CCR2−/−mice, but their contribution to the TH2 phenotype was unclear. Here we demonstrated that these cells were functionally important since elimination of them prior to infection, but not elimination of them at the time of infection, reduced the interleukin-4 level in infected CCR2−/−mice. However, the fungal burden was reduced only in CD4-depleted CCR2−/−mice that received yeast cell-loaded bone marrow-derived dendritic cells. Taken together, the data indicate that generation of excess interleukin-4 in lungs ofH. capsulatum-infected CCR2−/−mice is at least partially a consequence of decreased recruitment of dendritic cells capable of antigen presentation. Furthermore, CD4+T cells had a deleterious impact on immunity in infected CCR2−/−mice.
CdpA Is a
Burkholderia pseudomallei
Cyclic di-GMP Phosphodiesterase Involved in Autoaggregation, Flagellum Synthesis, Motility, Biofilm Formation, Cell Invasion, and Cytotoxicity
Authors: Lee Hwee Siang , Gu Feiyu , Ching Shi Min , Lam Yulin , Chua Kim Lee 
Published: March 2010

ABSTRACT

Cyclic diguanylic acid (c-di-GMP) is an intracellular signaling molecule involved in regulation of cellular functions such as motility, biofilm formation and virulence. Intracellular level of c-di-GMP is controlled through opposing diguanylate cyclase (DGC) and phosphodiesterase (PDE) activities of GGDEF and EAL domain proteins, respectively. We report the identification and characterization of
cdpA
, a gene encoding a protein containing an EAL domain in the Gram-negative soil bacillus and human pathogen
Burkholderia pseudomallei
KHW. Purified recombinant CdpA protein exhibited PDE activity
in vitro
. Evidence that CdpA is a major c-di-GMP-specific PDE in
B. pseudomallei
KHW was shown by an 8-fold-higher c-di-GMP level in the
cdpA-
null mutant as compared to the wild type and the complemented
cdpA
mutant. The presence of higher intracellular c-di-GMP levels in the
cdpA-
null mutant was associated with increased production of exopolysaccharides, increased cell-to-cell aggregation, absence of flagella and swimming motility, and increased biofilm formation. The relevance of CdpA in
B. pseudomallei
virulence was demonstrated by a 3-fold reduction in invasion of human lung epithelial cells and a 6-fold reduction in cytotoxicity on human macrophage cells infected with the
cdpA
mutant.
Inactivation of Phospholipase D DiminishesAcinetobacter baumanniiPathogenesis
Authors: Jacobs Anna C. , Hood Indriati , Boyd Kelli L. , Olson Patrick D. , Morrison John M. , Carson Steven , Sayood Khalid , Iwen Peter C. , Skaar Eric P. , Dunman Paul M. 
Published: March 2010

ABSTRACTAcinetobacter baumanniiis an emerging bacterial pathogen of considerable health care concern. Nonetheless, relatively little is known about the organism's virulence factors or their regulatory networks. Septicemia and ventilator-associated pneumonia are two of the more severe forms ofA. baumanniidisease. To identify virulence factors that may contribute to these disease processes, genetically diverseA. baumanniiclinical isolates were evaluated for the ability to proliferate in human serum. A transposon mutant library was created in a strain background that propagated well in serum and screened for members with decreased serum growth. The results revealed that disruption ofA. baumanniiphospholipase D (PLD) caused a reduction in the organism's ability to thrive in serum, a deficiency in epithelial cell invasion, and diminished pathogenesis in a murine model of pneumonia. Collectively, these results suggest that PLD is anA. baumanniivirulence factor.
Role of Host Sphingosine Kinase 1 in the Lung Response against Cryptococcosis
Authors: McQuiston Travis , Luberto Chiara , Del Poeta Maurizio 
Published: March 2010

ABSTRACTCryptococcus neoformansis a fungal pathogen causing pulmonary infection and a life-threatening meningoencephalitis in human hosts. The fungus infects the host through inhalation, and thus, the host response in the lung environment is crucial for containment or dissemination ofC. neoformansto other organs. In the lung, alveolar macrophages (AMs) are key players in the host lung immune response, and upon phagocytosis, they can killC. neoformansby evoking an effective immune response through a variety of signaling molecules. On the other hand, under conditions not yet fully defined, the fungus is able to survive and proliferate within macrophages. Since the host sphingosine kinase 1 (SK1) regulates many signaling functions of immune cells, particularly in macrophages, in this study we determined the role of SK1 in the host response toC. neoformansinfection. Using wild-type (SK1/2+/+) and SK1-deficient (SK1−/−) mice, we found that SK1 is dispensable during infection with a facultative intracellular wild-typeC. neoformansstrain. However, SK1 is required to form a host lung granuloma and to prevent brain infection by aC. neoformansmutant strain lacking the cell wall-associated glycosphingolipid glucosylceramide (Δgcs1), previously characterized as a mutant able to replicate only intracellularly. Specifically, in contrast to those from SK1/2+/+mice, lungs from SK1−/−mice have no collagen deposition upon infection withC. neoformansΔgcs1, and AMs from these mice contain significantly moreC. neoformanscells than AMs from SK1/2+/+mice, suggesting that under conditions in whichC. neoformansis more internalized by AMs, SK1 may become important to controlC. neoformansinfection. Indeed, when we induced immunosuppression, a host condition in which wild-typeC. neoformanscells are increasingly found intracellularly, SK1−/−survived significantly less than SK1/2+/+mice infected with a facultative intracellular wild-type strain, suggesting that SK1 has an important role in controllingC. neoformansinfection under conditions in which the fungus is predominantly found intracellularly.
Practitioner-based measurement
Authors: Parkinson S. T. , Hierons R. M. , Lycett M. , Norman M. 
Published: March 2010

Introduction

The established philosophy within the software development industry is that an organization implementing a program to improve software quality can expect to recoup the cost of the implementation many times over through the reduced cost associated with improvements in quality. Measurement initiatives are perceived to provide a key contribution to quality improvement as evidenced by the focus of early measurement based initiatives and the place of measurement in the higher echelons of process initiatives. In general, organizations pursue measurement initiatives from a perspective that, without measurement, control is not possible. While organizations recognize that there are potential benefits to measuring their processes and products, however, they typically find it difficult to structure ad-hoc measures into a formal program -- a situation that is compounded by the significant cost of implementing such programs. Although these problems have led to some organizations moving away from measurement programs, many companies still use measurement programs as illustrated by the continued interest in, for example, the Capability Maturity Model. Given the appetite and potential returns on investment of measurement frameworks and initiatives, ways of successfully implementing them are important.
With that importance in mind, this work evaluates the implementation of such a measurement framework in a major Insurance organization. A hybrid model -- practitioner-based -- was devised to incorporate the best aspects of current approaches and mitigate identified shortcomings. In order to continually improve software quality, research was conducted to understand the critical success factors in implementing software measurement programs, develop a measurement framework to address the critical success factors, implement a pilot program based on that framework, and reflect on the outcomes of implementation for future practice. We examine existing measurement frameworks in order to assess the critical success factors and the relative strengths and weaknesses of existing approaches in relation to those factors and describe the model that results from the outcomes of the analysis of strengths and weaknesses of existing approaches. Later, we describe the implementation of a pilot of the model in an established IT department and evaluate the success of the pilot and the implications for the state-of-the-art.
Modeling time in computing
Authors: Furia Carlo A. , Mandrioli Dino , Morzenti Angelo , Rossi Matteo 
Published: March 2010

The increasing relevance of areas such as real-time and embedded systems, pervasive computing, hybrid systems control, and biological and social systems modeling is bringing a growing attention to the temporal aspects of computing, not only in the computer science domain, but also in more traditional fields of engineering.This article surveys various approaches to the formal modeling and analysis of the temporal features of computer-based systems, with a level of detail that is also suitable for nonspecialists. In doing so, it provides a unifying framework, rather than just a comprehensive list of formalisms.The article first lays out some key dimensions along which the various formalisms can be evaluated and compared. Then, a significant sample of formalisms for time modeling in computing are presented and discussed according to these dimensions. The adopted perspective is, to some extent, historical, going from “traditional” models and formalisms to more modern ones.
A cost-effective load-balancing policy for tile-based, massive multi-core packet processors
Authors: Musoll Enric 
Published: March 2010

Massive multi-core architectures provide a computation platform with high processing throughput, enabling the efficient processing of workloads with a significant degree of thread-level parallelism found in networking environments.Communication-centric workloads, like those in LAN and WAN environments, are fundamentally composed of sets of packets, named flows. The packets within a flow usually have dependencies among them, which reduce the amount of parallelism. However, packets of different flows tend to have very few or no dependencies among them, and thus can exploit thread-level parallelism to its fullest extent.Therefore, in massive tile-based multi-core architectures, it is important that the processing of the packets of a particular flow takes place in a set of cores physically close to each other to minimize the communication latency among those cores. Moreover, it is also desirable to spread out the processing of the different flows across all the cores of the processor in order to minimize the stress on a reduced number of cores, thus minimizing the potential for thermal hotspots and increasing the reliability of the processor. In addition, the burst-like nature of packet-based workloads render most of the cores idle most of the time, enabling large power savings by power gating these idle cores.This work presents a high-level study of the performance, power, and thermal behavior of tile-based architectures with a large number of cores executing flow-based packet workloads, and proposes a load-balancing policy of assigning packets to cores that minimizes the communication latency while featuring a hotspot-free thermal profile.
Online memory compression for embedded systems
Authors: Yang Lei , Dick Robert P. , Lekatsas Haris , Chakradhar Srimat 
Published: March 2010

Memory is a scarce resource during embedded system design. Increasing memory often increases packaging costs, cooling costs, size, and power consumption. This article presents CRAMES, a novel and efficient software-based RAM compression technique for embedded systems. The goal of CRAMES is to dramatically increase effective memory capacity without hardware or application design changes, while maintaining high performance and low energy consumption. To achieve this goal, CRAMES takes advantage of an operating system's virtual memory infrastructure by storing swapped-out pages in compressed format. It dynamically adjusts the size of the compressed RAM area, protecting applications capable of running without it from performance or energy consumption penalties. In addition to compressing working data sets, CRAMES also enables efficient in-RAM filesystem compression, thereby further increasing RAM capacity.
CRAMES was implemented as a loadable module for the Linux kernel and evaluated on a battery-powered embedded system. Experimental results indicate that CRAMES is capable of doubling the amount of RAM available to applications running on the original system hardware. Execution time and energy consumption for a broad range of examples are rarely affected. When physical RAM is reduced to 62.5% of its original quantity, CRAMES enables the target embedded system to support the same applications with reasonable performance and energy consumption penalties (on average 9.5% and 10.5%), while without CRAMES those applications either may not execute or suffer from extreme performance degradation or instability. In addition to presenting a novel framework for dynamic data memory compression and in-RAM filesystem compression in embedded systems, this work identifies the software-based compression algorithms that are most appropriate for use in low-power embedded systems.
Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis
Authors: Pomeroy IM , Jordan EK , Frank JA , Matthews PM , Esiri MM 
Published: March 2010

Background: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. Results: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6—36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. Conclusions: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.
Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans
Authors: Stanković Aleksandra , Dinčić Evica , Ristić Smiljana , Lovrečić Luca , Starčević Cizmarević Nada , Djurić Tamara , Sepčić Juraj , Kapović Miljenko , Raičević Ranko , Peterlin Borut , Alavantić Dragan , Živković Maja 
Published: March 2010

The interleukin 7 receptor alpha single nucleotide polymorphism rs6897932 was identified as a multiple sclerosis susceptibility-modifying polymorphism in genome-wide and gene scan studies, mainly in populations in western countries. The aim of this study was to investigate the association of interleukin 7 receptor alpha rs6897932 with multiple sclerosis in populations from the Western Balkans: Serbia, Croatia, and Slovenia. A total of 678 unrelated white patients and 597 unrelated, ethnically matched healthy controls were included in the study. Genotyping was performed by real-time polymerase chain reaction. We found no significant difference in genotype or allele frequencies between controls and patients with multiple sclerosis either separately in Serbian, Croatian, and Slovenian populations or in the whole sample from the Western Balkans. The odds ratio for multiple sclerosis in this study was 1.04 (0.86—1.25) for the C allele. It is known that demographic as well as environmental factors have a substantial role in multiple sclerosis development, as well as population genetic background. The results of this study indicate that other types of genome variants should be required for the development and/or progression of multiple sclerosis, which may vary among populations.
Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment
Authors: Mei Baisong , Pan Clark , Jiang Haiyan , Tjandra Hendri , Strauss Jonathan , Chen Yaoqi , Liu Tongyao , Zhang Xin , Severs Joanne , Newgren Jim , Chen Jianmin , Gu Jian-Ming , Subramanyam Babu , Fournel Michael A. , Pierce Glenn F. , Murphy John E. 
Published: March 2010

Abstract
A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A.
Whole genome analysis of p38 SAPK-mediated gene expression upon stress
Authors: Ferreiro Isabel , Joaquin Manel , Islam Abul , Gomez-Lopez Gonzalo , Barragan Montserrat , Lombardía Luís , Domínguez Orlando , Pisano David G , Lopez-Bigas Nuria , Nebreda Angel R , Posas Francesc 
Published: March 2010

Abstract

Background
Cells have the ability to respond and adapt to environmental changes through activation of stress-activated protein kinases (SAPKs). Although p38 SAPK signalling is known to participate in the regulation of gene expression little is known on the molecular mechanisms used by this SAPK to regulate stress-responsive genes and the overall set of genes regulated by p38 in response to different stimuli.

Results
Here, we report a whole genome expression analyses on mouse embryonic fibroblasts (MEFs) treated with three different p38 SAPK activating-stimuli, namely osmostress, the cytokine TNFα and the protein synthesis inhibitor anisomycin. We have found that the activation kinetics of p38α SAPK in response to these insults is different and also leads to a complex gene pattern response specific for a given stress with a restricted set of overlapping genes. In addition, we have analysed the contribution of p38α the major p38 family member present in MEFs, to the overall stress-induced transcriptional response by using both a chemical inhibitor (SB203580) and p38α deficient (p38α-/-) MEFs. We show here that p38 SAPK dependency ranged between 60% and 88% depending on the treatments and that there is a very good overlap between the inhibitor treatment and the ko cells. Furthermore, we have found that the dependency of SAPK varies depending on the time the cells are subjected to osmostress.

Conclusions
Our genome-wide transcriptional analyses shows a selective response to specific stimuli and a restricted common response of up to 20% of the stress up-regulated early genes that involves an important set of transcription factors, which might be critical for either cell adaptation or preparation for continuous extra-cellular changes. Interestingly, up to 85% of the up-regulated genes are under the transcriptional control of p38 SAPK. Thus, activation of p38 SAPK is critical to elicit the early gene expression program required for cell adaptation to stress.
Genome-wide transcription factor binding site/promoter databases for the analysis of gene sets and co-occurrence of transcription factor binding motifs
Authors: Veerla Srinivas , Ringnér Markus , Höglund Mattias 
Published: March 2010

Abstract

Background
The use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures.

Results
We develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 105 gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes.

Conclusions
The presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes.