bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anaplasma phagocytophilum Dihydrolipoamide Dehydrogenase 1 Affects Host-Derived Immunopathology during Microbial Colonization
Authors: Chen Gang , Severo Maiara S. , Sakhon Olivia S. , Choy Anthony , Herron Michael J. , Felsheim Roderick F. , Wiryawan Hilda , Liao Jiayu , Johns Jennifer L. , Munderloh Ulrike G. , Sutterwala Fayyaz S. , Kotsyfakis Michail , Pedra Joao H. F. 
Published: July 2012

ABSTRACT

Anaplasma phagocytophilum
is a tick-borne rickettsial pathogen that provokes an acute inflammatory response during mammalian infection. The illness caused by
A. phagocytophilum
, human granulocytic anaplasmosis, occurs irrespective of pathogen load and results instead from host-derived immunopathology. Thus, characterizing
A. phagocytophilum
genes that affect the inflammatory process is critical for understanding disease etiology. By using an
A. phagocytophilum
Himar1 transposon mutant library, we showed that a single transposon insertion into the
A. phagocytophilum
dihydrolipoamide dehydrogenase 1 gene (
lpda1
[
APH
_
0065
]) affects inflammation during infection.
A. phagocytophilum
lacking
lpda1
revealed enlargement of the spleen, increased splenic extramedullary hematopoiesis, and altered clinicopathological abnormalities during mammalian colonization. Furthermore, LPDA1-derived immunopathology was independent of neutrophil infection and correlated with enhanced reactive oxygen species from NADPH oxidase and nuclear factor (NF)-κB signaling in macrophages. Taken together, these findings suggest the presence of different signaling pathways in neutrophils and macrophages during
A. phagocytophilum
invasion and highlight the importance of LPDA1 as an immunopathological molecule.
Biofilm-Infected Intracerebroventricular Shunts Elicit Inflammation within the Central Nervous System
Authors: Snowden Jessica N. , Beaver Matt , Smeltzer Mark S. , Kielian Tammy 
Published: July 2012

ABSTRACT

Central nervous system catheter infections are a serious complication in the treatment of hydrocephalus. These infections are commonly caused by
Staphylococcus epidermidis
and
Staphylococcus aureus
, both known to form biofilms on the catheter surface. Our objective was to generate a novel murine model of central nervous system catheter-associated biofilm infection using a clinical
S. aureus
isolate and characterize the nature of the inflammatory response during biofilm growth. Silicone catheters were precoated with
S. aureus
to facilitate bacterial attachment, whereupon infected or sterile catheters were stereotactically inserted into the lateral ventricle of the brain in C57BL/6 mice and evaluated at regular intervals through day 21 postinsertion. Animals tolerated the procedure well, with no clinical signs of illness or bacterial growth seen in the control group. Bacterial titers associated with central nervous system catheters were significantly elevated compared to those from the surrounding parenchyma, consistent with biofilm formation and minimal planktonic spread of infection. Catheter-associated bacterial burdens progressively increased, with maximal colonization achieved at day 7 postinfection. Analysis of inflammatory infiltrates by fluorescence-activated cell sorting (FACS) revealed significant macrophage and neutrophil influx, which peaked at days 3 and 5 to 7, respectively. In contrast, there were no detectable immune infiltrates associated with tissues surrounding sterile catheters. Biofilm infection led to significant increases in chemokine (CXCL1 and CCL2) and proinflammatory cytokine (interleukin 17 [IL-17]) expression in tissues surrounding infected central nervous system catheters. Based on these results, we propose this approach is a valid animal model for further investigations of catheter-associated central nervous system shunt infections.
Hcp2, a Secreted Protein of the Phytopathogen Pseudomonas syringae pv. Tomato DC3000, Is Required for Fitness for Competition against Bacteria and Yeasts
Authors: Haapalainen Minna , Mosorin Hanna , Dorati Federico , Wu Ru-Fen , Roine Elina , Taira Suvi , Nissinen Riitta , Mattinen Laura , Jackson Robert , Pirhonen Minna , Lin Nai-Chun 
Published: June 2012

ABSTRACTWhen analyzing the secretome of the plant pathogenPseudomonas syringaepv. tomato DC3000, we identified hemolysin-coregulated protein (Hcp) as one of the secreted proteins. Hcp is assumed to be an extracellular component of the type VI secretion system (T6SS). Two copies ofhcpgenes are present in theP. syringaepv. tomato DC3000 genome,hcp1(PSPTO_2539) andhcp2(PSPTO_5435). We studied the expression patterns of thehcpgenes and tested the fitness ofhcpknockout mutants in host plant colonization and in intermicrobial competition. We found that thehcp2gene is expressed most actively at the stationary growth phase and that the Hcp2 protein is secreted via the T6SS and appears in the culture medium as covalently linked dimers. Expression ofhcp2is not inducedin plantaand does not contribute to virulence in or colonization of tomato orArabidopsisplants. Instead,hcp2is required for survival in competition with enterobacteria and yeasts, and its function is associated with the suppression of the growth of these competitors. This is the first report on bacterial T6SS-associated genes functioning in competition with yeast. Our results suggest that the T6SS ofP. syringaemay play an important role in bacterial fitness, allowing this plant pathogen to survive under conditions where it has to compete with other microorganisms for resources.
Transcriptional Cross Talk within themar-sox-robRegulon in Escherichia coli Is Limited to therobandmarRABOperons
Authors: Chubiz Lon M. , Glekas George D. , Rao Christopher V. 
Published: June 2012

ABSTRACTBacteria possess multiple mechanisms to survive exposure to various chemical stresses and antimicrobial compounds. In the enteric bacteriumEscherichia coli, three homologous transcription factors—MarA, SoxS, and Rob—play a central role in coordinating this response. Three separate systems are known to regulate the expression and activities of MarA, SoxS, and Rob. However, a number of studies have shown that the three do not function in isolation but rather are coregulated through transcriptional cross talk. In this work, we systematically investigated the extent of transcriptional cross talk in themar-sox-robregulon. While the three transcription factors were found to have the potential to regulate each other's expression when ectopically expressed, the only significant interactions observed under physiological conditions were betweenmarandrobsystems. MarA, SoxS, and Rob all activate themarRABpromoter, more so when they are induced by their respective inducers: salicylate, paraquat, and decanoate. None of the three proteins affects thesoxSpromoter, though unexpectedly, it was mildly repressed by decanoate by an unknown mechanism. SoxS is the only one of the three proteins to repress therobpromoter. Surprisingly, salicylate somewhat activates transcription ofrob, while decanoate represses it a bit. Rob, in turn, activates not only its downstream promoters in response to salicylate but also themarRABpromoter. These results demonstrate that themarandrobsystems function together in response to salicylate.
Fatty Acid Biosynthesis in Pseudomonas aeruginosa Is Initiated by the FabY Class of β-Ketoacyl Acyl Carrier Protein Synthases
Authors: Yuan Yanqiu , Sachdeva Meena , Leeds Jennifer A. , Meredith Timothy C. 
Published: June 2012

ABSTRACT

The prototypical type II fatty acid synthesis (FAS) pathway in bacteria utilizes two distinct classes of β-ketoacyl synthase (KAS) domains to assemble long-chain fatty acids, the KASIII domain for initiation and the KASI/II domain for elongation. The central role of FAS in bacterial viability and virulence has stimulated significant effort toward developing KAS inhibitors, particularly against the KASIII domain of the β-acetoacetyl-acyl carrier protein (ACP) synthase FabH. Herein, we show that the opportunistic pathogen
Pseudomonas aeruginosa
does not utilize a FabH ortholog but rather a new class of divergent KAS I/II enzymes to initiate the FAS pathway. When a
P. aeruginosa
cosmid library was used to rescue growth in a
fabH
downregulated strain of
Escherichia coli
, a single unannotated open reading frame, PA5174, complemented
fabH
depletion. While deletion of all four KASIII domain-encoding genes in the same
P. aeruginosa
strain resulted in a wild-type growth phenotype, deletion of PA5174 alone specifically attenuated growth due to a defect in
de novo
FAS. Siderophore secretion and quorum-sensing signaling, particularly in the
rhl
and
Pseudomonas
quinolone signal (PQS) systems, was significantly muted in the absence of PA5174. The defect could be repaired by intergeneric complementation with
E. coli fabH
. Characterization of recombinant PA5174 confirmed a preference for short-chain acyl coenzyme A (acyl-CoA) substrates, supporting the identification of PA5174 as the predominant enzyme catalyzing the condensation of acetyl coenzyme A with malonyl-ACP in
P. aeruginosa
. The identification of the functional role for PA5174 in FAS defines the new FabY class of β-ketoacyl synthase KASI/II domain condensation enzymes.
Mortality with congenital heart defects in England and Wales, 1959–2009: exploring technological change through period and birth cohort analysis
Authors: Knowles Rachel L , Bull Catherine , Wren Christopher , Dezateux Carol 
Published: June 2012

BackgroundTechnological advances in surgery, intensive care and medical support have led to substantial decrease in mortality for children with congenital heart defects (CHDs) over the last 50 years.MethodsUsing routinely-collected mortality and population data for England and Wales from 1959 to 2009, the authors investigated age, period and birth cohort trends in child mortality attributable to CHDs.ResultsThe total number of deaths with CHDs at all ages between 1959 and 2009 was 61 903 (33 929 (55%) males). Absolute numbers of CHD-related deaths in children (under age 15 years) fell from 1460 in 1959 to 154 in 2009. Infants (aged under 1 year) comprised over 60% of all deaths due to CHD during the 5-year period 1959–1963, but this fell to 22% by 2004–2008. Age-standardised death rates have declined for both sexes but, despite narrowing sex differences, males continue to have higher death rates. Successive birth cohorts have experienced improved death rates in the first year of life; however, declining mortality across all age-groups has only been observed for birth cohorts originating after 1989. Poisson regression modelling predicts continuing generational decline in mortality.ConclusionsDeath rates attributable to CHDs have fallen dramatically with advances in paediatric cardiac surgery and intensive care, largely due to decreased mortality in infants aged under 1 year. Initially, mortality in later childhood rose as infant deaths fell, suggesting death was delayed beyond infancy. Children born within the last 20 years experienced lower mortality throughout childhood.
Paravirtualizing Linux in a real-time hypervisor
Authors: Legout Vincent , Lemerre Matthieu 
Published: July 2012

This paper describes a new hypervisor built to run Linux in a virtual machine. This hypervisor is built inside Anaxagoros, a real-time microkernel designed to execute safely hard real-time and non real-time tasks. This allows the execution of hard real-time tasks in parallel with Linux virtual machines without interfering with the execution of the real-time tasks.
We implemented this hypervisor and compared performances with other virtualization techniques. Our hypervisor does not yet provide high performance but gives correct results and we believe the design is solid enough to guarantee solid performances with its future implementation.
Bipartite graph structures for efficient balancing of heterogeneous loads
Authors: Leconte Mathieu , Lelarge Marc , Massoulié Laurent 
Published: July 2012

This paper considers large scale distributed content service platforms, such as peer-to-peer video-on-demand systems. Such systems feature two basic resources, namely storage and bandwidth. Their efficiency critically depends on two factors: (i) content replication within servers, and (ii) how incoming service requests are matched to servers holding requested content. To inform the corresponding design choices, we make the following contributions. We first show that, for underloaded systems, so-called proportional content placement with a simple greedy strategy for matching requests to servers ensures full system efficiency provided storage size grows logarithmically with the system size. However, for constant storage size, this strategy undergoes a phase transition with severe loss of efficiency as system load approaches criticality.
To better understand the role of the matching strategy in this performance degradation, we characterize the asymptotic system efficiency under an optimal matching policy. Our analysis shows that -in contrast to greedy matching- optimal matching incurs an inefficiency that is exponentially small in the server storage size, even at critical system loads. It further allows a characterization of content replication policies that minimize the inefficiency. These optimal policies, which differ markedly from proportional placement, have a simple structure which makes them implementable in practice.
On the methodological side, our analysis of matching performance uses the theory of local weak limits of random graphs, and highlights a novel characterization of matching numbers in bipartite graphs, which may both be of independent interest.
Workload analysis of a large-scale key-value store
Authors: Atikoglu Berk , Xu Yuehai , Frachtenberg Eitan , Jiang Song , Paleczny Mike 
Published: July 2012

Key-value stores are a vital component in many scale-out enterprises, including social networks, online retail, and risk analysis. Accordingly, they are receiving increased attention from the research community in an effort to improve their performance, scalability, reliability, cost, and power consumption. To be effective, such efforts require a detailed understanding of realistic key-value workloads. And yet little is known about these workloads outside of the companies that operate them. This paper aims to address this gap.
To this end, we have collected detailed traces from Facebook's Memcached deployment, arguably the world's largest. The traces capture over 284 billion requests from five different Memcached use cases over several days. We analyze the workloads from multiple angles, including: request composition, size, and rate; cache efficacy; temporal patterns; and application use cases. We also propose a simple model of the most representative trace to enable the generation of more realistic synthetic workloads by the community.
Our analysis details many characteristics of the caching workload. It also reveals a number of surprises: a GET/SET ratio of 30:1 that is higher than assumed in the literature; some applications of Memcached behave more like persistent storage than a cache; strong locality metrics, such as keys accessed many millions of times a day, do not always suffice for a high hit rate; and there is still room for efficiency and hit rate improvements in Memcached's implementation. Toward the last point, we make several suggestions that address the exposed deficiencies.
Does lean imply green?
Authors: Bhattacharya Suparna , Rajamani Karthick , Gopinath K. , Gupta Manish 
Published: July 2012

The presence of software bloat in large flexible software systems can hurt energy efficiency. However, identifying and mitigating bloat is fairly effort intensive. To enable such efforts to be directed where there is a substantial potential for energy savings, we investigate the impact of bloat on power consumption under different situations. We conduct the first systematic experimental study of the joint power-performance implications of bloat across a range of hardware and software configurations on modern server platforms. The study employs controlled experiments to expose different effects of a common type of Java runtime bloat, excess temporary objects, in the context of the SPECPower_ssj2008 workload. We introduce the notion of equi-performance power reduction to characterize the impact, in addition to peak power comparisons. The results show a wide variation in energy savings from bloat reduction across these configurations. Energy efficiency benefits at peak performance tend to be most pronounced when bloat affects a performance bottleneck and non-bloated resources have low energy-proportionality. Equi-performance power savings are highest when bloated resources have a high degree of energy proportionality.
We develop an analytical model that establishes a general relation between resource pressure caused by bloat and its energy efficiency impact under different conditions of resource bottlenecks and energy proportionality. Applying the model to different "what-if" scenarios, we predict the impact of bloat reduction and corroborate these predictions with empirical observations. Our work shows that the prevalent software-only view of bloat is inadequate for assessing its power-performance impact and instead provides a full systems approach for reasoning about its implications.
Modeling randomness in network traffic
Authors: Laner Markus , Svoboda Philipp , Rupp Markus 
Published: July 2012

A continuous challenge in the field of network traffic modeling is to map recorded traffic onto parameters of random processes, in order to enable simulations of the respective traffic. A key element thereof is a convenient model which is simple, yet, captures the most relevant statistics.
This work aims to find such a model which, more precisely, enables the generation of multiple random processes with arbitrary but jointly characterized distributions, auto-correlation functions and cross-correlations. Hence, we present the definition of a novel class of models, the derivation of a respective closed-form analytical representation and its application on real network traffic.
Our modeling approach comprises: (i) generating statistical dependent Gaussian random processes, (ii) introducing auto-correlation to each process with a linear filter and, (iii) transforming them sample-wise by real-valued polynomial functions in order to shape their distributions. This particular structure allows to split the parameter fitting problem into three independent parts, each of which solvable by standard methods. Therefore, it is simple and straightforward to fit the model to measurement data.
Mithramycin Represses Basal and Cigarette Smoke–Induced Expression ofABCG2and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells
Authors: Zhang Mary , Mathur Aarti , Zhang Yuwei , Xi Sichuan , Atay Scott , Hong Julie A. , Datrice Nicole , Upham Trevor , Kemp Clinton D. , Ripley R. Taylor , Wiegand Gordon , Avital Itzak , Fetsch Patricia , Mani Haresh , Zlott Daniel , Robey Robert , Bates Susan E. , Li Xinmin , Rao Mahadev , Schrump David S. 
Published: July 2012

AbstractCigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell–related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies. Cancer Res; 72(16); 4178–92. ©2012 AACR.
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
Authors: Cervantes Andres , Elez Elena , Roda Desamparados , Ecsedy Jeffrey , Macarulla Teresa , Venkatakrishnan Karthik , Roselló Susana , Andreu Jordi , Jung JungAh , Sanchis-Garcia Juan Manuel , Piera Adelaida , Blasco Inma , Maños Laura , Pérez-Fidalgo José-Alejandro , Fingert Howard , Baselga Jose , Tabernero Josep 
Published: July 2012

AbstractPurpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.