bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Lysozyme-Like Protein in Brucella abortus Is Involved in the Early Stages of Intracellular Replication
Authors: Del Giudice Mariela G. , Ugalde Juan E. , Czibener Cecilia 
Published: January 2013

ABSTRACT

Secretion of proteins in Gram-negative bacteria is a high-energy-consuming process that requires translocation across two membranes and a periplasmic space composed of a mesh-like layer, the peptidoglycan. To achieve this, bacteria have evolved complex secretion systems that cross these barriers, and in many cases there are specific peptidoglycanases that degrade the peptidoglycan to allow the proper assembly of the secretion machinery. We describe here the identification and characterization of a muramidase in
Brucella abortus
that participates in the intracellular multiplication in professional and nonprofessional phagocytes. We demonstrated that this protein has peptidoglycanase activity, that a strain with a clean deletion of the gene displayed a defect in the early stages of the intracellular multiplication curve, and that this is dependent on the lytic activity. While neither the attachment nor the invasion of the strain was affected, we demonstrated that it had a defect in excluding the lysosomal marker LAMP-1 but not in acquiring the reticulum endoplasmic marker calnexin, indicating that the gene participates in the early stages of the intracellular trafficking but not in the establishment of the replicative niche. Analysis of the assembly status and functionality of the VirB secretion apparatus indicated that the mutant has affected the proper function of this central virulence factor.
Increased Accumulation of Regulatory Granulocytic Myeloid Cells in Mannose Receptor C Type 1-Deficient Mice Correlates with Protection in a Mouse Model of Neurocysticercosis
Authors: Mishra Pramod Kumar , Morris Elizabeth G. , Garcia Jenny A. , Cardona Astrid E. , Teale Judy M. 
Published: January 2013

ABSTRACTNeurocysticercosis (NCC) is a central nervous system (CNS) infection caused by the metacestode stage of the parasiteTaenia solium. During NCC, the parasites release immunodominant glycan antigens in the CNS environment, invoking immune responses. The majority of the associated pathogenesis is attributed to the immune response against the parasites. Glycans from a number of pathogens, including helminths, act as pathogen-associated molecular pattern molecules (PAMPs), which are recognized by pattern recognition receptors (PRRs) known as C-type lectin receptors (CLRs). Using a mouse model of NCC by infection with the related parasiteMesocestoides corti, we have investigated the role of mannose receptor C type 1 (MRC1), a CLR which recognizes high-mannose-containing glycan antigens. Here we show that MRC1−/−mice exhibit increased survival times after infection compared with their wild-type (WT) counterparts. The decreased disease severity correlates with reduced levels of expression of markers implicated in NCC pathology, such as interleukin-1β (IL-1β), IL-6, CCL5, and matrix metalloproteinase 9 (MMP9), in addition to induction of an important repair marker, fibroblast growth factor 2 (FGF2). Furthermore, the immune cell subsets that infiltrate the brain of MRC1−/−mice are dramatically altered and characterized by reduced numbers of T cells and the accumulation of granulocytic cells with an immune phenotype resembling granulocytic myeloid-dependent suppressor cells (gMDSCs). The results suggest that MRC1 plays a critical role in myeloid plasticity, which in turn affects the adaptive immune response and immunopathogenesis during murine NCC.
Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia
Authors: Linke Michael J. , Ashbaugh Alan , Collins Margaret S. , Lynch Keeley , Cushion Melanie T. 
Published: January 2013

ABSTRACTPneumocystisspp. are yeast-like fungi that cause pneumocystis pneumonia (PcP) in immunocompromised individuals and exacerbate chronic lung diseases in immunocompetent individuals. ThePneumocystislife cycle includes trophic forms and asci (cyst forms). The cell walls ofPneumocystisasci contain β-1,3-d-glucan, and treatment of PcP with β-1,3-d-glucan synthase inhibitors, such as anidulafungin, results in depletion of asci, but not trophic forms. The pulmonary host response during immune reconstitution (IR)-mediated clearance of PcP in anidulafungin-treated and untreated mice was characterized to identify ascus-specific responses. During IR, similar numbers of trophic forms were present in the anidulafungin-treated and untreated mice; however, asci were only present in the untreated mice. IR resulted in a significant reduction of trophic forms from the lungs in both groups and asci in the untreated group. The presence of asci in untreated mice correlated with increased β-glucan content in the lungs. The untreated mice mounted immune responses associated with a deleterious host inflammatory response, including increased CD8+T cell influx and expression of macrophage inflammatory response markers. A more robust cellular response was also observed in the untreated mice, with increased numbers of macrophages and neutrophils that were associated with greater lung damage. Markers of a Th17 response were also elevated in the untreated mice. These results suggest that the host mounts unique responses to asci and trophic forms. That these 2 life cycle stages provoked distinct host response profiles has significant implications for clearance and interpretation of the host immune responses to PcP.
Vaccine Protection against Bacillus cereus-Mediated Respiratory Anthrax-Like Disease in Mice
Authors: Oh So-Young , Maier Hannah , Schroeder Jay , Richter G. Stefan , Elli Derek , Musser James M. , Quenee Lauriane E. , Missiakas Dominique M. , Schneewind Olaf 
Published: January 2013

ABSTRACT

Bacillus cereus
strains harboring a pXO1-like virulence plasmid cause respiratory anthrax-like disease in humans, particularly in welders. We developed mouse models for intraperitoneal as well as aerosol challenge with spores of
B. cereus
G9241, harboring pBCXO1 and pBC218 virulence plasmids. Compared to wild-type
B. cereus
G9241, spores with a deletion of the pBCXO1-carried protective antigen gene (
pagA1
) were severely attenuated, whereas spores with a deletion of the pBC218-carried protective antigen homologue (
pagA2
) were not. Anthrax vaccine adsorbed (AVA) immunization raised antibodies that bound and neutralized the
pagA1
-encoded protective antigen (PA1) but not the PA2 orthologue encoded by
pagA2
. AVA immunization protected mice against a lethal challenge with spores from
B. cereus
G9241 or
B. cereus
Elc4, a strain that had been isolated from a fatal case of anthrax-like disease. As the pathogenesis of
B. cereus
anthrax-like disease in mice is dependent on
pagA1
and PA-neutralizing antibodies provide protection, AVA immunization may also protect humans from respiratory anthrax-like death.
Anaphylaxis to ibuprofen in a 12-year-old boy
Authors: Kay Emily , Ben-Shoshan Moshe 
Published: January 2013

Non-steroidal anti-inflammatory (NSAIDs) drugs are a group of medications acting through cyclooxygenase (COX-1) and cyclooxygenase (COX-2) enzymes inhibition. Hypersensitivity reactions to NSAIDs, although not rare, are poorly characterised and often go undiagnosed especially in children. We present in this paper a case of ibuprofen anaphylaxis that exemplifies the challenges involved in diagnosis and management of hypersensitivity reactions to NSAIDs.
COMPLEX DYNAMICS IN A PENDULUM EQUATION WITH A PHASE SHIFT
Authors: CHEN XIANWEI , FU XIANGLING , JING ZHUJUN 
Published: January 2013

Pendulum equation with a phase shift, parametric and external excitations is investigated in detail. By applying Melnikov's method, we prove the criteria of existence of chaos under periodic perturbation. Numerical simulations, including bifurcation diagrams of fixed points, bifurcation diagrams of the system in three- and two-dimensional spaces, homoclinic and heteroclinic bifurcation surfaces, Maximum Lyapunov exponents (ML), Fractal Dimension (FD), phase portraits, Poincaré maps are plotted to illustrate the theoretical analysis, and to expose the complex dynamical behaviors including the onset of chaos, sudden conversion of chaos to period orbits, interior crisis, periodic orbits, the symmetry-breaking of periodic orbits, jumping behaviors of periodic orbits, new chaotic attractors including two-three-four-five-six-eight-band chaotic attractors, nonchaotic attractors, period-doubling bifurcations from period-1, 2, 3 and 5 to chaos, reverse period-doubling bifurcations from period-3 and 5 to chaos, and so on.By applying the second-order averaging method and Melnikov's method, we obtain the criteria of existence of chaos in an averaged system under quasi-periodic perturbation for Ω = nω + ϵν, n = 1, 2, 4, but cannot prove the criteria of existence of chaos in the averaged system under quasi-periodic perturbation for Ω = nω + ϵν, n = 3, 5 – 15, by Melnikov's method, where ν is not rational to ω. By using numerical simulation, we have verified our theoretical analysis and studied the effect of parameters of the original system on the dynamical behaviors generated under quasi-periodic perturbations, such as the onset of chaos, jumping behaviors of quasi-periodic orbits, interleaving occurrence of chaotic behaviors and nonchaotic behaviors, interior crisis, quasi-periodic orbits to chaotic attractors, sudden conversion of chaos to quasi-periodic behaviors, nonchaotic attractors, and so on. However, we did not find period-doubling and reverse period-doubling bifurcations. We found that the dynamical behaviors under quasi-periodic perturbations are different from that under periodic perturbations, and the dynamics with a phase shift are different from the dynamics without phase shift.
Accelerating throughput-aware runtime mapping for heterogeneous MPSoCs
Authors: Singh Amit Kumar , Kumar Akash , Srikanthan Thambipillai 
Published: January 2013

Modern embedded systems need to support multiple time-constrained multimedia applications that often employ multiprocessor-systems-on-chip (MPSoCs). Such systems need to be optimized for resource usage and energy consumption. It is well understood that a design-time approach cannot provide timing guarantees for all the applications due to its inability to cater for dynamism in applications. However, a runtime approach consumes large computation requirements at runtime and hence may not lend well to constrained-aware mapping.
In this article, we present a hybrid approach for efficient mapping of applications in such systems. For each application to be supported in the system, the approach performs extensive design-space exploration (DSE) at design time to derive multiple design points representing throughput and energy consumption at different resource combinations. One of these points is selected at runtime efficiently, depending upon the desired throughput while optimizing for energy consumption and resource usage. While most of the existing DSE strategies consider a fixed multiprocessor platform architecture, our DSE considers a generic architecture, making DSE results applicable to any target platform. All the compute-intensive analysis is performed during DSE, which leaves for minimum computation at runtime. The approach is capable of handling dynamism in applications by considering their runtime aspects and providing timing guarantees.
The presented approach is used to carry out a DSE case study for models of real-life multimedia applications: H.263 decoder, H.263 encoder, MPEG-4 decoder, JPEG decoder, sample rate converter, and MP3 decoder. At runtime, the design points are used to map the applications on a heterogeneous MPSoC. Experimental results reveal that the proposed approach provides faster DSE, better design points, and efficient runtime mapping when compared to other approaches. In particular, we show that DSE is faster by 83% and runtime mapping is accelerated by 93% for some cases. Further, we study the scalability of the approach by considering applications with large numbers of tasks.
Delicate Balance among Three Types of T Cells in Concurrent Regulation of Tumor Immunity
Authors: Izhak Liat , Ambrosino Elena , Kato Shingo , Parish Stanley T. , O'Konek Jessica J. , Weber Hannah , Xia Zheng , Venzon David , Berzofsky Jay A. , Terabe Masaki 
Published: January 2013

Abstract
The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here, we addressed this question for regulatory T cells (Treg) and type II natural killer T (NKT) cells in syngeneic models of colorectal and renal cancer. In mice with both type I and II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Tregs as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in 3 ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we showed that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As patients with cancer often have deficient type I NKT cell function, managing this delicate balance among 3 T-cell subsets may be critical for the success of immunotherapy for human cancer. Cancer Res; 73(5); 1514–23. ©2012 AACR.
Mixed Lineage Kinase MLK4 Is Activated in Colorectal Cancers Where It Synergistically Cooperates with Activated RAS Signaling in Driving Tumorigenesis
Authors: Martini Miriam , Russo Mariangela , Lamba Simona , Vitiello Elisa , Crowley Emily Hannah , Sassi Francesco , Romanelli Davide , Frattini Milo , Marchetti Antonio , Bardelli Alberto 
Published: January 2013

Abstract
Colorectal cancers (CRC) are commonly classified into those with microsatellite instability and those that are microsatellite stable (MSS) but chromosomally unstable. The latter are characterized by poor prognosis and remain largely intractable at the metastatic stage. Comprehensive mutational analyses have revealed that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in MSS CRC with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized previously and the relevance of MLK4 somatic mutations in oncogenesis has not been established. We report that MLK4-mutated alleles in CRC are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines. Gene expression silencing or targeted knockout of MLK4 impairs the oncogenic properties of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograft models. In establishing the role of MLK4 in intracellular signaling, we show it directly phosphorylates MEK1 (MAP2K1) and that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells. These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated CRCs and may provide a new opportunity for targeting such recalcitrant tumors. Cancer Res; 73(6); 1912–21. ©2012 AACR.
Genetic Amplification of the NOTCH Modulator LNX2 Upregulates the WNT/β-Catenin Pathway in Colorectal Cancer
Authors: Camps Jordi , Pitt Jason J. , Emons Georg , Hummon Amanda B. , Case Chanelle M. , Grade Marian , Jones Tamara L. , Nguyen Quang T. , Ghadimi B. Michael , Beissbarth Tim , Difilippantonio Michael J. , Caplen Natasha J. , Ried Thomas 
Published: January 2013

AbstractChromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification of the oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis of colorectal carcinomas that integrated genomic copy number changes and gene expression profiles. This analysis revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains of which occur often in colorectal cancers (CRC). RNA interference (RNAi)–mediated silencing identified eight candidates whose loss-of-function reduced cell viability 20% or more in CRC cell lines. The functional space of the genes NUPL1, LNX2, POLR1D, POMP, SLC7A1, DIS3, KLF5, and GPR180 was established by global expression profiling after RNAi exposure. One candidate, LNX2, not previously known as an oncogene, was involved in regulating NOTCH signaling. Silencing LNX2 reduced NOTCH levels but also downregulated the transcription factor TCF7L2 and markedly reduced WNT signaling. LNX2 overexpression and chromosome 13 amplification therefore constitutively activates the WNT pathway, offering evidence of an aberrant NOTCH–WNT axis in CRC. Cancer Res; 73(6); 2003–13. ©2012 AACR.
Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer
Authors: Rafiq Sajjad , Tapper William , Collins Andrew , Khan Sofia , Politopoulos Ioannis , Gerty Sue , Blomqvist Carl , Couch Fergus J. , Nevanlinna Heli , Liu Jianjun , Eccles Diana 
Published: January 2013

Abstract
Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10−7 was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ≤ 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33–1.96; P = 9.5 × 10−7]. Four further associations at or close to the PBX1, RORα, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10−6). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10−4 and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis. Cancer Res; 73(6); 1883–91. ©2012 AACR.
xCT Inhibition Depletes CD44v-Expressing Tumor Cells That Are Resistant to EGFR-Targeted Therapy in Head and Neck Squamous Cell Carcinoma
Authors: Yoshikawa Momoko , Tsuchihashi Kenji , Ishimoto Takatsugu , Yae Toshifumi , Motohara Takeshi , Sugihara Eiji , Onishi Nobuyuki , Masuko Takashi , Yoshizawa Kunio , Kawashiri Shuichi , Mukai Makio , Asoda Seiji , Kawana Hiromasa , Nakagawa Taneaki , Saya Hideyuki , Nagano Osamu 
Published: January 2013

Abstract
The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy. Cancer Res; 73(6); 1855–66. ©2012 AACR.
A 13-Gene Signature Prognostic of HPV-Negative OSCC: Discovery and External Validation
Authors: Lohavanichbutr Pawadee , Méndez Eduardo , Holsinger F. Christopher , Rue Tessa C. , Zhang Yuzheng , Houck John , Upton Melissa P. , Futran Neal , Schwartz Stephen M. , Wang Pei , Chen Chu 
Published: January 2013

Abstract
Purpose: To identify a prognostic gene signature for patients with human papilloma virus (HPV)–negative oral squamous cell carcinomas (OSCC).
Experimental Design: Two gene expression datasets were used: a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA; n = 97) and a validation dataset from the MD Anderson Cancer Center (MDACC, Houston, TX; n = 71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in patients with OSCCs to identify a prognostic model specific for patients with high-risk HPV-negative OSCCs. The models were tested with the MDACC dataset using a receiver operating characteristic (ROC) analysis.
Results: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (±SE) of patients with high-risk scores was 47.1% (±9.24%) compared with 6.35% (±4.42) for patients with low-risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score [0.78; 95% confidence interval (CI), 0.74–0.86] and risk score plus tumor stage (0.79; 95% CI, 0.75–0.87) were substantially higher than for the model with tumor stage (0.54; 95% CI, 0.48–0.62).
Conclusions: We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of patients with HPV-negative OSCCs. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted. Clin Cancer Res; 19(5); 1197–203. ©2012 AACR.