bluuebunny/crossref_metadata_2025_split huggingface dataset:
Killing of Candida albicans Filaments by Salmonella enterica Serovar Typhimurium Is Mediated by sopB Effectors, Parts of a Type III Secretion System
Authors: Kim Younghoon , Mylonakis Eleftherios 
Published: April 2011

ABSTRACT

Although bacterial-fungal interactions shape microbial virulence during polymicrobial infections, only a limited number of studies have evaluated this interaction on a genetic level. We report here that one interaction is mediated by
sopB
, an effector of a type III secretion system (TTSS) of
Salmonella enterica
serovar Typhimurium. In these studies, we screened 10 TTSS effector-related mutants and determined their role in the killing of
C. albicans
filaments
in vitro
during coinfection in planktonic environments. We found that deleting the
sopB
gene (which encodes inositol phosphatase) was associated with a significant decrease in
C. albicans
killing at 25°C after 5 days, similar to that caused by the deletion of
sipB
(which encodes TTSS translocation machinery components). The
sopB
deletion dramatically influenced the killing of
C. albicans
filaments. It was associated with repressed filamentation in the
Caenorhabditis elegans
model of
C. albicans
-
S.
Typhimurium coinfection, as well as with biofilm formation by
C. albicans
. We confirmed that SopB translocated to fungal filaments through SipB during coinfection. Using quantitative real-time PCR assays, we found that the
Candida
supernatant upregulated the
S.
Typhimurium genes associated with
C. albicans
killing (
sopB
and
sipB
). Interestingly, the s
opB
effector negatively regulated the transcription of
CDC42
, which is involved in fungal viability. Taken together, these results indicate that specific TTSS effectors, including SopB, play a critical role in bacterial-fungal interactions and are important to
S.
Typhimurium in order to selectively compete with fungal pathogens. These findings highlight a new role for TTSS of
S.
Typhimurium in the intestinal tract and may further explain the evolution and maintenance of these traits.
The Paf1 Complex Represses
ARG1
Transcription in Saccharomyces cerevisiae by Promoting Histone Modifications
Authors: Crisucci Elia M. , Arndt Karen M. 
Published: April 2011

ABSTRACT

The conserved multifunctional Paf1 complex is important for the proper transcription of numerous genes, and yet the exact mechanisms by which it controls gene expression remain unclear. While previous studies indicate that the Paf1 complex is a positive regulator of transcription, the repression of many genes also requires the Paf1 complex. In this study we used
ARG1
as a model gene to study transcriptional repression by the Paf1 complex in
Saccharomyces cerevisiae
. We found that several members of the Paf1 complex contribute to
ARG1
repression and that the complex localizes to the
ARG1
promoter and coding region in repressing conditions, which is consistent with a direct repressive function. Furthermore, Paf1 complex-dependent histone modifications are enriched at the
ARG1
locus in repressing conditions, and histone H3 lysine 4 methylation contributes to
ARG1
repression. Consistent with previous reports, histone H2B monoubiquitylation, the mark upstream of histone H3 lysine 4 methylation, is also important for
ARG1
repression. To begin to identify the mechanistic basis for Paf1 complex-mediated repression of
ARG1
, we focused on the Rtf1 subunit of the complex. Through an analysis of
RTF1
mutations that abrogate known Rtf1 activities, we found that Rtf1 mediates
ARG1
repression primarily by facilitating histone modifications. Other members of the Paf1 complex, such as Paf1, appear to repress
ARG1
through additional mechanisms. Together, our results suggest that Rtf1-dependent histone H2B ubiquitylation and H3 K4 methylation repress
ARG1
expression and that histone modifications normally associated with active transcription can occur at repressed loci and contribute to transcriptional repression.
Self-Induction of
a
/
a
or α/α Biofilms in Candida albicans Is a Pheromone-Based Paracrine System Requiring Switching
Authors: Yi Song , Sahni Nidhi , Daniels Karla J. , Lu Kevin L. , Huang Guanghua , Srikantha Thyagarajan , Soll David R. 
Published: April 2011

ABSTRACT

Like
MTL
-heterozygous (
a
/α) cells, white
MTL
-homozygous (
a
/
a
or α/α) cells of
Candida albicans
, to which a minority of opaque cells of opposite mating type have been added, form thick, robust biofilms. The latter biofilms are uniquely stimulated by the pheromone released by opaque cells and are regulated by the mitogen-activated protein kinase signal transduction pathway. However, white
MTL
-homozygous cells, to which opaque cells of opposite mating type have not been added, form thinner biofilms. Mutant analyses reveal that these latter biofilms are self-induced. Self-induction of
a
/
a
biofilms requires expression of the α-receptor gene
STE2
and the α-pheromone gene
MF
α, and self-induction of α/α biofilms requires expression of the
a
-receptor gene
STE3
and the
a
-pheromone gene
MF
a
. In both cases, deletion of
WOR1
, the master switch gene, blocks cells in the white phenotype and biofilm formation, indicating that self-induction depends upon low frequency switching from the white to opaque phenotype. These results suggest a self-induction scenario in which minority opaque
a
/
a
cells formed by switching secrete, in a mating-type-nonspecific fashion, α-pheromone, which stimulates biofilm formation through activation of the α-pheromone receptor of majority white
a
/
a
cells. A similar scenario is suggested for a white α/α cell population, in which minority opaque α/α cells secrete
a
-pheromone. This represents a paracrine system in which one cell type (opaque) signals a second highly related cell type (white) to undergo a complex response, in this case the formation of a unisexual white cell biofilm.
Tungsten and Molybdenum Regulation of Formate Dehydrogenase Expression in Desulfovibrio vulgaris Hildenborough
Authors: da Silva Sofia M. , Pimentel Catarina , Valente Filipa M. A. , Rodrigues-Pousada Claudina , Pereira Inês A. C. 
Published: April 2011

ABSTRACT

Formate is an important energy substrate for sulfate-reducing bacteria in natural environments, and both molybdenum- and tungsten-containing formate dehydrogenases have been reported in these organisms. In this work, we studied the effect of both metals on the levels of the three formate dehydrogenases encoded in the genome of
Desulfovibrio vulgaris
Hildenborough, with lactate, formate, or hydrogen as electron donors. Using Western blot analysis, quantitative real-time PCR, activity-stained gels, and protein purification, we show that a metal-dependent regulatory mechanism is present, resulting in the dimeric FdhAB protein being the main enzyme present in cells grown in the presence of tungsten and the trimeric FdhABC
3
protein being the main enzyme in cells grown in the presence of molybdenum. The putatively membrane-associated formate dehydrogenase is detected only at low levels after growth with tungsten. Purification of the three enzymes and metal analysis shows that FdhABC
3
specifically incorporates Mo, whereas FdhAB can incorporate both metals. The FdhAB enzyme has a much higher catalytic efficiency than the other two. Since sulfate reducers are likely to experience high sulfide concentrations that may result in low Mo bioavailability, the ability to use W is likely to constitute a selective advantage.
Cloning of the Major Outer Membrane Protein Expression Locus in Anaplasma platys and Seroreactivity of a Species-Specific Antigen
Authors: Lai Tzung-Huei , Orellana Nelson G. , Yuasa Yumi , Rikihisa Yasuko 
Published: April 2011

ABSTRACTAnaplasma platysinfects peripheral blood platelets and causes infectious cyclic thrombocytopenia in canines. The genes, proteins, and antigens ofA. platysare largely unknown, and an antigen for serodiagnosis ofA. platyshas not yet been identified. In this study, we cloned theA. platysmajor outer membrane protein cluster, including the P44/Msp2 expression locus (p44ES/msp2ES) and outer membrane protein (OMP), using DNA isolated from the blood of four naturally infected dogs from Venezuela and Taiwan, Republic of China.A. platysp44ESis located within a 4-kb genomic region downstream from a putative transcriptional regulator,tr1, and a homolog of theAnaplasma phagocytophilum, identified here asA. platysomp-1X. The predicted molecular masses of the four matureA. platysP44ES proteins ranged from 43.3 to 43.5 kDa. Comparative analyses of the deduced amino acid sequences of Tr1, OMP-1X, and P44/Msp2 proteins fromA. platyswith those fromA. phagocytophilumshowed sequence identities of 86.4% for Tr1, 45.9% to 46.3% for OMP-1X, and 55.0% to 56.9% for P44/Msp2. Comparison betweenA. platysandAnaplasma marginaleproteins showed sequence identities of 73.1% for Tr1/Tr, 39.8% for OMP-1X/OMP1, and 41.5% to 42.1% for P44/Msp2. A synthetic OMP-1X peptide was shown to react withA. platys-positive sera but not withA. platys-negative sera orA. phagocytophilum-positive sera. Together, determination of the genomic locus ofA. platysouter membrane proteins not only contributes to the fundamental understanding of this enigmatic pathogen but also helps in developingA. platys-specific PCR and serodiagnosis.
Molecular and Biochemical Characterization of the 5-Nitroanthranilic Acid Degradation Pathway in Bradyrhizobium sp. Strain JS329
Authors: Qu Yi , Spain Jim C. 
Published: April 2011

ABSTRACT

Biodegradation pathways of synthetic nitroaromatic compounds and anilines are well documented, but little is known about those of nitroanilines. We previously reported that the initial step in 5-nitroanthranilic acid (5NAA) degradation by
Bradyrhizobium
sp. strain JS329 is a hydrolytic deamination to form 5-nitrosalicylic acid (5NSA), followed by ring fission catalyzed by 5NSA dioxygenase. The mechanism of release of the nitro group was unknown. In this study, we subcloned, sequenced, and expressed the genes encoding 5NAA deaminase (5NAA aminohydrolase, NaaA), 5NSA dioxygenase (NaaB) and lactonase (NaaC), the key genes responsible for 5NAA degradation. Sequence analysis and enzyme characterization revealed that NaaA is a hydrolytic metalloenzyme with a narrow substrate range. The nitro group is spontaneously eliminated as nitrite concomitant with the formation of a lactone from the ring fission product of 5NSA dioxygenation. The elimination of the nitro group during lactone formation is a previously unreported mechanism for denitration of nitro aliphatic compounds.
Identification of a Conserved Sequence in Flavoproteins Essential for the Correct Conformation and Activity of the NADH Oxidase NoxE of Lactococcus lactis
Authors: Tachon Sybille , Chambellon Emilie , Yvon Mireille 
Published: April 2011

ABSTRACT

Water-forming NADH oxidases (encoded by
noxE
,
nox2
, or
nox
) are flavoproteins generally implicated in the aerobic survival of microaerophilic bacteria, such as lactic acid bacteria. However, some natural
Lactococcus lactis
strains produce an inactive NoxE. We examined the role of NoxE in the oxygen tolerance of
L. lactis
in the rich synthetic medium GM17. Inactivation of
noxE
suppressed 95% of NADH oxidase activity but only slightly affected aerobic growth, oxidative stress resistance, and NAD regeneration. However,
noxE
inactivation strongly impaired oxygen consumption and mixed-acid fermentation. We found that the A303T mutation is responsible for the loss of activity of a naturally occurring variant of NoxE. Replacement of A303 with T or G or of G307 with S or A by site-directed mutagenesis led to NoxE aggregation and the total loss of activity. We demonstrated that L299 is involved in NoxE activity, probably contributing to positioning flavin adenine dinucleotide (FAD) in the active site. These residues are part of the strongly conserved sequence LA(T)XXAXXXG included in an alpha helix that is present in other flavoprotein disulfide reductase (FDR) family flavoproteins that display very similar three-dimensional structures.
Aldehyde Dehydrogenase in Combination with CD133 Defines Angiogenic Ovarian Cancer Stem Cells That Portend Poor Patient Survival
Authors: Silva Ines A. , Bai Shoumei , McLean Karen , Yang Kun , Griffith Kent , Thomas Dafydd , Ginestier Christophe , Johnston Carolyn , Kueck Angela , Reynolds R. Kevin , Wicha Max S. , Buckanovich Ronald J. 
Published: April 2011

Abstract
Markers that reliably identify cancer stem cells (CSC) in ovarian cancer could assist prognosis and improve strategies for therapy. CD133 is a reported marker of ovarian CSC. Aldehyde dehydrogenase (ALDH) activity is a reported CSC marker in several solid tumors, but it has not been studied in ovarian CSC. Here we report that dual positivity of CD133 and ALDH defines a compelling marker set in ovarian CSC. All human ovarian tumors and cell lines displayed ALDH activity. ALDH+ cells isolated from ovarian cancer cell lines were chemoresistant and preferentially grew tumors, compared with ALDH− cells, validating ALDH as a marker of ovarian CSC in cell lines. Notably, as few as 1,000 ALDH+ cells isolated directly from CD133− human ovarian tumors were sufficient to generate tumors in immunocompromised mice, whereas 50,000 ALDH− cells were unable to initiate tumors. Using ALDH in combination with CD133 to analyze ovarian cancer cell lines, we observed even greater growth in the ALDH+CD133+ cells compared with ALDH+CD133− cells, suggesting a further enrichment of ovarian CSC in ALDH+CD133+ cells. Strikingly, as few as 11 ALDH+CD133+ cells isolated directly from human tumors were sufficient to initiate tumors in mice. Like other CSC, ovarian CSC exhibited increased angiogenic capacity compared with bulk tumor cells. Finally, the presence of ALDH+CD133+ cells in debulked primary tumor specimens correlated with reduced disease-free and overall survival in ovarian cancer patients. Taken together, our findings define ALDH and CD133 as a functionally significant set of markers to identify ovarian CSCs. Cancer Res; 71(11); 3991–4001. ©2011 AACR.
Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice
Authors: Wozniak Krystyna M. , Nomoto Kenichi , Lapidus Rena G. , Wu Ying , Carozzi Valentina , Cavaletti Guido , Hayakawa Kazuhiro , Hosokawa Satoru , Towle Murray J. , Littlefield Bruce A. , Slusher Barbara S. 
Published: April 2011

Abstract
Chemotherapy-induced neurotoxicity is a significant problem associated with successful treatment of many cancers. Tubulin is a well-established target of antineoplastic therapy; however, tubulin-targeting agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity. Eribulin mesylate, a novel microtubule-targeting analogue of the marine natural product halichondrin B, has recently shown antineoplastic activity, with relatively low incidence and severity of neuropathy, in metastatic breast cancer patients. The mechanism of chemotherapy-induced neuropathy is not well understood. One of the main underlying reasons is incomplete characterization of pathology of peripheral nerves from treated subjects, either from patients or preclinically from animals. The current study was conducted to directly compare, in mice, the neuropathy-inducing propensity of three drugs: paclitaxel, ixabepilone, and eribulin mesylate. Because these drugs have different potencies and pharmacokinetics, we compared them on the basis of a maximum tolerated dose (MTD). Effects of each drug on caudal and digital nerve conduction velocity, nerve amplitude, and sciatic nerve and dorsal root ganglion morphology at 0.25 × MTD, 0.5 × MTD, 0.75 × MTD, and MTD were compared. Paclitaxel and ixabepilone, at their respective MTDs, produced significant deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia and sciatic nerve. In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Overall, our findings indicate that eribulin mesylate induces less neuropathy in mice than paclitaxel or ixabepilone at equivalent MTD-based doses. Cancer Res; 71(11); 3952–62. ©2011 AACR.
Genome-Wide “Pleiotropy Scan” Identifies HNF1A Region as a Novel Pancreatic Cancer Susceptibility Locus
Authors: Pierce Brandon L. , Ahsan Habibul 
Published: April 2011

Abstract
In genome-wide association (GWA) studies, hundreds of thousands of single-nucleotide polymorphisms (SNP) are tested for association with a disease trait. Typically, GWA studies give equal consideration to all SNPs tested, regardless of existing knowledge of an SNP's functionality or biological plausibility of association. Because many tests are conducted, very low statistical significance thresholds (P &lt; 5 × 10−8) are required to identify true associations with confidence. By restricting GWA analyses to SNPs with enhanced prior probabilities of association, we can reduce the number of tests conducted and relax the required significance threshold, increasing power to detect association. In this analysis of existing GWA data on pancreatic cancer cases (n = 1,736) and controls (n = 1,802) of European descent (the PanScan study), we conduct a GWA scan restricted to SNPs that have been reported to associate with human phenotypes in previous GWA studies (with P &lt; 5 × 10−8). Using this method, we drastically reduce the number of tests conducted (from ∼550,000 to 1,087) and test only SNPs that are known to be (or tag) variants that influence human biological processes. Of the 1,087 SNPs tested, the strongest association observed was for HNF1A SNP rs7310409 (P = 3 × 10−5; PBonferroni = 0.03), an SNP known to associate with circulating C-reactive protein. This association was replicated in an independent sample of 1,094 cases and 1,165 controls (P = 0.02), producing a highly significant association in the combined data sets (P = 2 × 10−6; PBonferroni = 0.002). The HNF1A region also harbors variants that influence several human traits, including maturity-onset diabetes of the young, type 2 diabetes, low-density lipoprotein cholesterol, and N-glycan levels. This novel “pleiotropy scan” method may be useful for identifying susceptibility loci for other cancer phenotypes. Cancer Res; 71(13); 4352–8. ©2011 AACR.
Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism
Authors: Zhao Yuhua , Liu Hao , Liu Zixing , Ding Yan , LeDoux Susan P. , Wilson Glenn L. , Voellmy Richard , Lin Yifeng , Lin Wensheng , Nahta Rita , Liu Bolin , Fodstad Oystein , Chen Jieqing , Wu Yun , Price Janet E. , Tan Ming 
Published: April 2011

Abstract
Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance. Cancer Res; 71(13); 4585–97. ©2011 AACR.
Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors
Authors: Zindy Pierre , Bergé Yann , Allal Ben , Filleron Thomas , Pierredon Sandra , Cammas Anne , Beck Samantha , Mhamdi Loubna , Fan Li , Favre Gilles , Delord Jean-Pierre , Roché Henri , Dalenc Florence , Lacroix-Triki Magali , Vagner Stéphan 
Published: April 2011

Abstract
Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor. Cancer Res; 71(12); 4068–73. ©2011 AACR.
New Strategies in Barrett's Esophagus: Integrating Clonal Evolutionary Theory with Clinical Management
Authors: Reid Brian J. , Kostadinov Rumen , Maley Carlo C. 
Published: April 2011

Abstract
Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition. Clin Cancer Res; 17(11); 3512–9. ©2011 AACR.