bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Type III Secretion System in a Hypervirulent Lineage of
Bordetella bronchiseptica
Authors: Buboltz Anne M. , Nicholson Tracy L. , Weyrich Laura S. , Harvill Eric T. 
Published: July 2009

ABSTRACT

Despite the fact that closely related bacteria can cause different levels of disease, the genetic changes that cause some isolates to be more pathogenic than others are generally not well understood. We use a combination of approaches to determine which factors contribute to the increased virulence of a
Bordetella bronchiseptica
lineage. A strain isolated from a host with
B. bronchiseptica
-induced disease, strain 1289, was 60-fold more virulent in mice than one isolated from an asymptomatically infected host, strain RB50. Transcriptome analysis and quantitative reverse transcription-PCR showed that the type III secretion system (TTSS) genes were more highly expressed by strain 1289 than strain RB50. Compared to strain RB50, strain 1289 exhibited greater TTSS-mediated cytotoxicity of a mammalian cell line. Additionally, we show that the increase in virulence of strain 1289 compared to that of RB50 was partially attributable to the TTSS. Using multilocus sequence typing, we identified another strain from the same lineage as strain 1289. Similar to strain 1289, we implicate the TTSS in the increased virulence of this strain. Together, our data suggest that the TTSS is involved in the increased virulence of a
B. bronchiseptica
lineage which appears to be disproportionately associated with disease. These data are consistent with the view that
B. bronchiseptica
lineages can have different levels of virulence, which may contribute to this species' ability to cause different severities of respiratory disease.
Effect of autophagy on multiple myeloma cell viability
Authors: Hoang Bao , Benavides Angelica , Shi Yijiang , Frost Patrick , Lichtenstein Alan 
Published: July 2009

Abstract
Because accumulation of potentially toxic malfolded protein may be extensive in immunoglobulin-producing multiple myeloma (MM) cells, we investigated the phenomenon of autophagy in myeloma, a physiologic process that can protect against malfolded protein under some circumstances. Autophagy in MM cell lines that express and secrete immunoglobulin and primary specimens was significantly increased by treatment with the endoplasmic reticulum stress–inducing agent thapsigargin, the mammalian target of rapamycin inhibitor rapamycin, and the proteasome inhibitor bortezomib. Inhibition of basal autophagy in these cell lines and primary cells by use of the inhibitors 3-methyladenine and chloroquine resulted in a cytotoxic effect that was associated with enhanced apoptosis. Use of small interfering RNA to knock down expression of beclin-1, a key protein required for autophagy, also inhibited viable recovery of MM cells. Because the data suggested that autophagy protected MM cell viability, we predicted that autophagy inhibitors would synergize with bortezomib for enhanced antimyeloma effects. However, the combination of these drugs resulted in an antagonistic response. In contrast, the autophagy inhibitor 3-methyladenine did synergize with thapsigargin for an enhanced cytotoxic response. These data suggest that autophagy inhibitors have therapeutic potential in myeloma but caution against combining such drugs with bortezomib. [Mol Cancer Ther 2009;8(7):1974–84]
The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel
Authors: Goldblatt Erin M. , Gentry Erin R. , Fox Melanie J. , Gryaznov Sergei M. , Shen Changyu , Herbert Brittney-Shea 
Published: July 2009

Abstract
Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85% to 90% of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting. [Mol Cancer Ther 2009;8(7):2027–35]
Preclinical evaluation of a novel pyrimidopyrimidine for the prevention of nucleoside and nucleobase reversal of antifolate cytotoxicity
Authors: Thomas Huw D. , Saravanan Kappusamy , Wang Lan-Zhen , Lin Mei-Ju , Northen Julian S. , Barlow Hannah , Barton Marion , Newell David R. , Griffin Roger J. , Golding Bernard T. , Curtin Nicola J. 
Published: July 2009

Abstract
Antifolates have been used to treat cancer for the last 50 years and remain the mainstay of many therapeutic regimes. Nucleoside salvage, which depends on plasma membrane transport, can compromise the activity of antifolates. The cardiovascular drug dipyridamole inhibits nucleoside transport and enhances antifolate cytotoxicity in vitro, but its clinical activity is compromised by binding to the plasma protein α1-acid glycoprotein (AGP). We report the development of a novel pyrimidopyrimidine analogue of dipyridamole, NU3153, which has equivalent potency to dipyridamole, remains active in the presence of physiologic levels of AGP, inhibits thymidine incorporation into DNA, and prevents thymidine and hypoxanthine rescue from the multitargeted antifolate, pemetrexed. Pharmacokinetic evaluation of NU3153 suggested that a soluble prodrug would improve the in vivo activity. The valine prodrug of NU3153, NU3166, rapidly broke down to NU3153 in vitro and in vivo. Plasma NU3153 concentrations commensurate with rescue inhibition in vitro were maintained for at least 16 hours following administration of NU3166 to mice at 120 mg/kg. However, maximum inhibition of thymidine incorporation into tumors was only 50%, which was insufficient to enhance pemetrexed antitumor activity in vivo. Comparison with the cell-based studies revealed that pemetrexed enhancement requires substantial (≥90%) and durable inhibition of nucleoside transport. In conclusion, we have developed non-AGP binding nucleoside transport inhibitors. Pharmacologically active concentrations of the inhibitors can be achieved in vivo using prodrug approaches, but greater potency is required to evaluate inhibition of nucleoside rescue as a therapeutic maneuver. [Mol Cancer Ther 2009;8(7):1828–37]
Kinship, Ethnic Segregation and Multiculturalism in Singapore: A Relational Study
Authors: Chua Vincent 
Published: July 2009

AbstractThe question of inter-ethnic integration and segregation in multicultural societies has been characterised by remarkable tensions at the level of public and scholarly debate between optimists who see 'good' inter-ethnic relations and pessimists who see 'bad' ones. In reality, the ethnic situation in multicultural societies is often more nuanced than these labels suggest. Using personal network analysis applied to a segment of Singapore society, I show that estimates of interethnic contact are highly-contingent upon a range of methodological and social factors. Substantively, I discuss how inter-ethnic interactions may often be hampered by in-group pressures arising from kinship relations. In practice, where 'keeping family' often means 'keeping ethnicity', kinship pre-eminence in everyday life tends to suppress inter-ethnic friendship in intimate regions of personal networks. By contrast, inter-ethnic integration is more readily seen in outer regions of personal networks, suggesting that 'multiculturalism' is, in practice, a form of society based on weak ties rather than strong bonds.
B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders
Authors: Wilcox Ryan A. , Feldman Andrew L. , Wada David A. , Yang Zhi-Zhang , Comfere Nneka I. , Dong Haidong , Kwon Eugene D. , Novak Anne J. , Markovic Svetomir N. , Pittelkow Mark R. , Witzig Thomas E. , Ansell Stephen M. 
Published: July 2009

AbstractStromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell–derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironment's role in T cell–derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/coinhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach.
Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men
Authors: Liu Miao , Kurosaki Takayuki , Suzuki Motofumi , Enomoto Yutaka , Nishimatsu Hiroaki , Arai Tomio , Sawabe Motoji , Hosoi Takayuki , Homma Yukio , Kitamura Tadaichi 
Published: July 2009

Abstract

Background
Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population.

Results
We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population.

Conclusion
Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men.
Genome wide analysis of human genes transcriptionally and post-transcriptionally regulated by the HTLV-I protein p30
Authors: Taylor John M , Ghorbel Sofiane , Nicot Christophe 
Published: July 2009

AbstractBackgroundHuman T-cell leukemia virus type 1 (HTLV-I) is a human retrovirus that is etiologically linked to adult T-cell leukemia (ATL), an aggressive and fatal lymphoproliferative disease. The viral transactivator, Tax, is thought to play an important role during the initial stages of CD4+T-cell immortalization by HTLV-1. Tax has been shown to activate transcription through CREB/ATF and NF-KB, and to alter numerous signaling pathways. These pleiotropic effects of Tax modify the expression of a wide array of cellular genes. Another viral protein encoded by HTLV-I, p30, has been shown to affect virus replication at the transcriptional and posttranscriptional levels. Little is currently known regarding the effect of p30 on the expression and nuclear export of cellular host mRNA transcripts. Identification of these RNA may reveal new targets and increase our understanding of HTLV-I pathogenesis. In this study, using primary peripheral blood mononuclear cells, we report a genome wide analysis of human genes transcriptionally and post-transcriptionally regulated by the HTLV-I protein p30.ResultsUsing microarray analysis, we analyzed total and cytoplasmic cellular mRNA transcript levels isolated from PBMCs to assess the effect of p30 on cellular RNA transcript expression and their nuclear export. We report p30-dependent transcription resulting in the 2.5 fold up-regulation of 15 genes and the down-regulation of 65 human genes. We further tested nuclear export of cellular mRNA and found that p30 expression also resulted in a 2.5 fold post-transcriptional down-regulation of 90 genes and the up-regulation of 33 genes.ConclusionOverall, our study describes that expression of the HTLV-I protein p30 both positively and negatively alters the expression of cellular transcripts. Our study identifies for the first time the cellular genes for which nuclear export is affected by p30. These results suggest that p30 may possess a more global function with respect to mRNA transcription and the nuclear shuttling of cellular mRNA transcripts. In addition, these alterations in gene expression may play a role in cell transformation and the onset of leukemia.
Extent and consistency of linkage disequilibrium and identification of DNA markers for production and egg quality traits in commercial layer chicken populations
Authors: Abasht Behnam , Sandford Erin , Arango Jesus , Settar Petek , Fulton Janet E , O'Sullivan Neil P , Hassen Abebe , Habier David , Fernando Rohan L , Dekkers Jack CM , Lamont Susan J 
Published: July 2009

Abstract

Background
The genome sequence and a high-density SNP map are now available for the chicken and can be used to identify genetic markers for use in marker-assisted selection (MAS). Effective MAS requires high linkage disequilibrium (LD) between markers and quantitative trait loci (QTL), and sustained marker-QTL LD over generations. This study used data from a 3,000 SNP panel to assess the level and consistency of LD between single nucleotide polymorphisms (SNPs) over consecutive years in two egg-layer chicken lines, and analyzed one line by two methods (SNP-wise association and genome-wise Bayesian analysis) to identify markers associated with egg-quality and egg-production phenotypes.

Results
The LD between markers pairs was high at short distances (r2 > 0.2 at < 2 Mb) and remained high after one generation (correlations of 0.80 to 0.92 at < 5 Mb) in both lines. Single- and 3-SNP regression analyses using a mixed model with SNP as fixed effect resulted in 159 and 76 significant tests (P < 0.01), respectively, across 12 traits. A Bayesian analysis called BayesB, that fits all SNPs simultaneously as random effects and uses model averaging procedures, identified 33 SNPs that were included in the model >20% of the time (φ > 0.2) and an additional ten 3-SNP windows that had a sum of φ greater than 0.35. Generally, SNPs included in the Bayesian model also had a small P-value in the 1-SNP analyses.

Conclusion
High LD correlations between markers at short distances across two generations indicate that such markers will retain high LD with linked QTL and be effective for MAS. The different association analysis methods used provided consistent results. Multiple single SNPs and 3-SNP windows were significantly associated with egg-related traits, providing genomic positions of QTL that can be useful for both MAS and to identify causal mutations.
DNA-binding by Haemophilus influenzae and Escherichia coli YbaB, members of a widely-distributed bacterial protein family
Authors: Cooley Anne E , Riley Sean P , Kral Keith , Miller M Clarke , DeMoll Edward , Fried Michael G , Stevenson Brian 
Published: July 2009

Abstract

Background
Genes orthologous to the ybaB loci of Escherichia coli and Haemophilus influenzae are widely distributed among eubacteria. Several years ago, the three-dimensional structures of the YbaB orthologs of both E. coli and H. influenzae were determined, revealing a novel "tweezer"-like structure. However, a function for YbaB had remained elusive, with an early study of the H. influenzae ortholog failing to detect DNA-binding activity. Our group recently determined that the Borrelia burgdorferi YbaB ortholog, EbfC, is a DNA-binding protein. To reconcile those results, we assessed the abilities of both the H. influenzae and E. coli YbaB proteins to bind DNA to which B. burgdorferi EbfC can bind.

Results
Both the H. influenzae and the E. coli YbaB proteins bound to tested DNAs. DNA-binding was not well competed with poly-dI-dC, indicating some sequence preferences for those two proteins. Analyses of binding characteristics determined that both YbaB orthologs bind as homodimers. Different DNA sequence preferences were observed between H. influenzae YbaB, E. coli YbaB and B. burgdorferi EbfC, consistent with amino acid differences in the putative DNA-binding domains of these proteins.

Conclusion
Three distinct members of the YbaB/EbfC bacterial protein family have now been demonstrated to bind DNA. Members of this protein family are encoded by a broad range of bacteria, including many pathogenic species, and results of our studies suggest that all such proteins have DNA-binding activities. The functions of YbaB/EbfC family members in each bacterial species are as-yet unknown, but given the ubiquity of these DNA-binding proteins among Eubacteria, further investigations are warranted.
Yersinia outer protein YopE affects the actin cytoskeleton in Dictyostelium discoideumthrough targeting of multiple Rho family GTPases
Authors: Vlahou Georgia , Schmidt Oxana , Wagner Bettina , Uenlue Handan , Dersch Petra , Rivero Francisco , Weissenmayer Barbara A 
Published: July 2009

Abstract

Background
All human pathogenic Yersinia species share a virulence-associated type III secretion system that translocates Yersinia effector proteins into host cells to counteract infection-induced signaling responses and prevent phagocytosis. Dictyostelium discoideum has been recently used to study the effects of bacterial virulence factors produced by internalized pathogens. In this study we explored the potential of Dictyostelium as model organism for analyzing the effects of ectopically expressed Yersinia outer proteins (Yops).

Results
The Yersinia pseudotuberculosis virulence factors YopE, YopH, YopM and YopJ were expressed de novo within Dictyostelium and their effects on growth in axenic medium and on bacterial lawns were analyzed. No severe effect was observed for YopH, YopJ and YopM, but expression of YopE, which is a GTPase activating protein for Rho GTPases, was found to be highly detrimental. GFP-tagged YopE expressing cells had less conspicuous cortical actin accumulation and decreased amounts of F-actin. The actin polymerization response upon cAMP stimulation was impaired, although chemotaxis was unaffected. YopE also caused reduced uptake of yeast particles. These alterations are probably due to impaired Rac1 activation. We also found that YopE predominantly associates with intracellular membranes including the Golgi apparatus and inhibits the function of moderately overexpressed RacH.

Conclusion
The phenotype elicited by YopE in Dictyostelium can be explained, at least in part, by inactivation of one or more Rho family GTPases. It further demonstrates that the social amoeba Dictyostelium discoideum can be used as an efficient and easy-to-handle model organism in order to analyze the function of a translocated GAP protein of a human pathogen.
Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia
Authors: Hu Xiaohan , Wu Xiangyang , Xu Jiali , Zhou Jin , Han Xiao , Guo Jun 
Published: July 2009

Abstract

Background
The regulation of protein phosphorylation requires a balance in the activity of protein kinases and protein phosphatases. Our previous data indicates that Src can increase ERK activity through Raf kinase in response to ischemic stimuli. This study examined the molecular mechanisms by which Src activates ERK cascade through protein phosphatases following cerebral ischemia.

Results
Ischemia-induced Src activation is followed by phosphorylation of PP2A at Tyr307 leading to its inhibition in the rat hippocampus. SU6656, a Src inhibitor, up-regulates PP2A activity, resulting in a significant decreased activity in ERK and its targets, CREB and ERα. In addition, the PP2A inhibitor, cantharidin, led to an up-regulation of ERK activity and was able to counteract Src inhibition during ischemia.

Conclusion
Src induces up-regulation of ERK activity and its target transcription factors, CREB and ERα, through attenuation of PP2A activity. Therefore, activation of ERK is the result of a crosstalk between two pathways, Raf-dependent positive regulators and PP2A-dependent negative regulators.
Activation of the pre-supplementary motor area but not inferior prefrontal cortex in association with short stop signal reaction time – an intra-subject analysis
Authors: Chao Herta HA , Luo Xi , Chang Jeremy LK , Li Chiang-shan R 
Published: July 2009

Abstract

Background
Our previous work described the neural processes of motor response inhibition during a stop signal task (SST). Employing the race model, we computed the stop signal reaction time (SSRT) to index individuals' ability in inhibitory control. The pre-supplementary motor area (preSMA), which shows greater activity in individuals with short as compared to those with long SSRT, plays a role in mediating response inhibition. In contrast, the right inferior prefrontal cortex (rIFC) showed greater activity during stop success as compared to stop error. Here we further pursued this functional differentiation of preSMA and rIFC on the basis of an intra-subject approach.

Results
Of 65 subjects who participated in four sessions of the SST, we identified 30 individuals who showed a difference in SSRT but were identical in other aspects of stop signal performance between the first ("early") and last two ("late") sessions. By comparing regional brain activation between the two sessions, we confirmed greater preSMA but not rIFC activity during short as compared to long SSRT session within individuals. Furthermore, putamen, anterior cerebellum and middle/posterior cingulate cortex also showed greater activity in association with short SSRT.

Conclusion
These results are consistent with a role of medial prefrontal cortex in controlled action and inferior frontal cortex in orienting attention. We discussed these findings with respect to the process of attentional monitoring and inhibitory motor control during stop signal inhibition.