bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fur Negatively Regulates
hns
and Is Required for the Expression of HilA and Virulence in
Salmonella enterica
Serovar Typhimurium
Authors: Troxell Bryan , Sikes Michael L. , Fink Ryan C. , Vazquez-Torres Andres , Jones-Carson Jessica , Hassan Hosni M. 
Published: November 2010

ABSTRACT

Iron is an essential element for the survival of living cells. However, excess iron is toxic, and its uptake is exquisitely regulated by the ferric uptake regulator, Fur. In
Salmonella
, the
Salmonella
pathogenicity island 1 (SPI-1) encodes a type three secretion system, which is required for invasion of host epithelial cells in the small intestine. A major activator of SPI-1 is HilA, which is encoded within SPI-1. One known regulator of
hilA
is Fur. The mechanism of
hilA
regulation by Fur is unknown. We report here that Fur is required for virulence in
Salmonella enterica
serovar Typhimurium and that Fur is required for the activation of
hilA
, as well as of other HilA-dependent genes,
invF
and
sipC
. The Fur-dependent regulation of
hilA
was independent of PhoP, a known repressor of
hilA
. Instead, the expression of the gene coding for the histone-like protein,
hns
, was significantly derepressed in the
fur
mutant. Indeed, the activation of
hilA
by Fur was dependent on 28 nucleotides located upstream of
hns
. Moreover, we used chromatin immunoprecipitation to show that Fur bound,
in vivo
, to the upstream region of
hns
in a metal-dependent fashion. Finally, deletion of
fur
in an
hns
mutant resulted in Fur-independent activation of
hilA
. In conclusion, Fur activates
hilA
by repressing the expression of
hns
.
XerCD-Mediated Site-Specific Recombination Leads to Loss of the 57-Kilobase Gonococcal Genetic Island
Authors: Domínguez Nadia M. , Hackett Kathleen T. , Dillard Joseph P. 
Published: November 2010

ABSTRACT

Most strains of
Neisseria gonorrhoeae
carry the 57-kb gonococcal genetic island (GGI), as do a few strains of
Neisseria meningitidis
. The GGI is inserted into the chromosome at the
dif
site (
difA
) and is flanked by a partial repeat of the
dif
site (
difB
). Since
dif
is a sequence recognized by the site-specific recombinases XerC and XerD and the GGI shows evidence of horizontal acquisition, we hypothesized that the GGI may be acquired or lost by XerCD-mediated site-specific recombination. We show that while the GGI flanked by wild-type
dif
sites,
difA
and
difB
, is not readily lost from the gonococcal chromosome, the substitution of
difB
with another copy of
difA
allows the frequent excision and loss of the GGI. In mutants carrying two
difA
sites (
difA

+

difA

+

), the GGI can be detected as an extrachromosomal circle that exists transiently. A mutation of
xerD
diminished GGI excision from the chromosome of a
difA

+

difA

+

strain, while mutations in
recA
or type IV secretion genes had no effect on the loss of the GGI. These data indicate that the GGI is maintained by the replication of the chromosome and that GGI excision and loss are dependent upon the
dif
sequence and
xerD
. The detection of a circular form of the GGI in a wild-type strain suggests that GGI excision may occur naturally and could function to facilitate GGI transfer. These data suggest a model of GGI excision and loss explaining the absence of the GGI from some gonococcal strains and the maintenance of variant GGIs in some gonococcal and meningococcal isolates.
MexT Regulates the Type III Secretion System through MexS and PtrC in
Pseudomonas aeruginosa
Authors: Jin Yongxin , Yang Hongjiang , Qiao Mingqiang , Jin Shouguang 
Published: November 2010

ABSTRACT

The type III secretion system (T3SS) is the most important virulence factor in
Pseudomonas aeruginosa
, and its expression level varies in different isolates. We studied the molecular basis for such differences in two laboratory strains, PAK and PAO1. A chromosomal clone library from the high-T3SS-producer strain PAK was introduced into the low-producer strain PAO1, and we found that a
mexS
gene from PAK confers high T3SS expression in the PAO1 background. Further tests demonstrated that both
mexS
and its neighboring
mexT
gene are required for the repression of the T3SS in PAO1, while the PAK genome encodes a defective MexS, accounting for the derepression of the T3SS in PAK and the dominant negative effect when it is introduced into PAO1. MexS is a probable oxidoreductase whose expression is dependent on MexT, a LysR-type transcriptional regulator. Various genetic data support the idea that MexS modulates the transcriptional regulator function of MexT. In searching for the MexT-dependent repressor of the T3SS, a small gene product of PA2486 (
ptrC
) was found effective in suppressing the T3SS upon overexpression. However, deletion of
ptrC
in the PAO1 background did not result in derepression of the T3SS, indicating the presence of another repressor for the T3SS. Interestingly, overexpression of functional
mexS
alone was sufficient to repress T3SS even in the absence of MexT, suggesting that MexS is another mediator of MexT-dependent T3SS repression. Overexpression of
mexS
alone had no effect on the well-known MexT-dependent genes, including those encoding MexEF efflux pump, elastase, and pyocyanin, indicating alternative regulatory mechanisms. A model has been proposed for the MexS/MexT-mediated regulation of the T3SS, the MexEF efflux pump, and the production of elastase and pyocyanin.
Genome Sequence of the Marine
Janibacter
Sp. Strain HTCC2649
Authors: Thrash J. Cameron , Cho Jang-Cheon , Bertagnolli Anthony D. , Ferriera Steve , Johnson Justin , Vergin Kevin L. , Giovannoni Stephen J. 
Published: November 2010

ABSTRACT

Janibacter
sp. strain HTCC2649 is a novel marine member of the
Actinobacteria
, family
Intrasporangiaceae
, and is closely related to
Janibacter melonis
CM2104
T
and
Knoellia sinensis
HKI 0119
T
. The organism was isolated from a sample collected at Hydrostation S south of Bermuda by using high-throughput culturing techniques. Here we present the genome sequence of
Janibacter
sp. strain HTCC2649.
Understanding the effect of compensation on recovery from severe motor vehicle crash injuries: a qualitative study
Authors: Murgatroyd Darnel F , Cameron Ian D , Harris Ian A 
Published: November 2010

ObjectiveTo explore the factors that influence recovery from serious injuries sustained in motor vehicle crashes, particularly differences between those with compensable and non-compensable injuries.Design and settingQualitative study using grounded theory and focus group methods within the trauma service of a university teaching hospital.Participants34 subjects (27 male, 7 female), of whom 21 were participants with a compensation claim and 13 were not. Each had sustained injuries in motor vehicle crashes between two and seven years previously.Main outcome measureThemes identified from transcripts of the focus groups.ResultsThe themes identified from participants claiming compensation were a strong sense of entitlement and injustice, a difficult claims and settlement process, an inability to move on with life during the claims process, an extreme dislike of medico-legal assessments, the necessity of legal representation to assist with the claims process, and a perceived lack of trust about having to prove an injury or disability. The themes common to all participants were the significance of the trauma experience, the importance of family and social support, and, if self-employed, financial hardship and difficult experiences in returning to work.ConclusionsThe injury recovery experience was difficult for all subjects, but it was particularly stressful for those claiming compensation. Based on this study, the claims process, particularly medico-legal examinations, and other factors that could impact on injury recovery, are targets for further research, possible policy review, or legislative change.
Impact of common mental disorders on sickness absence in an occupational cohort study
Authors: Stansfeld Stephen A , Fuhrer Rebecca , Head Jenny 
Published: November 2010

ObjectivesCommon mental disorders are associated with impaired functioning and sickness absence. We examine whether sub-clinical as well as clinical psychiatric morbidity predict long spells of sickness absence for both psychiatric and non-psychiatric illness. We also examine whether recent common mental disorders and those present on two occasions have a stronger association with sickness absence than less recent and single episodes of disorder.MethodsCommon mental disorders measured by the General Health Questionnaire were linked with long spells of sickness absence in 5104 civil servants from the longitudinal Whitehall II Study. Negative binomial models were used to estimate rate ratios for long spells of sickness absence with and without a psychiatric diagnosis (mean follow-up 5.3 years).ResultsClinical but not sub-threshold common mental disorders were associated with increased risk of long spells of psychiatric sickness absence for men, but not for women, after adjusting for covariates (rate ratios (RR) 1.67, 95% CI 1.13 to 2.46). Risk of psychiatric sickness absence was associated with recent common mental disorders (RR 2.08, 95% CI 1.29 to 3.35) and disorder present on two occasions (RR 1.65, 95% CI 0.98 to 2.71) for men only. Common mental disorders were not associated with increased risk of non-psychiatric sickness absence after adjustment for covariates.ConclusionsIdentification and treatment of common mental disorders may reduce the economic burden of long term psychiatric sickness absence. Our results suggest that public health and clinical services should focus on the identification of workers with elevated mental health symptoms. Studies are needed of the efficacy of early identification and management of mental health symptoms for the prevention of long spells of sickness absence.
A Novel Fusion Toxin Derived from an EpCAM-Specific Designed Ankyrin Repeat Protein Has Potent Antitumor Activity
Authors: Martin-Killias Patricia , Stefan Nikolas , Rothschild Sacha , Plückthun Andreas , Zangemeister-Wittke Uwe 
Published: November 2010

Abstract
Purpose: Designed ankyrin repeat proteins (DARPins) hold great promise as a new class of binding molecules to overcome the limitations of antibodies for biomedical applications. Here, we assessed the potential of an epithelial cell adhesion molecule (EpCAM)–specific DARPin (Ec4) for tumor targeting as a fusion toxin with Pseudomonas aeruginosa exotoxin A.
Experimental design: DARPin Ec4 was genetically fused to a truncated form of Pseudomonas aeruginosa exotoxin A (ETA″) and expressed in Escherichia coli. The cytotoxicity of Ec4-ETA″ was measured against tumor cell lines of various histotypes in vitro. Tumor localization and antitumor activity were determined in mice bearing 2 different EpCAM-positive tumor xenografts.
Results: Ec4-ETA″ expressed very well in soluble form in the cytoplasm of E. coli and yielded up to 40 mg after purification per liter of culture. The protein was monomeric and the disulfides of ETA″ formed spontaneously. Ec4-ETA″ bound to EpCAM with low nanomolar affinity, similar to free Ec4. Furthermore, it was highly cytotoxic against various EpCAM-positive tumor cell lines in vitro with IC50 values less than 0.005 pmol/L. This effect was competed by free Ec4, but not by unspecific DARPins. Upon systemic administration in athymic mice, Ec4-ETA″ efficiently localized to EpCAM-positive tumors to achieve maximum accumulation 48 to 72 hours after injection, whereas an irrelevant control fusion toxin did not accumulate. Tumor targeting with Ec4-ETA″ resulted in a strong antitumor response including complete regressions in some animals.
Conclusions: Our data show for the first time the potential of DARPins for the generation of protein therapeutics for tumor targeting, and that Ec4-ETA″ deserves attention for clinical development. Clin Cancer Res; 17(1); 100–10. ©2010 AACR.
A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis
Authors: Wang Hongbo , Ma Xujun , Ren Shumei , Buolamwini John K. , Yan Chunhong 
Published: November 2010

Abstract
The p53 inactivation caused by aberrant expression of its major regulators (e.g., MDM2 and MDMX) contributes to the genesis of a large number of human cancers. Recent studies have shown that restoration of p53 activity by counteracting p53 repressors is a promising anticancer strategy. Although agents (e.g., nutlin-3a) that disrupt MDM2–p53 interaction can inhibit tumor growth, they are less effective in cancer cells that express high levels of MDMX. MDMX binds to p53 and can repress the tumor suppressor function of p53 through inhibiting its trans-activation activity and/or destabilizing the protein. Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. Treatments of MCF-7 cells with this small-molecule MDMX inhibitor activated p53, resulting in elevated expression of proapoptotic genes (e.g., PUMA, BAX, and PIG3). Importantly, this novel small-molecule p53 activator caused MCF-7 cells to undergo apoptosis and acted additively with nutlin-3a to activate p53 and decrease the viability of cancer cells. These results thus show that small molecules targeting MDMX expression would be of therapeutic benefits. Mol Cancer Ther; 10(1); 69–79. ©2010 AACR.
B1, a Novel Amonafide Analogue, Overcomes the Resistance Conferred by Bcl-2 in Human Promyelocytic Leukemia HL60 Cells
Authors: Liang Xin , Xu Yufang , Xu Ke , Liu Jianwen , Qian Xuhong 
Published: November 2010

AbstractIn the course of screening for novel anticancer compounds, B1 [N-(2-(dimethylamino)ethyl)-2-aminothiazonaphthalimide], a novel amonafide analogue, was generated as a new anticancer candidate. In the present study, B1 displayed stronger antitumor effects than amonafide in HL60 cells. We further examined whether B1 overcomes the resistance conferred by Bcl-2, as overcoming the resistance conferred by Bcl-2 represents an attractive therapeutic strategy against cancer. Our viability assay showed that B1 overcomes the resistance conferred by Bcl-2 in human promyelocytic leukemia HL60 cells. Various apoptosis assessment assays showed that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells by inducing apoptosis. Noticeably, we elucidated the marked downregulation of 14-3-3σ protein by B1, indicating that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells via 14-3-3σ. The analysis of chromatin immunoprecipitation assay indicated that MBD2 was associated with the methylated 14-3-3σ promoter-associated CpG island and thus interfered with transcriptional activity of the methylated promoter. Furthermore, knockdown of MBD2, using siRNA transfection, inhibited B1-induced apoptosis and overcame the resistance conferred by Bcl-2. Accordingly, these data showed the involvement of MBD2 in B1-induced apoptosis and overcoming the resistance conferred by Bcl-2, which suggested that MBD2 might guide the development of future anticancer agents. Mol Cancer Res; 8(12);1619–32. ©2010 AACR.
Screening for Obstructive Sleep Apnea by Cyclic Variation of Heart Rate
Authors: Hayano Junichiro , Watanabe Eiichi , Saito Yuji , Sasaki Fumihiko , Fujimoto Keisaku , Nomiyama Tetsuo , Kawai Kiyohiro , Kodama Itsuo , Sakakibara Hiroki 
Published: November 2010

Background—
Despite the adverse cardiovascular consequences of obstructive sleep apnea, the majority of patients remain undiagnosed. To explore an efficient ECG-based screening tool for obstructive sleep apnea, we examined the usefulness of automated detection of cyclic variation of heart rate (CVHR) in a large-scale controlled clinical setting.

Methods and Results—

We developed an algorithm of autocorrelated wave detection with adaptive threshold (ACAT). The algorithm was optimized with 63 sleep studies in a training cohort, and its performance was confirmed with 70 sleep studies of the Physionet Apnea-ECG database. We then applied the algorithm to ECGs extracted from all-night polysomnograms in 862 consecutive subjects referred for diagnostic sleep study. The number of CVHR per hour (the CVHR index) closely correlated (
r
=0.84) with the apnea-hypopnea index, although the absolute agreement with the apnea-hypopnea index was modest (the upper and lower limits of agreement, 21 per hour and −19 per hour) with periodic leg movement causing most of the disagreement (
P
<0.001). The CVHR index showed a good performance in identifying the patients with an apnea-hypopnea index ≥15 per hour (area under the receiver-operating characteristic curve, 0.913; 83% sensitivity and 88% specificity, with the predetermined cutoff threshold of CVHR index ≥15 per hour). The classification performance was unaffected by older age (≥65 years) or cardiac autonomic dysfunction (SD of normal-to-normal R-R intervals over the entire length of recording <65 ms; area under the receiver-operating characteristic curve, 0.915 and 0.911, respectively).

Conclusions—
The automated detection of CVHR with the ACAT algorithm provides a powerful ECG-based screening tool for moderate-to-severe obstructive sleep apnea, even in older subjects and in those with cardiac autonomic dysfunction.
Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction
Authors: Westermann Dirk , Lindner Diana , Kasner Mario , Zietsch Christine , Savvatis K. , Escher F. , von Schlippenbach J. , Skurk C. , Steendijk Paul , Riad Alexander , Poller Wolfgang , Schultheiss Heinz-Peter , Tschöpe Carsten 
Published: November 2010

Background—
The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF.

Methods and Results—
We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-β. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-β resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction.

Conclusions—
Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.
Why Professions Matter: Structural Invariance, Institutional Consequences, Bias
Authors: Sciulli David 
Published: November 2010

AbstractReceived wisdom in the sociology of professions employs two approaches, a narrow socio-economic approach (largely in the Anglo-American world) and a much broader cultural and social-psychological approach (largely on the Continent). Both approaches agree on two points. First, professions cannot be distinguished at a conceptual level from other occupations. Second, whatever consequences either successful or failed professionalism introduces into civil society or state administration are confined to the occupational order and stratification system. They do not and cannot affect the direction of social change. The alternative approach outlined and discussed here is structural and institutional. With this approach we distinguish professions proper analytically from other occupations and we identify consequences of professionalism proper that uniquely reflect or anticipate notable shifts in the direction of social change.
The Concept of Profession Today: A Disquieting Misnomer?
Authors: Olgiati Vittorio 
Published: November 2010

AbstractThe aim of the paper is to go beyond current theoretical disputes about the heuristic value of notions of “profession” and “professionalism” in contemporary (western) society and try to re-assess the everlasting pillars of their epistemological foundations, the existing gap between what a professional or a professional performance is, could be or ought to be. Surely what we still call “profession” and “professionalism” are socially constructed issues. Their social meaning and their empirically testable frames of references stem from a variety of space-time conditions. However, historical evidence shows that these terms always have been referring to a particular type of social actor tailored to handle certain basic human problems according to given expertise in order to achieve trans-personal aims relevant at a broader social level. It would be seriously misleading, and even wrong, therefore, to abandon such terms now, when troublesome human experiences ‐ weakenesses, dangers, fears, risks, etc. ‐ are not withering away at all, but, on the contrary are spreading and will remain ubiquitous in the future. Accordingly, a major emphasis is put on the requirement of the social utility and necessity of the professional mandate as a “disposition of means“ to deal procedurally with occasional but socially recurrent “calls for help,” which implies a particular knowledge, a special personal committment and a highly refined relational interation as a way somewhat to “normalise” given societal dynamics.
Analyzing the Professions: The Case for the Neo-Weberian Approach
Authors: Saks Mike 
Published: November 2010

AbstractThis paper makes the case for the neo-Weberian approach for analyzing the professions. It starts by reviewing the difficulties of other main approaches to the sociology of professions ‐ including the trait approach, functionalism, interactionism, Marxism and Foucauldianism. It is argued that the issues they pose are largely addressed by the neo-Weberian approach, the key features of which are outlined and illustrated with reference to the pivotal case of health care. The neo-Weberian approach itself is then critically evaluated. The paper concludes that, despite the recent emergence of a broader approach to analyzing occupational groups centred on the discourse of professionalism, the neo-Weberian approach remains the most incisive and empirically fruitful perspective on the sociology of professions.