bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Level of AdpA Directly Affects Expression of Developmental Genes in Streptomyces coelicolor
Authors: Wolański Marcin , Donczew Rafał , Kois-Ostrowska Agnieszka , Masiewicz Paweł , Jakimowicz Dagmara , Zakrzewska-Czerwińska Jolanta 
Published: September 2011

ABSTRACT

AdpA is a key regulator of morphological differentiation in
Streptomyces
. In contrast to
Streptomyces griseus
, relatively little is known about AdpA protein functions in
Streptomyces coelicolor
. Here, we report for the first time the translation accumulation profile of the
S. coelicolor
adpA
(

adpA
Sc

) gene; the level of
S. coelicolor
AdpA (AdpA

Sc

) increased, reaching a maximum in the early stage of aerial mycelium formation (after 36 h), and remained relatively stable for the next several hours (48 to 60 h), and then the signal intensity decreased considerably. AdpA

Sc

specifically binds the

adpA
Sc

promoter region
in vitro
and
in vivo
, suggesting that its expression is autoregulated; surprisingly, in contrast to
S. griseus
, the protein presumably acts as a transcriptional activator. We also demonstrate a direct influence of AdpA

Sc

on the expression of several genes whose products play key roles in the differentiation of
S. coelicolor
: STI, a protease inhibitor; RamR, an atypical response regulator that itself activates expression of the genes for a small modified peptide that is required for aerial growth; and ClpP1, an ATP-dependent protease. The diverse influence of AdpA

Sc

protein on the expression of the analyzed genes presumably results mainly from different affinities of AdpA

Sc

protein to individual promoters.
CodY-Mediated Regulation of Guanosine Uptake in Bacillus subtilis
Authors: Belitsky Boris R. , Sonenshein Abraham L. 
Published: September 2011

ABSTRACT

CodY is a global transcriptional regulator known to control expression of more than 100 genes and operons in
Bacillus subtilis
. Some of the most strongly repressed targets of CodY, the
nupNOPQ
(formerly,
yufNOPQ
) genes, were found to encode a guanosine transporter. Using DNase I footprinting experiments, we identified two high-affinity CodY-binding sites in the regulatory region of the
nupN
gene. The two sites are located 50 bp upstream and 163 bp downstream of the transcription start site. The downstream site was responsible for 6- to 8-fold
nupN
repression in the absence of the upstream site. When the upstream site was intact, however, only a minor contribution of the downstream site to
nupN
regulation could be detected under the conditions tested. Both sites contained 15-bp CodY-binding motifs with two mismatches each with respect to the consensus sequence, AATTTTCWGTTTTAA. However, the experimentally determined binding sites included additional sequences flanking the 15-bp CodY-binding motifs. An additional version of the 15-bp CodY-binding motif, with 5 mismatches with respect to the consensus but essential for efficient regulation by CodY, was found within the upstream site. The presence of multiple 15-bp motifs may be a common feature of CodY-binding sites.
Expression Level of a Chimeric Kinase Governs Entry into Sporulation in Bacillus subtilis
Authors: Eswaramoorthy Prahathees , Dravis Ashlee , Devi Seram Nganbiton , Vishnoi Monika , Dao Hoang-Anh , Fujita Masaya 
Published: September 2011

ABSTRACTUpon starvation,Bacillus subtiliscells switch from growth to sporulation. It is believed that the N-terminal sensor domain of the cytoplasmic histidine kinase KinA is responsible for detection of the sporulation-specific signal(s) that appears to be produced only under starvation conditions. Following the sensing of the signal, KinA triggers autophosphorylation of the catalytic histidine residue in the C-terminal domain to transmit the phosphate moiety, via phosphorelay, to the master regulator for sporulation, Spo0A. However, there is no direct evidence to support the function of the sensor domain, because the specific signal(s) has never been found. To investigate the role of the N-terminal sensor domain, we replaced the endogenous three-PAS repeat in the N-terminal domain of KinA with a two-PAS repeat derived fromEscherichia coliand examined the function of the resulting chimeric protein. Despite the introduction of a foreign domain, we found that the resulting chimeric protein, in a concentration-dependent manner, triggered sporulation by activating Spo0A through phosphorelay, irrespective of nutrient availability. Further, by using chemical cross-linking, we showed that the chimeric protein exists predominantly as a tetramer, mediated by the N-terminal domain, as was found for KinA. These results suggest that tetramer formation mediated by the N-terminal domain, regardless of the origin of the protein, is important and sufficient for the kinase activity catalyzed by the C-terminal domain. Taken together with our previous observations, we propose that the primary role of the N-terminal domain of KinA is to form a functional tetramer, but not for sensing an unknown signal.
How event reporting by US hospitals has changed from 2005 to 2009
Authors: Farley Donna O , Haviland Amelia , Haas Ann , Pham Chau , Munier William B , Battles James B 
Published: September 2011

ContextInformation is needed on the performance of hospitals' adverse-event reporting systems and the effects of national patient-safety initiatives, including the Patient Safety and Quality Improvement Act (PSQIA) of 2005. Results are presented of a 2009 survey of a sample of non-federal US hospitals and changes between 2005 and 2009 are examined.MethodsThe Adverse Event Reporting System survey was fielded in 2005 and 2009 using a mixed-mode design with stratified random samples of non-federal US hospitals; risk managers were respondents. Response rates were 81% in 2005 and 79% in 2009.ResultsVirtually all hospitals reported they had centralised adverse-event-reporting systems. However, scores on four performance indexes suggested that hospitals have not effectively implemented key components of reporting systems. Average index scores improved somewhat between 2005 and 2009 for supportive environment (0.7 increase; p<0.05) and types of staff reporting (0.08 increase; p<0.001). Average scores did not change for timely distribution of event reports or discussion with key departments and committees. Some within-hospital inconsistencies in responses between 2005 and 2009 were found. These self-reported responses may be optimistic assessments of hospital performance.ConclusionsThe 2009 survey confirmed improvement needs identified by the 2005 survey for hospitals' event reporting processes, while finding signs of progress. Optimising the use of surveys to assess the effects of national patient-safety initiatives such as PSQIA will require decreasing within-hospital variations in reporting rates.
A novel fluorinated stilbene exerts hepatoprotective properties in CCl4-induced acute liver damage
Authors: Rivera Horacio , Morales-Ríos Martha S. , Bautista Wendy , Shibayama Mineko , Tsutsumi Víctor , Muriel Pablo , Pérez-Álvarez Víctor 
Published: September 2011

There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl4)-induced acute liver damage. To achieve this, CCl4 (4 g·kg–1, per os) was administered to male Wistar rats, followed by either 2-fluoro-4′-methoxystilbene (FME) or 2,3-difluoro-4′-methoxystilbene (DFME) (10 mg·kg–1, per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl4 administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl4-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.
Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth
Authors: Yakes F. Michael , Chen Jason , Tan Jenny , Yamaguchi Kyoko , Shi Yongchang , Yu Peiwen , Qian Fawn , Chu Felix , Bentzien Frauke , Cancilla Belinda , Orf Jessica , You Andrew , Laird A. Douglas , Engst Stefan , Lee Lillian , Lesch Justin , Chou Yu-Chien , Joly Alison H. 
Published: September 2011

AbstractThe signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. Mol Cancer Ther; 10(12); 2298–308. ©2011 AACR.
Fetal Growth and Preterm Birth Influence Cardiovascular Risk Factors and Arterial Health in Young Adults
Authors: Skilton Michael R. , Viikari Jorma S.A. , Juonala Markus , Laitinen Tomi , Lehtimäki Terho , Taittonen Leena , Kähönen Mika , Celermajer David S. , Raitakari Olli T. 
Published: September 2011

Objective—
Impaired fetal growth is associated with cardiovascular disease in adulthood. The mechanisms of this association remain poorly described. We aimed to determine the associations of impaired fetal growth and preterm birth with cardiovascular risk factors and arterial health in a large cohort of young adults.

Methods and Results—

Carotid intima-media thickness, brachial flow-mediated dilatation and cardiovascular risk factors were compared between young adults (24–45 years) born at term with impaired fetal growth (birth weight <10th percentile; n=207), born preterm (<37 weeks' gestation; n=253), and a control group born at term with normal fetal growth (birth weight 50–90th percentile; n=835), in the Cardiovascular Risk in Young Finns study. Compared with controls, those with impaired fetal growth had elevated triglycerides (
P
=0.006), C-reactive protein (
P
=0.004), low-density lipoprotein cholesterol, systolic blood pressure (both
P
=0.06), and intima-media thickness and impaired flow-mediated dilatation (both
P
=0.02), the latter partially mediated by systolic blood pressure, C-reactive protein, and triglycerides. Those born preterm had higher intima-media thickness (
P
=0.005) and lower flow-mediated dilatation (
P
=0.03) compared with controls, although this was restricted to those with concurrent fetal growth restriction.

Conclusion—
Impaired fetal growth is associated with impaired endothelial function and elevated preclinical atherosclerosis in young adults, partly mediated by inflammation, blood pressure, and triglycerides. This association is most marked for those also born preterm.
Proteomic Analysis of Polymorphonuclear Neutrophils Identifies Catalase as a Novel Biomarker of Abdominal Aortic Aneurysm: Potential Implication of Oxidative Stress in Abdominal Aortic Aneurysm Progression
Authors: Ramos-Mozo Priscila , Madrigal-Matute Julio , Martinez-Pinna Roxana , Blanco-Colio Luis Miguel , Lopez Juan Antonio , Camafeita Emilio , Meilhac Olivier , Michel Jean-Baptiste , Aparicio Cesar , de Ceniga Melina Vega , Egido Jesus , Martín-Ventura José Luis 
Published: September 2011

Objective—
Polymorphonuclear neutrophils (PMNs) play a main role in abdominal aortic aneurysm (AAA) progression. We have analyzed circulating PMNs isolated from AAA patients and controls by a proteomic approach to identify proteins potentially involved in AAA pathogenesis.

Methods and Results—

PMNs from 8 AAA patients (4 large AAA >5 cm and 4 small AAA 3–5 cm) and 4 controls were analyzed by 2D differential in-gel electrophoresis. Among differentially expressed spots, several proteins involved in redox balance were identified by mass spectrometry (eg, cyclophilin, thioredoxin reductase, catalase). Diminished catalase expression and activity were observed in PMNs from AAA patients compared with controls. In contrast, PMNs from AAA patients displayed higher H
2
O
2
and myeloperoxidase levels than PMNs from controls. Moreover, a significant decrease in catalase mRNA levels was observed in PMNs after phorbol 12-myristate 13-acetate incubation. Catalase plasma levels were also decreased in large (n=47) and small (n=56) AAA patients compared with controls (n=34). We observed catalase expression in AAA thrombus and thrombus-conditioned medium, associated with PMN infiltration. Furthermore, increased H
2
O
2
levels were observed in AAA thrombus-conditioned medium compared with the media layer.

Conclusion—
Diminished catalase levels in circulating PMNs and plasma are observed in AAA patients, supporting an important role of oxidative stress in AAA evolution.
Notch3 Arg170Cys Knock-In Mice Display Pathologic and Clinical Features of the Neurovascular Disorder Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Wallays Goedele , Nuyens Dieter , Silasi-Mansat Robert , Souffreau Joris , Callaerts-Vegh Zsuzsanna , Van Nuffelen An , Moons Lieve , D'Hooge Rudi , Lupu Florea , Carmeliet Peter , Collen Désiré , Dewerchin Mieke 
Published: September 2011

Objective—
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset neurovascular disorder caused by stereotyped mutations in the NOTCH3 receptor. Elucidation of its pathobiology is still incomplete and remains a challenge, in part because the available preclinical mouse models to date do not reproduce the full spectrum of CADASIL pathology and clinical disease.

Methods and Results—

Here, we report a novel knock-in mouse with Arg170Cys substitution in murine Notch3, corresponding to the prevalent Arg169Cys substitution in CADASIL. The Notch3
Arg170Cys
mice displayed late-onset, dominant CADASIL arteriopathy with typical granular osmiophilic material deposition and developed brain histopathology including thrombosis, microbleeds, gliosis, and microinfarction. Furthermore, Notch3
Arg170Cys
mice experienced neurological symptoms with motor defects such as staggering gait and limb paresis.

Conclusion—
This model, for the first time, phenocopies the arteriopathy and the histopathologic as well as clinical features of CADASIL and may offer novel opportunities to investigate disease pathogenesis.
Clinical Value of Absolute Quantification of Myocardial Perfusion With
15
O-Water in Coronary Artery Disease
Authors: Kajander Sami A. , Joutsiniemi Esa , Saraste Markku , Pietilä Mikko , Ukkonen Heikki , Saraste Antti , Sipilä Hannu T. , Teräs Mika , Mäki Maija , Airaksinen Juhani , Hartiala Jaakko , Knuuti Juhani 
Published: September 2011

Background—
The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow and compared that with relative uptake.

Methods and Results—

One hundred four patients with moderate (30%–70%) pretest likelihood of coronary artery disease (CAD) underwent PET imaging during adenosine stress using
15
O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis.

Conclusions—
The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation of myocardial perfusion. As expected, multivessel disease is more accurately detected.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00627172.
Left Atrial Remodeling and Response to Valsartan in the Prevention of Recurrent Atrial Fibrillation
Authors: Staszewsky Lidia , Wong Maylene , Masson Serge , Raimondi Elena , Gramenzi Silvana , Proietti Gianni , Bicego Dario , Emanuelli Carlo , Pulitanò Giancarlo , Taddei Filippo , Nicolis Enrico B. , Correale Ernesto , Fabbri Gianna , Bertocchi Federico , Franzosi Maria Grazia , Maggioni Aldo P. , Tognoni Gianni , Disertori Marcello , Latini Roberto 
Published: September 2011

Background—
Left atrial (LA) dilation precedes or appears early after the onset of atrial fibrillation (AF) and factors in perpetuating the arrhythmia. Angiotensin receptor blockers were proposed for reversing LA remodeling. We evaluated the effect of valsartan on LA remodeling in patients with a recent episode of AF and the effect of LA size on AF recurrence (AFr).

Methods and Results—

LA and left ventricular (LV) echocardiographic variables were measured at baseline and 6 and 12 months in 340 patients from GISSI-AF, a trial testing valsartan prevention of AFr. Reversal of remodeling was considered as a decrease in LA size over 12 months. Changes in patients with and without recurrence and the relationship to duration of AFr were analyzed. Patients were 68.4±8.8 years old, with history of hypertension (85.3%) and cardioversion in the previous 2 weeks (87.4%) or ≥2 AFr in the previous 6 months (40.4%). Baseline LA maximal volume (LAVmax) was severely increased (>40 mL/m
2
); LV dimensions and function were relatively normal. Over 12 months, 54.4% of patients had AFr. LAVmax was unchanged by rhythm, time, or randomized treatment. Higher baseline LAVmax and lower LA emptying fraction were linearly related to increasing AFr duration during follow-up.

Conclusions—
GISSI-AF patients in sinus rhythm and history of AF showed severely increased LAVmax with mostly normal LV volume, mass, and systolic and diastolic function. Valsartan for 1 year did not reverse LA remodeling or prevent AFr. Half of the patients without AFr had severe LA dilation; therefore, mechanisms other than structural remodeling triggered recurrence.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00376272.
Siblings With Ischemic Stroke Study
Authors: Meschia James F. , Nalls Michael , Matarin Mar , Brott Thomas G. , Brown Robert D. , Hardy John , Kissela Brett , Rich Stephen S. , Singleton Andrew , Hernandez Dena , Ferrucci Luigi , Pearce Kerra , Keller Margaret , Worrall Bradford B. ,   for the Siblings With Ischemic Stroke Study Investigators*
Published: September 2011

Background and Purpose—
Ischemic stroke has a strong familial component to risk. The Siblings With Ischemic Stroke Study (SWISS) is a genome-wide, family-based analysis that included use of imputed genotypes. The Siblings With Ischemic Stroke Study was conducted to examine the associations between single-nucleotide polymorphisms (SNPs) and risk of stroke and stroke subtypes within pairs.

Methods—
The Siblings With Ischemic Stroke Study enrolled 312 probands with ischemic stroke from 70 US and Canadian centers. Affected siblings were ascertained by centers and confirmed by central record review; unaffected siblings were ascertained by telephone contact. Ischemic stroke was subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria. Genotyping was performed with an Illumina 610 quad array (probands) and an Illumina linkage V array (affected siblings). SNPs were imputed by using 1000 Genomes Project data and MACH software. Family-based association analyses were conducted by using the sibling transmission-disequilibrium test.

Results—

For all pairs, the correlation of age at stroke within pairs of affected siblings was
r
=0.83 (95% CI, 0.78–0.86;
P
<2.2×10
−16
). The correlation did not differ substantially by subtype. The concordance of stroke subtypes among affected pairs was 33.8% (kappa=0.13;
P
=5.06×10
−4
) and did not differ by age at stroke in the proband. Although no SNP achieved genome-wide significance for risk of ischemic stroke, there was clustering of the most associated SNPs on chromosomes 3p and 6p.

Conclusions—
Stroke subtype and age at stroke in affected sibling pairs exhibit significant clustering. No individual SNP reached genome-wide significance. However, 2 promising candidate loci were, although these risk loci warrant further examination in larger sample collections.
Systemic Hematologic Status Following Intraventricular Recombinant Tissue-Type Plasminogen Activator for Intraventricular Hemorrhage
Authors: Herrick Daniel B. , Ziai Wendy C. , Thompson Carol B. , Lane Karen , McBee Nichol A. , Hanley Daniel F. 
Published: September 2011

Background and Purpose—
This is the first prospective evaluation of changes in systemic hematologic status following administration of intraventricular recombinant tissue-type plasminogen activator in patients with intraventricular hemorrhage (IVH).

Methods—
Laboratory data from subjects enrolled onto the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Trials were analyzed. We analyzed pre- and post- recombinant tissue-type plasminogen activator dosing coagulation parameters. Longer-term changes in hematologic status were studied in subjects who received the study agent after blood clot in the third/fourth ventricles had resolved radiologically.

Results—
Plasma fibrinogen increased significantly in both treatment groups. Dosing did not have a significant impact on any systemic coagulation parameters in either treatment group.

Conclusions—
Intraventricular recombinant tissue-type plasminogen activator is unlikely to impact systemic coagulation or to compound the effects of systemic anticoagulation for deep venous thrombosis prophylaxis.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00650858.