bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-Based Functional Studies of the Effects of Amino Acid Substitutions in GerBC, the C Subunit of the Bacillus subtilis GerB Spore Germinant Receptor
Authors: Li Yunfeng , Catta Parvathimadhavi , Stewart Kerry-Ann V. , Dufner Matthew , Setlow Peter , Hao Bing
Published: June 2011

Highly conserved amino acid residues in the C subunits of the germinant receptors (GRs) of spores of
Bacillus
and
Clostridium
species have been identified by amino acid sequence comparisons, as well as structural predictions based on the high-resolution structure recently determined for the C subunit of the
Bacillus subtilis
GerB GR (GerBC). Single and multiple alanine substitutions were made in these conserved residues in three regions of GerBC, and the effects of these changes on
B. subtilis
spore germination via the GerB GR alone or in concert with the GerK GR, as well as on germination via the GerA GR, were determined. In addition, levels of the GerBC variants in the spore inner membrane were measured, and a number of the GerBC proteins were expressed and purified and their solubility and aggregation status were assessed. This work has done the following: (i) identified a number of conserved amino acids that are crucial for GerBC function in spore germination via the GerB GR and that do not alter spores' levels of these GerBC variants; (ii) identified other conserved GerBC amino acid essential for the proper folding of the protein and/or for assembly of GerBC in the spore inner membrane; (iii) shown that some alanine substitutions in GerBC significantly decrease the GerA GR's responsiveness to its germinant
l
-valine, consistent with there being some type of interaction between GerA and GerB GR subunits in spores; and (iv) found no alanine substitutions that specifically affect interaction between the GerB and GerK GRs.
Draft Genome Sequence of Streptomyces Strain S4, a Symbiont of the Leaf-Cutting Ant Acromyrmex octospinosus
Authors: Seipke Ryan F. , Crossman Lisa , Drou Nizar , Heavens Darren , Bibb Mervyn J. , Caccamo Mario , Hutchings Matthew I.
Published: June 2011

Streptomyces
spp. are common symbionts of the leaf-cutting ant species
Acromyrmex octospinosus
, which feeds on basidiomycete fungus leaf matter and harvests the lipid- and carbohydrate-rich gongylidia as a food source.
A. octospinosus
and other ant genera use antifungal compounds produced by
Streptomyces
spp. and other actinomycetes in order to help defend their fungal gardens from parasitic fungi. Herein, we report the draft genome sequence of
Streptomyces
strain S4, an antifungal-producing symbiont of
A. octospinosus
.
Complete Genome Sequence of a Novel Clinical Isolate, the Nontuberculous Mycobacterium Strain JDM601
Authors: Zhang Zhuo-Yang , Sun Zhan-Qiang , Wang Zi-Ling , Wen Zi-Lu , Sun Qing-Wen , Zhu Zhao-Qin , Song Yan-Zheng , Zhao Jun-Wei , Wang Hong-Hai , Zhang Shu-Lin , Guo Xiao-Kui
Published: June 2011

Mycobacteriosis is on the increase. Nontuberculous mycobacteria (NTM) are resistant to most antituberculosis drugs naturally. We determined the complete genome sequence of a novel NTM strain, JDM601, of the
Mycobacterium terrae
complex, which was isolated from a patient with tuberculosis-like disease and with various antibiotic resistances.
Genome Sequence of Lactococcus garvieae 8831, Isolated from Rainbow Trout Lactococcosis Outbreaks in Spain
Authors: Aguado-Urda Mónica , López-Campos Guillermo H. , Gibello Alicia , Cutuli M. Teresa , López-Alonso Victoria , Fernández-Garayzábal José F. , Blanco M. Mar
Published: June 2011

Lactococcus garvieae
is the etiological agent of lactococcosis, one of the most important disease threats to the sustainability of the rainbow trout farming industry. Here, we present the draft genome sequence of
Lactococcus garvieae
strain 8831, isolated from diseased rainbow trout, which is composed of 2,087,276 bp with a G+C content of 38%.
Genome Sequence of Acinetobacter sp. Strain P8-3-8, Isolated from Fistularia commersonii in Vietnam
Authors: Kim Young-Ok , Kim Woo-Jin , Choi Sang-Haeng , Kim Dae-Soo , Kim Dong-Wook , Lee Jun-Seo , Kong Hee Jeong , Nam Bo-Hye , Kim Bong-Seok , Lee Sang-Jun , Park Hong-Seog , Chae Sung-Hwa
Published: June 2011

Acinetobacter
sp. strain P8-3-8 is an aerobic, Gram-negative marine bacterium isolated from the intestine of the bluespotted cornetfish (
Fistularia commersonii
). Here, we present the draft genome sequence of
Acinetobacter
sp. P8-3-8 (3,905,565 bp, with a G+C content of 37.6%) containing 3,621 putative coding sequences. The genome data reveal a high density of genes encoding transcriptional regulators involved in anaerobic respiration.
Draft Genome Sequence of Kocuria rhizophila P7-4
Authors: Kim Woo-Jin , Kim Young-Ok , Kim Dae-Soo , Choi Sang-Haeng , Kim Dong-Wook , Lee Jun-Seo , Kong Hee Jeong , Nam Bo-Hye , Kim Bong-Seok , Lee Sang-Jun , Park Hong-Seog , Chae Sung-Hwa
Published: June 2011

We report the draft genome sequence of
Kocuria rhizophila
P7-4, which was isolated from the intestine of
Siganus doliatus
caught in the Pacific Ocean. The 2.83-Mb genome sequence consists of 75 large contigs (>100 bp in size) and contains 2,462 predicted protein-coding genes.
Genome of Ochrobactrum anthropi ATCC 49188
T
, a Versatile Opportunistic Pathogen and Symbiont of Several Eukaryotic Hosts
Authors: Chain Patrick S. G. , Lang Dorothy M. , Comerci Diego J. , Malfatti Stephanie A. , Vergez Lisa M. , Shin Maria , Ugalde Rodolfo A. , Garcia Emilio , Tolmasky Marcelo E.
Published: June 2011

Ochrobactrum anthropi
is a common soil alphaproteobacterium that colonizes a wide spectrum of organisms and is being increasingly recognized as an opportunistic human pathogen. Potentially life-threatening infections, such as endocarditis, are included in the list of reported
O. anthropi
infections. These reports, together with the scant number of studies and the organism's phylogenetic proximity to the highly pathogenic brucellae, make
O. anthropi
an attractive model of bacterial pathogenicity. Here we report the genome sequence of the type strain
O. anthropi
ATCC 49188, which revealed the presence of two chromosomes and four plasmids.
Genome Sequence of Corynebacterium nuruki S6-4
T
, Isolated from Alcohol Fermentation Starter
Authors: Shin Na-Ri , Whon Tae Woong , Roh Seong Woon , Kim Min-Soo , Jung Mi-Ja , Lee Jina , Bae Jin-Woo
Published: June 2011

Corynebacterium nuruki
S6-4
T
, isolated from Korean alcohol fermentation starter, is a strictly aerobic, nonmotile, Gram-positive, and rod-shaped bacterium belonging to the genus
Corynebacterium
and the actinomycete group. We report here the draft genome sequence of
C. nuruki
strain S6-4
T
(3,106,595 bp, with a G+C content of 69.5%).
QSAR study of a series of cholesteryl ester transfer protein inhibitors
Authors: Chhabria Mahesh T. , Suhagia Bhanubhai N. , Mandhare Appaji B. , Brahmkshatriya Pathik S.
Published: June 2011

Cholesteryl ester transfer protein (CETP), an enzyme which catalyses the transfer of cholesteryl ester from HDL to VLDL, is a promising target for discovery of novel antihyperlipidemic agents due to its pivotal role in HDL metabolism and reverse cholesterol transport. Quantitative structure activity relationship study of a series of CETP inhibitors was carried out using genetic function approximation to study various structural requirements for CETP inhibition. Various lipophilic, electronic, geometric and spatial descriptors were correlated with CETP inhibitory activity. Developed models were found predictive as indicated by their goodr2predvalues and satisfactory internal and external cross-validation results. Study reveals that lipophilicity (ClogP), with parabolic relationship, contributed significantly to the activity along with some electronic, geometric and quantum mechanical descriptors. The present study can be applied to future lead optimization of CETP inhibitors.
Informed consent for clinical trials of deep brain stimulation in psychiatric disease: challenges and implications for trial design: Table 1
Authors: Lipsman Nir , Giacobbe Peter , Bernstein Mark , Lozano Andres M
Published: June 2011

Advances in neuromodulation and an improved understanding of the anatomy and circuitry of psychopathology have led to a resurgence of interest in surgery for psychiatric disease. Clinical trials exploring deep brain stimulation (DBS), a focally targeted, adjustable and reversible form of neurosurgery, are being developed to address the use of this technology in highly selected patient populations. Psychiatric patients deemed eligible for surgical intervention, such as DBS, typically meet stringent inclusion criteria, including demonstrated severity, chronicity and a failure of conventional therapy. Although a humanitarian device exemption by the US Food and Drug Administration exists for its use in obsessive-compulsive disorder, DBS remains a largely experimental treatment in the psychiatric context, with its use currently limited to clinical trials and investigative studies. The combination of a patient population at the limits of conventional therapy and a novel technology in a new indication poses interesting challenges to the informed consent process as it relates to clinical trial enrollment. These challenges can be divided into those that relate to the patient, their disease and the technology, with each illustrating how traditional conceptualisations of research consent may be inadequate in the surgical psychiatry context. With specific reference to risk analysis, patient autonomy, voluntariness and the duty of the clinician-researcher, this paper will discuss the unique challenges that clinical trials of surgery for refractory psychiatric disease present to the consent process. Recommendations are also made for an ethical approach to clinical trial consent acquisition in this unique patient population.
Endothelial C-reactive protein increases platelet adhesion under flow conditions
Authors: Grad Etty , Pachino Rachel M. , Danenberg Haim D.
Published: June 2011

While data regarding the pathogenetic role of C-reactive protein (CRP) in atherothrombosis are accumulating, it is still controversial whether local CRP secretion is of any pathobiological significance. The present study examined whether endothelial-derived CRP modulates autocrine prothrombotic activity. Endothelial cells were isolated from hearts of mice transgenic to human CRP and grown in primary cultures. Human CRP expression was confirmed in these cells compared with no expression in cultures derived from wild-type congenes. Adhesion of human platelets to endothelial cells was studied in the “cone and plate” flow system. Platelet adhesion to cells expressing CRP was significantly increased compared with that in controls ( n = 6, P < 0.01). The proadhesive effect of CRP was significantly suppressed in mouse heart endothelial cells and in human umbilical vein endothelial cells following treatment with small interfering RNA for human CRP. Adhesion was modulated by an increase in P-selectin. P-selectin expression correlated with a proadhesive phenotype, and blocking P-selectin with neutralizing antibody significantly decreased the adhesion of platelets to CRP-expressing cells (40.4 ± 10.5 to 9.4 ± 6.9 platelets/high-power field, n = 5 to 6, P < 0.01). In conclusion, human CRP that is locally produced in endothelial cells increases platelet adhesion to endothelial cells under normal shear flow conditions. These findings indicate that CRP exerts a local effect on endothelial cells via P-selectin expression, which promotes platelet adhesion and subsequent thrombus formation.
Creation of myocardial fibrosis by transplantation of fibroblasts primed with survival factors
Authors: Lee Dong-Won , Lee Tae-Kyu , Cho Ik-Sung , Park Hyo Eun , Jin Sooryeonhwa , Cho Hyun-Jai , Kim Soon Ha , Oh Seil , Kim Hyo-Soo
Published: June 2011

One of the major obstacles in the creation of myocardial fibrosis using fibroblasts is massive cell death after cell injection. To overcome this problem, a method that delivers fibroblasts primed with survival factors was studied. Cardiac fibroblasts were isolated from wild-type male C57BL/6 mice. Female mice were randomly placed into the following three groups: 1) fibroblasts transfected with β-galactosidase-containing adenovirus (control group), 2) fibroblasts treated with a necrosis inhibitor (NI group), and 3) fibroblasts transfected with Akt-containing adenovirus (Akt group). Pretreated cells were transplanted into the recipient heart by direct injection after a thoracotomy. Quantitative real-time PCR and morphometric analysis were performed to investigate the effects of survival factor priming on the induction of cell engraftment and fibrosis. In addition, a canine model was used to investigate the development of fibrosis and conduction modification using autologous dermal fibroblasts. The NI and Akt groups showed a better engraftment rate: 13 (NI group) and 7 (Akt group) times greater at 21 days compared with the control group. Increased fibrosis and conduction delay were also observed in the NI and Akt groups compared with the control group. Survival factor priming increased cellular engraftment and enhanced the efficacy of cell transplantation. Delivery of fibroblasts primed with survival factors might be a promising approach to develop conduction modification as a novel strategy to treat arrhythmias.
Differential regulation of metabolism by nitric oxide andS-nitrosothiols in endothelial cells
Authors: Diers Anne R. , Broniowska Katarzyna A. , Darley-Usmar Victor M. , Hogg Neil
Published: June 2011

S-nitrosation of thiols in key proteins in cell signaling pathways is thought to be an important contributor to nitric oxide (NO)-dependent control of vascular (patho)physiology. Multiple metabolic enzymes are targets of both NO and S-nitrosation, including those involved in glycolysis and oxidative phosphorylation. Thus it is important to understand how these metabolic pathways are integrated by NO-dependent mechanisms. Here, we compared the effects of NO and S-nitrosation on both glycolysis and oxidative phosphorylation in bovine aortic endothelial cells using extracellular flux technology to determine common and unique points of regulation. The compound S-nitroso-l-cysteine (l-CysNO) was used to initiate intracellular S-nitrosation since it is transported into cells and results in stable S-nitrosation in vitro. Its effects were compared with the NO donor DetaNONOate (DetaNO). DetaNO treatment caused only a decrease in the reserve respiratory capacity; however, l-CysNO impaired both this parameter and basal respiration in a concentration-dependent manner. In addition, DetaNO stimulated extracellular acidification rate (ECAR), a surrogate marker of glycolysis, whereas l-CysNO stimulated ECAR at low concentrations and inhibited it at higher concentrations. Moreover, a temporal relationship between NO- and S-nitrosation-mediated effects on metabolism was identified, whereby NO caused a rapid impairment in mitochondrial function, which was eventually overwhelmed by S-nitrosation-dependent processes. Taken together, these results suggest that severe pharmacological nitrosative stress may differentially regulate metabolic pathways through both intracellular S-nitrosation and NO-dependent mechanisms. Moreover, these data provide insight into the role of NO and related compounds in vascular (patho)physiology.
Improved functional vasodilation in obese Zucker rats following exercise training
Authors: Sebai Mohamad , Lu Silu , Xiang Lusha , Hester Robert L.
Published: June 2011

Obese individuals exhibit impaired functional vasodilation and exercise performance. We have demonstrated in obese Zucker rats (OZ), a model of morbid obesity, that insulin resistance impairs functional vasodilation via an increased thromboxane receptor (TP)-mediated vasoconstriction. Chronic treadmill exercise training improves functional vasodilation in the spinotrapezius muscle of the OZ, but the mechanisms responsible for the improvement in functional vasodilation are not clear. Based on evidence that exercise training improves insulin resistance, we hypothesized that, in the OZ, exercise training increases functional vasodilation and exercise capability due to decreases TP-mediated vasoconstriction associated with improved insulin sensitivity. Six-week-old lean Zucker rats (LZ) and OZ were exercised on a treadmill (24 m/min, 30 min/day, 5 days/wk) for 6 wk. An oral glucose tolerance test was performed at the end of the training period. We measured functional vasodilation in both exercise trained (spinotrapezius) and nonexercise trained (cremaster) muscles to determine whether the improved functional vasodilation following exercise training in OZ is due to a systemic improved insulin resistance. Compared with LZ, the sedentary OZ exhibited impairments in glucose tolerance and functional vasodilation in both muscles. The TP antagonist SQ-29548 improved the vasodilator responses in the sedentary OZ with no effect in the LZ. Exercising training of the LZ increased the functional vasodilation in spinotrapezius muscle, with no effect in the cremaster muscle. Exercising training of the OZ improved glucose tolerance, along with increased functional vasodilation, in both the spinotrapezius and cremaster muscles. SQ-29548 treatment had no effect on the vasodilator responses in either cremaster or spinotrapezius muscles of the exercise-trained OZ. These results suggest that, in the OZ, there is a global effect of exercising training to improve insulin resistance and increase functional vasodilation via a decreased TP-mediated vasoconstriction.
P2X7 receptor agonists pre- and postcondition the heart against ischemia-reperfusion injury by opening pannexin-1/P2X7 channels
Authors: Vessey Donald A. , Li Luyi , Kelley Michael
Published: June 2011

Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X7 receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X7 receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 μM ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X7 receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin-1/P2X7 channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X7 agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X7 channel antagonists. The data point out for the first time the potential of P2X7 agonists as cardioprotectants.
Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI
Authors: Ohayon Jacques , Gharib Ahmed M. , Garcia Alberto , Heroux Julie , Yazdani Saami K. , Malvè Mauro , Tracqui Philippe , Martinez Miguel-Angel , Doblare Manuel , Finet Gérard , Pettigrew Roderic I.
Published: June 2011

Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions. Therefore, the aim of this study was to quantify WS/S and stiffness in coronary bifurcations and to investigate correlations with plaque sites. Anatomic coronary geometry and cardiac motion were generated based on both computed tomography and MRI examinations of eight patients with minimal coronary disease. Computational structural analyses using the finite element method were subsequently performed, and spatial luminal arterial wall stretch (LWStretch) and stiffness (LWStiff) distributions in the left main coronary bifurcations were calculated. Our results show that all plaque sites were concomitantly subject to high LWStretch and high LWStiff, with mean amplitudes of 34.7 ± 1.6% and 442.4 ± 113.0 kPa, respectively. The mean LWStiff amplitude was found slightly greater at the plaque sites on the left main coronary artery (mean value: 482.2 ± 88.1 kPa) compared with those computed on the left anterior descending and left circumflex coronary arteries (416.3 ± 61.5 and 428.7 ± 181.8 kPa, respectively). These findings suggest that local wall stiffness plays a role in the initiation of atherosclerotic lesions.
ROS-induced ROS release in vascular biology: redox-redox signaling
Authors: Zinkevich Natalya S. , Gutterman David D.
Published: June 2011

The involvement of reactive oxygen species (ROS) in regulating vascular function both in normal vessels and as part of an adaptive response during disease has been intensively studied. From the recognition that ROS serve as important signaling molecules has emerged multiple lines of evidence that there is a functional connectivity between intracellular sites of ROS production. This cross talk has been termed ROS-induced ROS release (RIRR) and is supported by a variety of observations showing that RIRR is a common mechanism for ROS amplification and regional ROS generation. The compartmentalization of ROS production within a cell is critical to its signaling function and is facilitated by microlocalization of specific scavengers. This review will provide descriptions and examples of important mechanisms of RIRR.
Human immunodeficiency virus transgenic rats exhibit pulmonary hypertension
Authors: Lund Amie K. , Lucero JoAnn , Herbert Lindsay , Liu Yushi , Naik Jay S.
Published: June 2011

Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a serious noninfectious disease involving an aberrant increase in pressure in the blood vessels of the lung, which leads to right ventricular (RV) heart failure and can eventually result in death. A lack of viable animal models of HIV-PAH has limited the identification of signaling pathways involved in HIV-mediated onset and progression of PAH. To determine whether the HIV-1 transgenic (HIV Tg) rat displays pathophysiological end points associated with PAH, we evaluated peak RV systolic pressure (RVSP), RV hypertrophy, pulmonary vessel remodeling, and alterations in gene expression by real-time PCR and microarray. RVSP was measured by RV catheterization via the right jugular vein in 3- and 9-mo-old HIV Tg and age-matched Fischer 344 (control) male rats while under 2% isoflurane anesthesia. RVSP was elevated in the HIV Tg rats (34.2 ± 2.5 mmHg) compared with the F344 controls (21.2 ± 2.5 mmHg), with more significant elevations in the 9-mo-old HIV Tg rats (42.5 ± 3.7 mmHg). We observed significant increases in RV wall thickness in HIV Tg rats compared with controls, both histologically and by echocardiograph measurement. HIV Tg rats also show increased thickening of the pulmonary artery and remodeling of small pulmonary arteries, as well as altered expression of gene pathways associated with PAH. These data represent the first analysis of PAH in HIV Tg rats and suggest that this model will be useful for investigating pathways and identifying potential therapies for HIV-PAH.
TGF-β2reduces nitric oxide synthase mRNA through a ROCK-dependent pathway in airway epithelial cells
Authors: Jiang Jingjing , George Steven C.
Published: June 2011

Exhaled NO (eNO) is a potential noninvasive biomarker of inflammation in asthma. The significant intersubject variability of eNO within clinically similar patients has contributed to its limited clinical application. Arginase and NO synthase (NOS) utilize the same substrate (l-arginine) and contribute to the fibrotic and inflammatory features of asthma, respectively. Interestingly, TGF-β2can increase the expression of arginase, stimulates fibrosis, and is overexpressed in asthma. We hypothesized that TGF-β2-enhanced arginase activity would decrease gas phase NO release from lung epithelial cells by limiting l-arginine availability for NOS. Our results show that TGF-β2(5 ng/ml) significantly enhances total arginase activity up to two- to threefold in both primary small airway epithelial cells (SAECs) and the A549 cell line. Preincubation with TGF-β2prior to cytokine (IL-1β, TNF-α, and IFN-γ, 10 ng/ml each) stimulation decreases gas phase NO release to baseline levels (from 1.66 ± 0.52 to 0.30 ± 0.12 pl·s−1·cm−2and from 0.27 ± 0.03 pl·s−1·cm−2to near zero in SAEC and A549 cells, respectively). Addition of arginase inhibitor ( Nω-hydroxy-nor-l-arginine) or small interfering RNA only partly reverses the reduction. In contrast, Rho-kinase (ROCK) pathway inhibitor (Y-27632) completely recovers the cytokine-induced NO flux in the present of TGF-β2. Inducible NO synthase (iNOS) mRNA and protein levels change in a similar trend as NO release from the cells. We conclude that TGF-β2impacts cytokine-induced NO production in airway epithelial cells by reducing iNOS mRNA and protein levels through a ROCK-dependent pathway.
Retinoic Acid Enhances TRAIL-Induced Apoptosis in Cancer Cells by Upregulating TRAIL Receptor 1 Expression
Authors: Dhandapani Latha , Yue Ping , Ramalingam Suresh S. , Khuri Fadlo R. , Sun Shi-Yong
Published: June 2011

Many human cancer cells are sensitive to killing by the proapoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL), which is under study for cancer treatment in clinical trials. The TRAIL receptor (TRAIL-R1; also known as death receptor 4) is a transmembrane receptor that mediates TRAIL-induced apoptosis in cancer cells. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. All-trans retinoic acid (ATRA) upregulated TRAIL-R1 expression in human cancer cells at the transcriptional level. The ability of ATRA to activate TRAIL-R1 expression was inhibited by retinoic acid receptor (RAR) antagonists or siRNAs, but augmented by several RAR agonists. In analyzing how ATRA induces RAR-dependent transcriptional upregulation of TRAIL-R1, we identified 2 putative retinoic acid response elements termed Pal-17 (a palindrome separated by 17 bases) and DR-11 (a direct repeat separated by 11 bases) in the 5′-flanking region of TRAIL-R1 gene. Deletion of DR-11, but not Pal-17, abrogated the ability of ATRA to stimulate TRAIL-R1 promoter activity. Consistent with this observation, RAR binding to DR-11, but not to Pal-17, was detected by chromatin immunoprecipitation assay in ATRA-treated cells, arguing that DR-11 was responsible for ATRA-mediated activation of the TRAIL-R1 gene. ATRA augmented TRAIL-induced apoptosis of cancer cells, and this activity was attenuated by a blockade to upregulation of TRAIL-R1 expression. Taken together, our findings establish that ATRA accentuates TRAIL-induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL. Cancer Res; 71(15); 5245–54. ©2011 AACR.
Cancer Stem Cells in Squamous Cell Carcinoma Switch between Two Distinct Phenotypes That Are Preferentially Migratory or Proliferative
Authors: Biddle Adrian , Liang Xiao , Gammon Luke , Fazil Bilal , Harper Lisa J. , Emich Helena , Costea Daniela Elena , Mackenzie Ian C.
Published: June 2011

Epithelial-to-mesenchymal transition (EMT) is an important driver of tumor invasion and metastasis, which causes many cancer deaths. Cancer stem cells (CSC) that maintain and initiate tumors have also been implicated in invasion and metastasis, but whether EMT is an important contributor to CSC function is unclear. In this study, we investigated whether a population of CSCs that have undergone EMT (EMT CSCs) exists in squamous cell carcinoma (SCC). We also determined whether a separate population of CSCs that retain epithelial characteristics (non-EMT CSCs) is also present. Our studies revealed that self-renewing CSCs in SCC include two biologically-distinct phenotypes. One phenotype, termed CD44highESAhigh, was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44highESAlow, was migratory and had mesenchymal traits characteristic of EMT CSCs. We found that non-EMT and EMT CSCs could switch their epithelial or mesenchymal traits to reconstitute the cellular heterogeneity which was characteristic of CSCs. However, the ability of EMT CSCs to switch to non-EMT character was restricted to cells that were also ALDH1+, implying that only ALDH1+ EMT cells had the ability to seed a new epithelial tumor. Taken together, our findings highlight the identification of two distinct CSC phenotypes and suggest a need to define therapeutic targets that can eradicate both of these variants to achieve effective SCC treatment. Cancer Res; 71(15); 5317–26. ©2011 AACR.
Anthropometric Measures, Physical Activity, and Risk of Glioma and Meningioma in a Large Prospective Cohort Study
Authors: Michaud Dominique S. , Bové Gerald , Gallo Valentina , Schlehofer Brigitte , Tjønneland Anne , Olsen Anja , Overvad Kim , Dahm Christina C. , Teucher Brigit , Boeing Heiner , Steffen Annika , Trichopoulou Antonia , Bamia Christina , Kyrozis Andreas , Sacerdote Carlotta , Agnoli Claudia , Palli Domenico , Tumino Rosario , Mattiello Amalia , Bueno-de-Mesquita H. Bas , Peeters Petra H. M. , May Anne M. , Barricarte Aurelio , Chirlaque Maria-Dolores , Dorronsoro Miren , José Sánchez Maria , Rodríguez Laudina , Duell Eric J. , Hallmans Göran , Melin Beatrice S. , Manjer Jonas , Borgquist Signe , Khaw Kay-Tee , Wareham Nick , Allen Naomi E. , Travis Ruth C. , Romieu Isabelle , Vineis Paolo , Riboli Elio
Published: June 2011

Body fatness has been associated with increased risk of a number of hormone-dependent cancers. Recent studies suggest that body mass index (BMI) may be related to meningiomas, which are more common in women than men, and for which estrogens are believed to play a role. Using data from a large European propective cohort, 203 incident cases of meningioma and 340 cases of glioma were included in the analysis for measures of body fat, height, and physical activity among 380,775 participants. All analyses were conducted using Cox proportional hazards model and controlling for age, sex, country, and education. A 71% increase in risk of meningioma was observed among men and women in the top quartile of waist circumference (HR = 1.71, 95% CI = 1.08–2.73, Ptrend = 0.01). A positive association was also observed for BMI and meningioma (HR = 1.48, 95% CI = 0.98–2.23, for BMI ≥30 compared with a BMI of 20–24.9, Ptrend = 0.05). An association with height and meningioma was also suggestive (HR = 1.24, 95% 0.96–1.51, for each 10 cm increase). In contrast, no associations were observed for height and different measures of body fat and risk of glioma. Physical activity was not related to either type of brain tumors. Results from this study support an increase in risk of meningioma with higher body fatness among both men and women. No association was observed between anthropometric measures and risk of glioma. Cancer Prev Res; 4(9); 1385–92. ©2011 AACR.
Iron Homeostasis and Distal Colorectal Adenoma Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Cross Amanda J. , Sinha Rashmi , Wood Richard J. , Xue Xiaonan , Huang Wen-Yi , Yeager Meredith , Hayes Richard B. , Gunter Marc J.
Published: June 2011

Red meat consumption has been positively associated with colorectal cancer; however, the biological mechanism underlying this relationship is not understood. Red meat is a major source of iron, which may play a role in colorectal carcinogenesis via increased crypt cell proliferation, cytotoxicity, and endogenous N-nitrosation. In a nested case–control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we prospectively evaluated multiple iron exposure parameters, including dietary intake and serum measures of iron, ferritin, transferrin, total iron binding capacity (TIBC), and unsaturated iron binding capacity (UIBC) in relation to incident colorectal adenoma in 356 cases and 396 matched polyp-free controls. We also investigated variation in eight key genes involved in iron homeostasis in relation to colorectal adenoma in an additional series totaling 1,126 cases and 1,173 matched controls. We observed a positive association between red meat intake and colorectal adenoma [OR comparing extreme quartiles (ORq4-q1) = 1.59, 95% CI = 1.02–2.49, Ptrend = 0.03]. Serum TIBC and UIBC were inversely associated with colorectal adenoma (ORq4-q1 = 0.57, 95% CI = 0.37–0.88, Ptrend = 0.03; and ORq4-q1 = 0.62, 95% CI = 0.40–0.95, Ptrend = 0.04, respectively). Colorectal adenoma was not associated with serum ferritin, iron, or transferrin saturation or with polymorphisms in genes involved in iron homeostasis. Serum TIBC and UIBC, parameters that have a reciprocal relationship with overall iron load, were inversely related to colorectal adenoma, suggesting that individuals with lower iron status have a reduced risk of developing colorectal adenoma. Cancer Prev Res; 4(9); 1465–75. ©2011 AACR.
Hypoxia Does neither Stimulate Pulmonary Artery Endothelial Cell Proliferation in Mice and Rats with Pulmonary Hypertension and Vascular Remodeling nor in Human Pulmonary Artery Endothelial Cells
Authors: Yu Lunyin , Hales Charles A.
Published: June 2011

Background: Hypoxia results in pulmonary hypertension and vascular remodeling due to induction of pulmonary artery cell proliferation. Besides pulmonary artery smooth muscle cells, pulmonary artery endothelial cells (PAECs) are also involved in the development of pulmonary hypertension, but the effect of hypoxia on PAEC proliferation has not been completely understood. Methods: We investigated PAEC proliferation in mice and rats with hypoxia-induced pulmonary hypertension and vascular remodeling as well as in human PAECs under hypoxia. Results and Conclusion: We did not find significant PAEC proliferation in chronically hypoxic rats or mice. There was a slight decrease in proliferation in mice and rats with pulmonary hypertension and vascular remodeling. We also did not find significant human PAEC proliferation and cell cycle progression under different levels of oxygen (1, 2, 3, 5 and 10%) for one day, although the same conditions of hypoxia induced significant proliferation and cell cycle progression in pulmonary artery smooth muscle cells and pulmonary artery fibroblasts. Exposure to hypoxia for 7 days also did not increase PAEC proliferation. These results demonstrated that hypoxia alone is not a stimulus to PAEC proliferation in vivo and in vitro. The present study provides a novel role for PAECs in hypoxia-induced pulmonary hypertension and vascular remodeling.
Shear Stress Induces the Release of an Endothelial Elastase: Role in Integrin αvβ3-Mediated FGF-2 Release
Authors: Hennig Theres , Mogensen Christina , Kirsch Julian , Pohl Ulrich , Gloe Torsten
Published: June 2011

Background/Aims: Laminar shear stress is an important stimulus in the endothelium-dependent control of vascular tone and of vascular remodeling processes. Based on previous studies demonstrating integrin-mediated release of fibroblast growth factor 2 (FGF-2), we investigated whether shear stress-induced integrin activation requires the involvement of an extracellular protease. Methods: Cultured porcine aortic endothelial cells (PAEC) were exposed to laminar shear stress (16 dyn/cm2), whereas static cells served as controls. Results: Exposure of PAEC to shear stress led to an increased activity of a protease in supernatants. This protease could be characterized as elastase but was different from neutrophil and pancreatic elastases. The enhanced activity was accompanied by the activation of integrin αvβ3 and p38 MAPK, and followed by an increased FGF-2 concentration in the supernatant. Pretreatment with inhibitors of either elastase or integrin αvβ3 resulted in a reduction of FGF-2 release. The observed effects of shear stress on integrin αvβ3 and p38 MAPK activation, as well as on FGF-2 release could be mimicked by application of pancreatic elastase to static endothelial cells. Conclusion: By inducing the release of an endothelial elastase, shear stress induces an integrin-dependent release of FGF-2 from endothelial cells.
Role of Circadian Neuroendocrine Rhythms in the Control of Behavior and Physiology
Authors: Urbanski Henryk F.
Published: June 2011

Hormones play a major role in regulating behavior and physiology, and their efficacy is often dependent on the temporal pattern in which they are secreted. Significant insights into the mechanisms underlying rhythmic hormone secretion have been gained from transgenic rodent models, suggesting that many of the body’s rhythmic functions are regulated by a coordinated network of central and peripheral circadian pacemakers. Some neuroendocrine rhythms are driven by transcriptional-posttranslational feedback circuits comprising ‘core clock genes’, while others represent a cyclic cascade of neuroendocrine events. This review focuses on recent data from the rhesus macaque, a non-human primate model with high clinical translation potential. With primary emphasis on adrenal and gonadal steroids, it illustrates the rhythmic nature of hormone secretion, and discusses the impact that fluctuating hormone levels have on the accuracy of clinical diagnoses and on the design of effective hormone replacement therapies in the elderly. In addition, this minireview raises awareness of the rhythmic expression patterns shown by many genes, and discusses how this could impact interpretation of data obtained from gene profiling studies, especially from nocturnal rodents.
Heritable Cardiac Conduction and Myocardial Disease: From the Clinic to the Basic Science Laboratory and Back to the Clinic
Authors: Sparks Elizabeth A. , Boudoulas Konstantinos Dean , Raman Subha V. , Sasaki Takeshi , Graber Harry L. , Nelson Steven D. , Seidman Christine E. , Boudoulas Harisios
Published: June 2011

A close collaboration between the physicians-scientists of the Division of Cardiology, The Ohio State University and the basic scientists of the Department of Genetics, Harvard Medical School was essential to define the multiple phenotypic expressions and the genetic abnormalities in the heritable conduction and myocardial disease in a family from central Ohio (Family OSU). The Family OSU presents evidence of sequential hierarchical progression through multiple cardiac phenotypes (sinus bradycardia, atrioventricular conduction defects requiring pacemaker, supraventricular arrhythmias including atrial fibrillation, heart failure, and sudden cardiac death) on a decade-to-decade basis. In this setting, each phenotype may be mistakenly considered as a specific diagnosis by physicians working without a pedigree or long-term follow-up. Genetic analysis, however, confirms lamin A/C mutation. The role of the physician-scientist and the basic scientist for the study of heritable disorders is equally important but different. Only the physician-scientist, however, who is in constant contact with the patient understands the complexity of the disease. The physician-scientist with an interest in a particular disease can guide the basic scientist to define molecular mechanisms of that disease and by extension learn important lessons for other diseases.
Emotional Working Memory in Alzheimer’s Disease Patients
Authors: Satler Corina , Tomaz Carlos
Published: June 2011

Background: Few studies have assessed whether emotional content affects processes supporting working memory in Alzheimer disease (AD) patients. Methods: We assessed 22 AD patients and 40 elderly controls (EC) with a delayed matching and non-matching to sample task (DMST/DNMST), and a spatial-delayed recognition span task (SRST; unique/varied) using emotional stimuli. Results: AD patients showed decreased performance on both tasks compared with EC. With regard to the valence of the stimuli, we did not observe significant performance differences between groups in the DMST/DNMST. However, both groups remembered a larger number of negative than positive or neutral pictures on unique SRST. Conclusion: The results suggest that AD patients show a relative preservation of working memory for emotional information, particularly for negative stimuli.
Direct Inhibition of Expressed Cardiac L-Type Ca
2+
Channels by
S
-Nitrosothiol Nitric Oxide Donors
Authors: Hu Nipavan Chiamvimonvat Toshio Yamagishi Eduardo Marban Hai
Published: June 2011

Abstract
NO donors have complex effects on Ca
2+
currents in native cardiac cells, with reports of direct stimulation and indirect cGMP-mediated inhibition or stimulation. To investigate the molecular basis of these effects, we tested the effects of one class of NO donors,
S
-nitrosothiols (RSNOs), on expressed cardiovascular L-type Ca
2+
channels (α
1C
±β
1a
±α
2
or α
1C
±β
2a
±α
2
) in human embryonic kidney (HEK293) cells. The RSNO compounds we used were
S
-nitroso-
N
-acetylpenicillamine (SNAP, 5 to 10 nmol/L or 100 to 800 μmol/L),
S
-nitrosocysteine (SNC, 100 μmol/L or 1 mmol/L), and
S
-nitrosoglutathione (GSNO, 1 mmol/L). Currents were measured using whole-cell patch recordings with 2 to 10 mmol/L Ba
2+
as the charge carrier. SNAP reduced the amplitude of barium currents (I
Ba
) through all the subunit combinations, with an EC
50
of 360 μmol/L for α
1C
+β
1a
channels. SNC or GSNO also inhibited I
Ba
, albeit less potently. The inhibitory effect of SNAP was not affected by methylene blue (10 to 30 μmol/L) or 8-bromo-cGMP (200 to 400 μmol/L). The effects are relatively specific for Ca
2+
channels, as expressed cardiac or skeletal muscle Na
+
channels, which have a similar overall architecture, were barely affected by SNAP at concentrations as high as 1 mmol/L. We conclude that in the HEK293 expression system, the
S
-nitrosothiol NO donors inhibit L-type Ca
2+
channels by a mechanism independent of cGMP.
Common Variants in
CASQ2
,
GPD1L
, and
NOS1AP
Are Significantly Associated With Risk of Sudden Death in Patients With Coronary Artery Disease
Authors: Westaway Shawn K. , Reinier Kyndaron , Huertas-Vazquez Adriana , Evanado Audrey , Teodorescu Carmen , Navarro Jo , Sinner Moritz F. , Gunson Karen , Jui Jonathan , Spooner Peter , Kaab Stefan , Chugh Sumeet S.
Published: June 2011

Background—

Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD.

Methods and Results—

We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values <0.01) in the initial study sample. These SNPs were subsequently tested for replication in an independent case-control study sample from the Ore-SUDS (n=688). The association analysis in the replication stage revealed 6 SNPs associated with SCD: CASQ2 region (rs17500488,
P
=0.04; rs3010396,
P
=0.007; rs7366407;
P
=0.04), NOS1AP (rs12084280,
P
=0.04; rs10918859,
P
=0.02), and 1 SNP located ≈26 kb upstream of GPD1L (rs9862154,
P
=0.04).

Conclusions—

Common variations in or near
CASQ2, GPD1L
, and
NOS1AP
are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted.
CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess
Authors: Chu Po-Yin , Zatta Amanda , Kiriazis Helen , Chin-Dusting Jaye , Du Xiao-Jun , Marshall Tanneale , Kaye David M.
Published: June 2011

Background—

Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role.

Methods and Results—

We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition.

Conclusions—

Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.
The Timing of Cloud-to-Ground Lightning Relative to Total Lightning Activity
Authors: MacGorman Donald R. , Apostolakopoulos Ivy R. , Lund Nicole R. , Demetriades Nicholas W. S. , Murphy Martin J. , Krehbiel Paul R.
Published: June 2011

The first flash produced by a storm usually does not strike ground, but little has been published concerning the time after the first flash before a cloud-to-ground flash occurs, particularly for a variety of climatological regions. To begin addressing this issue, this study analyzed data from very-high-frequency (VHF) lightning mapping systems, which detect flashes of all types, and from the U.S. National Lightning Detection Network (NLDN), which identifies flash type and detects roughly 90% of cloud-to-ground flashes overall. VHF mapping data were analyzed from three regions: north Texas, Oklahoma, and the high plains of Colorado, Kansas, and Nebraska. The percentage of storms in which a cloud-to-ground flash was detected in the first minute of lightning activity varied from 0% in the high plains to 10%–20% in Oklahoma and north Texas. The distribution of delays to the first cloud-to-ground flash varied similarly. In Oklahoma and north Texas, 50% of storms produced a cloud-to-ground flash within 5–10 min, and roughly 10% failed to produce a cloud-to-ground flash within 1 h. In the high plains, however, it required 30 min for 50% of storms to have produced a cloud-to-ground flash, and 20% produced no ground flash within 1 h. The authors suggest that the reason high plains storms take longer to produce cloud-to-ground lightning is because the formation of the lower charge needed to produce most cloud-to-ground flashes is inhibited either by delaying the formation of precipitation in the mid- and lower levels of storms or by many of the storms having an inverted-polarity electrical structure.