bluuebunny/crossref_metadata_2025 huggingface dataset:
Human CD59 Inhibitor Sensitizes Rituximab-Resistant Lymphoma Cells to Complement-Mediated Cytolysis
Authors: Hu Weiguo , Ge Xiaowen , You Tao , Xu Ting , Zhang Jinyan , Wu Gongxiong , Peng Zhihai , Chorev Michael , Aktas Bertal H. , Halperin Jose A. , Brown Jennifer R. , Qin Xuebin
Published: January 2011

Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non–Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here, we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining pharmcokinetic/pharmacodynamic profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occur due to selection of preexisting clones rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Furthermore, they suggest that preemptive elimination of CD59-overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance. Cancer Res; 71(6); 2298–307. ©2011 AACR.
Overexpression of HMGA2 Promotes Metastasis and Impacts Survival of Colorectal Cancers
Authors: Wang Xiaochen , Liu Xiyong , Li Angela Ying-Jian , Chen Lirong , Lai Lily , Lin Her Helen , Hu Shuya , Yao Lifang , Peng Jiaping , Loera Sofia , Xue Lijun , Zhou Bingsen , Zhou Lun , Zheng Shu , Chu Peiguo , Zhang Suzhan , Ann David Kong , Yen Yun
Published: January 2011

Purpose: This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC).

Experimental Design: This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan–Meier analysis and COX proportional hazard model were employed to analyze the survivability.

Results: Multivariate logistic analysis indicated that the expression of HMGA2 significantly correlates with distant metastasis in training set (odds ratio, OR = 3.53, 95% CI: 1.37–9.70) and validation set (OR = 6.38, 95% CI: 1.47–43.95). Survival analysis revealed that the overexpression of HMGA2 is significantly associated with poor survival of CRC patients (P < 0.05). The adjusted HRs for overall survival were 2.38 (95% CI: 1.30–4.34) and 2.14 (95% CI: 1.21–3.79) in training and validation sets, respectively. Further investigation revealed that HMGA2 delays the clearance of γ-H2AX in HCT-116 and SW480 cells post γ-irradiation, which supports our finding that CRC patients with HMAG2-positive staining in primary tumors had augmented the efficacy of adjuvant radiotherapy (HR = 0.18, 95% CI: 0.04–0.63).

Conclusion: Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy. Clin Cancer Res; 17(8); 2570–80. ©2011 AACR.
Enhanced Anticancer Effect of the Combination of Cisplatin and TRAIL in Triple-Negative Breast Tumor Cells
Authors: Xu Liping , Yin Shuping , Banerjee Sanjeev , Sarkar Fazlul , Reddy Kaladhar B.
Published: January 2011

Women with triple-negative breast cancer (TNBC) have a worse prognosis compared with other breast cancer subtypes. Hormonal or Herceptin-based therapies were found to be ineffective because of the loss of target receptors, such as ER, PR, and HER-2 amplification. Conventional chemo- and/ or radiation therapy also seems to have limited efficacy in TNBC patients. We studied the effects of cisplatin plus TRAIL on 1 normal and 2 TNBC cells in vitro. The in vitro studies indicate that cisplatin plus TRAIL significantly enhanced cell death in TNBC cell lines CRL2335 and MDA-MB-468 by approximately 60%–70% compared with approximately 10%–15% in CRL8799 normal breast cell line. Treatment with cisplatin/TRAIL also inhibited the expression of EGFR, p63, survivin, Bcl-2, and Bcl-xL in TNBC cells. Specific inhibition of EGFR and/or p63 protein in TNBC cells by small interfering RNA (siRNA) does not increase TRAIL-induced apoptosis. However, inhibition of survivin by siRNA enhances TRAIL-induced apoptosis. These observations suggested the possibility that survivin played an important role in cisplatin plus TRAIL-induced apoptosis in TNBC cells. In vivo experiments, treatment of mice with cisplatin plus TRAIL resulted in a significant inhibition of CRL2335 xenograft tumors compared with untreated control tumors. Taken together the data suggest that cisplatin plus TRAIL treatment have the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients. Mol Cancer Ther; 10(3); 550–7. ©2011 AACR.
Global microRNA Analysis of the NCI-60 Cancer Cell Panel
Authors: Søkilde Rolf , Kaczkowski Bogumil , Podolska Agnieszka , Cirera Susanna , Gorodkin Jan , Møller Søren , Litman Thomas
Published: January 2011

MicroRNAs (miRNA) are a group of short noncoding RNAs that regulate gene expression at the posttranscriptional level. They are involved in many biological processes, including development, differentiation, apoptosis, and carcinogenesis. Because miRNAs may play a role in the initiation and progression of cancer, they comprise a novel class of promising diagnostic and prognostic molecular markers and potential drug targets. By applying an LNA-enhanced microarray platform, we studied the expression profiles of 955 miRNAs in the NCI-60 cancer cell lines and identified tissue- and cell-type–specific miRNA patterns by unsupervised hierarchical clustering and statistical analysis. A comparison of our data to three previously published miRNA expression studies on the NCI-60 panel showed a remarkably high correlation between the different technical platforms. In addition, the current work contributes expression data for 369 miRNAs that have not previously been profiled. Finally, by matching drug sensitivity data for the NCI-60 cells to their miRNA expression profiles, we found numerous drug–miRNAs pairs, for which the miRNA expression and drug sensitivity profiles were highly correlated and thus represent potential candidates for further investigation of drug resistance and sensitivity mechanisms. Mol Cancer Ther; 10(3); 375–84. ©2011 AACR.
Diabetic Patients’ Knowledge of Therapeutic Goals in Kuwait
Authors: Awad Abdelmoneim , Dalle Hala , Enlund Hannes
Published: January 2011

Objective: This study was conducted to analyze patients’ knowledge about therapeutic goals for diabetic patients and factors associated with good knowledge. Methods: A total of 266 diabetic patients were randomly selected from 6 diabetes clinics in Kuwait to be included in a cross-sectional patient survey. Data were collected via face-to-face structured interviews using a pretested questionnaire. Descriptive and logistic regression analysis was used in data analysis. Results: The response rate was 93% (n = 247). The percentages [95% confidence interval (CI)] of patients who reported knowing their recent levels of low-density lipoprotein cholesterol (LDL-C), blood pressure (BP), and glycosylated hemoglobin (HbA1c) were 5% (2–8), 54% (48–60), and 8% (5–11), respectively. The percentages (95% CI) of patients who admitted knowing the target goals for LDL-C, BP, HbA1c, fasting, and postprandial blood glucose levels were 3% (1–6), 49% (43–55), 6% (3–9), 62% (56–68) and 55% (49–61), respectively. Correct target goals for LDL-C, BP, HbA1c, fasting, and postprandial blood glucose levels were reported by 2% (1–4), 43% (37–49), 5% (2–8), 60% (54–66), and 47% (41–53), respectively. Those with a high education (OR = 4.76; 95% CI 2.34–9.68) and those with a family history of diabetes (OR = 3.05; 95% CI 1.50–6.19) had good knowledge about correct targets. Conclusion: The current findings revealed that lack of knowledge about recent levels of BP, LDL-C and HbA1c and therapeutic goals was alarmingly high, which highlights the need for the implementation of an effective multidisciplinary team approach to encourage patient education and self-care.
Prevalence of Hypertension in a Population of Healthy Individuals
Authors: Elkhalifa Ashraf M. , Kinsara Abdulhalim Jamal , Almadani Doha A.
Published: January 2011

Objectives: To assess the prevalence of hypertension (HTN) in a random sample of individuals in Jeddah, Kingdom of Saudi Arabia. Subjects and Methods: A total of 243 participants were randomly selected at a megamall in Jeddah, on May 2008. Questionnaires were distributed to all the participants by one of the researchers, who explained the purpose of the study and the content of the questionnaire. The questionnaire was designed to gather information regarding the prevalence of HTN in the general population in addition to identifying other risk factors associated with HTN. Notably, accurate blood pressure measurements were performed on all the participants. Results: Of the 243 participants, 55 (22.6%) were hypertensive. Of these, 28 (50.9%) were males and 27 (49.1%) females. The probability of having HTN was significantly higher with increasing age with 7 (38.9%) of the participants >50 years of age. Similarly, HTN increased proportionately with the participant’s body mass index. With regard to other risk factors, 13 (50%) of the diabetics, 10 (27.0%) of the dyslipidemic participants and 9 (18.4%) of the cigarette-smoking participants had HTN. Conclusions: The occurrence of HTN was high and was strongly associated with diabetes, the aging process and obesity.
Safety of Intratympanic Injection of AM-101 in Patients with Acute Inner Ear Tinnitus
Authors: Muehlmeier G. , Biesinger E. , Maier H.
Published: January 2011

Effective pharmacological treatments for tinnitus have proven elusive. Emerging evidence suggests that dysregulation of cochlear N-methyl-D-aspartate (NMDA) receptors may underlie aberrant excitation of the auditory nerve, which in turn is perceived as tinnitus. The blocking of these receptors thus represents a promising therapeutic approach. In a recent phase I/II clinical trial, the safety and local tolerance of intratympanic injections of the NMDA receptor antagonist AM-101 was evaluated for the first time in humans. The results from the double-blind, randomized, placebo-controlled study show that intratympanically injected AM-101 was well tolerated by study participants, and provided the first indications of therapeutic efficacy.
Ischemic Stroke Outcome and Early Infection: Its Deleterious Effect Seems to Operate Also among Tissue Plasminogen Activator-Treated Patients
Authors: Salat David , Delgado Pilar , Alonso Sara , Ribó Marc , Santamarina Estevo , Quintana Manuel , Alvarez-Sabín José , Montaner Joan
Published: January 2011

Background: Infection has been recognized as a significant predictor of outcome for ischemic stroke patients, although the mechanisms by which this association is operative have not been fully established, and their potential roles in a setting of close clinical monitoring, such as that of stroke units offering reperfusion therapies, have not been evaluated. Methods: We reviewed the medical records of 139 consecutive tissue plasminogen activator-treated stroke patients admitted to our stroke unit to evaluate potential predictors of neurological outcome. Results: 57 patients (41%) did not show neurological improvement by discharge, and 11.5% died during admission. Infections were related to lack of improvement (29.8 vs. 14.6%; p = 0.03) and PH-type hemorrhagic transformation (42.1 vs. 17.5%; p = 0.014); the latter was associated with a higher mortality rate (26.3 vs. 9.2%; p = 0.03). Conclusions: Infection may be associated with poor functional outcome among tissue plasminogen activator-treated stroke patients.
Pneumothorax and Bullae in Marfan Syndrome
Authors: Karpman Craig , Aughenbaugh Gregory L. , Ryu Jay H.
Published: January 2011

Background: Increased risk of spontaneous pneumothorax has been described in patients with Marfan syndrome and has been attributed, in part, to the presence of apical blebs and bullae. Objectives: We assess the risk of pneumothorax and its relationship to the presence of apical blebs and bullae in patients with Marfan syndrome in the era of CT imaging. Methods: A retrospective cohort study was performed of all patients 13 years or older with Marfan syndrome evaluated at the Mayo Clinic, Rochester, Minn., USA, from 1998 through 2008. One hundred and sixty-six patients met the current diagnostic criteria for Marfan syndrome and had chest imaging studies available for review. Results: The median age was 40 years (range 14–71); 37% had a smoking history. Eight of 166 patients (4.8%) had experienced 1 or more episodes of spontaneous pneumothorax, and 2 of these 8 patients had 2 or more episodes. Apical blebs or bullae were identified on radiologic imaging in 16 patients (9.6%). Four of 16 (25%) patients with apical blebs or bullae had a history of spontaneous pneumothorax compared to 4 of 150 patients (2.7%) without blebs or bullae (p = 0.003). Conclusions: The frequency of blebs is relatively low in patients with Marfan syndrome but the risk of pneumothorax is significantly higher in those with radiologically detectable blebs or bullae. Chest CT scanning to identify blebs and bullae may allow risk stratification for pneumothorax in patients with Marfan syndrome.
Impact of Hypotension and Low Cerebral Perfusion Pressure on Outcomes in Children Treated with Hypothermia Therapy following Severe Traumatic Brain Injury: A post hoc Analysis of the Hypothermia Pediatric Head Injury Trial
Authors: Hutchison James S. , Frndova Helena , Lo Tsz-Yan M. , Guerguerian Anne-Marie ,   for the Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group
Published: January 2011

Hypotension and low cerebral perfusion pressure are known to be associated with unfavorable outcome in children and adults with traumatic brain injury. Using the database from a previously published, randomized controlled trial of 24 h of hypothermia therapy in children with severe traumatic brain injury, we compared the number of patients with hypotension or low cerebral perfusion pressure between the hypothermia therapy and normothermia groups. We also determined the association between these physiologic insults and unfavorable outcome using regression analysis. There were more patients with episodes of hypotension or low cerebral perfusion pressure in the hypothermia therapy group than in the normothermia group. These physiologic insults were associated with unfavorable outcome in both intervention groups. Hypotension and low cerebral perfusion pressure should be anticipated and prevented in future trials of hypothermia therapy in patients with traumatic brain injury.
Tissue Factor–Bearing Microparticles and Thrombus Formation
Authors: Zwicker Jeffrey I. , Trenor Cameron C. , Furie Barbara C. , Furie Bruce
Published: January 2011

Blood microparticles are vesicular structures with a diameter of 100 to 1000 nm that are present in the blood of normal subjects and in patients with various diseases. These microparticles are derived from cells that circulate in the blood and cells associated with the blood vessel wall. Microparticle membranes retain the protein receptors of their parent cells and may retain RNAs and other cytosolic content. On the basis of surface protein expression, microparticles are known to be derived from platelets, granulocytes, monocytes, endothelial cells, smooth muscle cells, and tumor cells. Only a subpopulation of these microparticles expresses tissue factor.
Cosegregation of Aortic Root Atherosclerosis and Intermediate Lipid Phenotypes on Chromosomes 2 and 8 in an Intercross of C57BL/6 and BALBc/ByJ Low-Density Lipoprotein Receptor
−/−
Mice
Authors: Burkhardt Ralph , Sündermann Simon , Ludwig Doris , Ceglarek Uta , Holdt Lesca M. , Thiery Joachim , Teupser Daniel
Published: January 2011

Objective—

We sought to identify novel atherosclerosis-modifying loci and their potential functional links in a genome-wide approach using cosegregation analysis of atherosclerosis and related intermediate phenotypes in mice.

Methods and Results—

We carried out an F2 intercross between atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant BALB/cByJ mice on the low-density lipoprotein receptor
−/−
background to examine the genetic basis for their differences in atherosclerosis susceptibility. Atherosclerotic lesion size and a comprehensive panel of 61 atherosclerosis-related phenotypes, including plasma levels of lipids, cytokines, and chemokines were measured in 376 F2 mice. Quantitative trait locus mapping revealed a novel significant locus (logarithm of odds, 6.18) for atherosclerosis on proximal mouse chromosome (Chr) 2 (Ath39), which was associated with major variations in lesion size (14%). Plasma very-low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lanosterol, and phytosterol levels cosegregated with atherosclerosis at this locus. Moreover, these lipid traits showed significant correlations with lesion size, suggesting that they share the same underlying genetic factor. We also describe a second male-specific locus on Chr 8 (Ath40) where atherosclerosis and lipids cosegregated.

Conclusion—

Our study revealed new loci for atherosclerosis susceptibility on mouse Chr 2 and 8, which might exert their effects on lesion size via plasma lipid levels.
Lipoprotein(a) Genetic Variants Associated With Coronary and Peripheral Vascular Disease but Not With Stroke Risk in the Heart Protection Study
Authors: Hopewell Jemma C. , Clarke Robert , Parish Sarah , Armitage Jane , Lathrop Mark , Hager Jorg , Collins Rory
Published: January 2011

Background—

Genetic studies have identified 2 single-nucleotide polymorphisms (SNPs) at the
LPA
locus (rs3798220 and rs10455872) that are strongly and independently related to lipoprotein(a) levels and to coronary disease risk, but their relevance for other atherothrombotic disease is uncertain.

Methods and Results—

These 2
LPA
SNPs were examined together as an
LPA
genotype score for associations with vascular outcomes among participants in the Heart Protection Study. The
LPA
score was examined first in 12 236 participants with prevalent vascular disease (9277 coronary disease cases, and 1326 ischemic stroke and 2011 peripheral vascular disease cases with no history of coronary disease) and 3687 vascular disease-free controls and, subsequently, in 3251 participants who had incident major vascular events during follow-up (2106 coronary disease, 507 ischemic stroke, and 707 peripheral vascular disease events). For prevalent disease, the
LPA
score was strongly associated with coronary disease (odds ratio [OR] per variant allele, 1.19; 95% CI, 1.08 to 1.30) and peripheral vascular disease (OR, 1.18; 95% CI, 1.04 to 1.34) but not with ischemic stroke (OR, 1.03; 95% CI, 0.89 to 1.20). Similarly, for incident disease, the
LPA
score was strongly associated with coronary disease (hazard ratio [HR], 1.19; 95% CI, 1.09 to 1.30) and peripheral vascular disease (HR, 1.20; 95% CI, 1.02 to 1.40) but not with ischemic stroke (HR, 0.83; 95% CI, 0.67 to 1.03).

Conclusions—

The comparable strength of associations of the
LPA
score with coronary disease and peripheral vascular disease but not with stroke suggest that lipoprotein(a) may have effects on atherothrombotic vascular disease that are only relevant at specific sites.

Clinical Trial Registration—

URL:
http://isrctn.org
. Unique identifier: ISRCTN48489393.
Reactive Oxygen Species–Activated Ca/Calmodulin Kinase IIδ Is Required for Late
I
Na
Augmentation Leading to Cellular Na and Ca Overload
Authors: Wagner Stefan , Ruff Hanna M. , Weber Sarah L. , Bellmann Sarah , Sowa Thomas , Schulte Timo , Anderson Mark E. , Grandi Eleonora , Bers Donald M. , Backs Johannes , Belardinelli Luiz , Maier Lars S.
Published: January 2011

Rationale:

In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late
I
Na
leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation.

Objective:

We tested whether CaMKIIδ is required for ROS-dependent late
I
Na
regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved.

Methods and Results:

40 μmol/L H
2
O
2
significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca]
i
(5 mmol/L BAPTA/1 mmol/L Br
2
-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 μmol/L), the H
2
O
2
-dependent CaMKII oxidation and autophosphorylation was abolished. H
2
O
2
significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H
2
O
2
increased late
I
Na
(whole cell patch-clamp). This increase was abolished in CaMKIIδ
−/−
myocytes. H
2
O
2
-induced [Na]
i
and [Ca]
i
accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKIIδ
−/−
myocytes (versus WT). CaMKIIδ
−/−
myocytes developed significantly less H
2
O
2
-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late
I
Na
, [Na]
i
and [Ca]
i
accumulation) were obtained by overexpression of CaMKIIδ in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 μmol/L KN93 or 0.1 μmol/L AIP [autocamtide 2–related inhibitory peptide]).

Conclusions:

Free [Ca]
i
and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIδ enhances late
I
Na
, which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression.
Endothelial Cell–Specific Deficiency of Ang II Type 1a Receptors Attenuates Ang II–Induced Ascending Aortic Aneurysms in LDL Receptor
−/−
Mice
Authors: Rateri Debra L. , Moorleghen Jessica J. , Balakrishnan Anju , Owens A. Phillip , Howatt Deborah A. , Subramanian Venkateswaran , Poduri Aruna , Charnigo Richard , Cassis Lisa A. , Daugherty Alan
Published: January 2011

Rationale:

Human studies and mouse models have provided evidence for angiotensin II (Ang II)–based mechanisms as an underlying cause of aneurysms localized to the ascending aorta. In agreement with this associative evidence, we have published recently that Ang II infusion induces aneurysmal pathology in the ascending aorta.

Objective:

The aim of this study was to define the role of angiotensin II type 1a (AT
1a
) receptors and their cellular location in Ang II–induced ascending aortic aneurysms (AAs).

Methods and Results:

Male LDL receptor
−/−
mice were fed a saturated fat–enriched diet for 1 week before osmotic mini-pump implantation and infused with either saline or Ang II (1000 ng/kg per minute) for 28 days. Intimal surface areas of ascending aortas were measured to quantify ascending AAs. Whole body AT
1a
receptor deficiency ablated Ang II–induced ascending AAs (
P
<0.001). To determine the role of AT
1a
receptors on leukocytes, LDL receptor
−/−
×AT
1a
receptor
+/+
or AT
1a
receptor
−/−
mice were irradiated and repopulated with bone marrow–derived cells isolated from either AT
1a
receptor
+/+
or AT
1a
receptor
−/−
mice. Deficiency of AT
1a
receptors in bone marrow–derived cells had no effect on Ang II–induced ascending AAs. To determine the role of AT
1a
receptors on vascular wall cells, we developed AT
1a
receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT
1a
receptor deletion in smooth muscle cells had no effect on ascending AAs. In contrast, endothelial-specific depletion attenuated this pathology.

Conclusions:

Ang II infusion promotes aneurysms in the ascending aorta via stimulation of AT
1a
receptors that are expressed on endothelial cells.
Notch Signaling Regulates Smooth Muscle Differentiation of Epicardium-Derived Cells
Authors: Grieskamp Thomas , Rudat Carsten , Lüdtke Timo H.-W. , Norden Julia , Kispert Andreas
Published: January 2011

Rationale:

The embryonic epicardium plays a crucial role in the formation of the coronary vasculature and in myocardial development, yet the exact contribution of epicardium-derived cells (EPDCs) to the vascular and connective tissue of the heart, and the factors that regulate epicardial differentiation, are insufficiently understood.

Objective:

To define the role of Notch signaling in murine epicardial development.

Methods and Results:

Using in situ hybridization and RT-PCR analyses, we detected expression of a number of Notch receptor and ligand genes in early epicardial development, as well as during formation of coronary arteries. Mice with epicardial deletion of
Rbpj
, the unique intracellular mediator of Notch signaling, survived to adulthood and exhibited enlarged coronary venous and arterial beds. Using a
Tbx18
-based genetic lineage tracing system, we show that EPDCs give rise to fibroblasts and coronary smooth muscle cells (SMCs) but not to endothelial cells in the wild type, whereas in
Rbpj
-deficient embryos EPDCs form and surround the developing arteries but fail to differentiate into SMCs. Conditional activation of Notch signaling results in premature SMC differentiation of epicardial cells and prevents coronary angiogenesis. We further show that Notch signaling regulates, and cooperates with transforming growth factor β signaling in SM differentiation of EPDCs.

Conclusions:

Notch signaling is a crucial regulator of SM differentiation of EPDCs, and thus, of formation of a functional coronary system.
An Investigation of Interruptions and Resumptions in Multi-Tasking Dialogues
Authors: Yang Fan , Heeman Peter A. , Kun Andrew L.
Published: January 2011

In this article we focus on human–human multi-tasking dialogues, in which pairs of conversants, using speech, work on an ongoing task while occasionally completing real-time tasks. The ongoing task is a poker game in which conversants need to assemble a poker hand, and the real-time task is a picture game in which conversants need to find out whether they have a certain picture on their displays. We employ empirical corpus studies and machine learning experiments to understand the mechanisms that people use in managing these complex interactions. First, we examine task interruptions: switching from the ongoing task to a real-time task. We find that generally conversants tend to interrupt at a less disruptive context in the ongoing task when possible. We also find that the discourse markers oh and wait occur in initiating a task interruption twice as often as in the conversation of the ongoing task. Pitch is also found to be statistically correlated with task interruptions; in fact, the more disruptive the task interruption, the higher the pitch. Second, we examine task resumptions: returning to the ongoing task after completing an interrupting real-time task. We find that conversants might simply resume the conversation where they left off, but sometimes they repeat the last utterance or summarize the critical information that was exchanged before the interruption. Third, we apply machine learning to determine how well task interruptions can be recognized automatically and to investigate the usefulness of the cues that we find in the corpus studies. We find that discourse context, pitch, and the discourse markers oh and wait are important features to reliably recognize task interruptions; and with non-lexical features one can improve the performance of recognizing task interruptions with more than a 50% relative error reduction over a baseline. Finally, we discuss the implication of our findings for building a speech interface that supports multi-tasking dialogue.
Grammar Factorization by Tree Decomposition
Authors: Gildea Daniel
Published: January 2011

We describe the application of the graph-theoretic property known as treewidth to the problem of finding efficient parsing algorithms. This method, similar to the junction tree algorithm used in graphical models for machine learning, allows automatic discovery of efficient algorithms such as the O(n4) algorithm for bilexical grammars of Eisner and Satta. We examine the complexity of applying this method to parsing algorithms for general Linear Context-Free Rewriting Systems. We show that any polynomial-time algorithm for this problem would imply an improved approximation algorithm for the well-studied treewidth problem on general graphs.
Event-related Repetitive TMS Reveals Distinct, Critical Roles for Right OFA and Bilateral Posterior STS in Judging the Sex and Trustworthiness of Faces
Authors: Dzhelyova Milena P. , Ellison Amanda , Atkinson Anthony P.
Published: January 2011

Judging the sex of faces relies on cues related to facial morphology and spatial relations between features, whereas judging the trustworthiness of faces relies on both structural and expressive cues that signal affective valence. The right occipital face area (OFA) processes structural cues and has been associated with sex judgments, whereas the posterior STS processes changeable facial cues related to muscle movements and is activated when observers judge trustworthiness. It is commonly supposed that the STS receives inputs from the OFA, yet it is unknown whether these regions have functionally dissociable, critical roles in sex and trustworthiness judgments. We addressed this issue using event-related, fMRI-guided repetitive transcranial magnetic stimulation (rTMS). Twelve healthy volunteers judged the sex of individually presented faces and, in a separate session, whether those same faces were trustworthy or not. Relative to sham stimulation, RTs were significantly longer for sex judgments when rTMS was delivered over the right OFA but not the right or left STS, and for trustworthiness judgments on male but not female faces when rTMS was delivered over the right STS or left STS but not the right OFA. Nonetheless, an analysis of the RT distributions revealed a possible critical role also for the right OFA in trustworthiness judgments, limited to faces with longer RTs, perhaps reflecting the later, ancillary use of structural cues related to the sex of the face. On the whole, our findings provide evidence that evaluations of the trustworthiness and sex of faces rely on functionally dissociable cortical regions.
Second-language Instinct and Instruction Effects: Nature and Nurture in Second-language Acquisition
Authors: Yusa Noriaki , Koizumi Masatoshi , Kim Jungho , Kimura Naoki , Uchida Shinya , Yokoyama Satoru , Miura Naoki , Kawashima Ryuta , Hagiwara Hiroko
Published: January 2011

Adults seem to have greater difficulties than children in acquiring a second language (L2) because of the alleged “window of opportunity” around puberty. Postpuberty Japanese participants learned a new English rule with simplex sentences during one month of instruction, and then they were tested on “uninstructed complex sentences” as well as “instructed simplex sentences.” The behavioral data show that they can acquire more knowledge than is instructed, suggesting the interweaving of nature (universal principles of grammar, UG) and nurture (instruction) in L2 acquisition. The comparison in the “uninstructed complex sentences” between post-instruction and pre-instruction using functional magnetic resonance imaging reveals a significant activation in Broca's area. Thus, this study provides new insight into Broca's area, where nature and nurture cooperate to produce L2 learners' rich linguistic knowledge. It also shows neural plasticity of adult L2 acquisition, arguing against a critical period hypothesis, at least in the domain of UG.
Task-invariant Brain Responses to the Social Value of Faces
Authors: Todorov Alexander , Said Christopher P. , Oosterhof Nikolaas N. , Engell Andrew D.
Published: January 2011

In two fMRI experiments (n = 44) using tasks with different demands—approach–avoidance versus one-back recognition decisions—we measured the responses to the social value of faces. The face stimuli were produced by a parametric model of face evaluation that reduces multiple social evaluations to two orthogonal dimensions of valence and power [Oosterhof, N. N., & Todorov, A. The functional basis of face evaluation. Proceedings of the National Academy of Sciences, U.S.A., 105, 11087–11092, 2008]. Independent of the task, the response within regions of the occipital, fusiform, and lateral prefrontal cortices was sensitive to the valence dimension, with larger responses to low-valence faces. Additionally, there were extensive quadratic responses in the fusiform gyri and dorsal amygdala, with larger responses to faces at the extremes of the face valence continuum than faces in the middle. In all these regions, participants' avoidance decisions correlated with brain responses, with faces more likely to be avoided evoking stronger responses. The findings suggest that both explicit and implicit face evaluation engage multiple brain regions involved in attention, affect, and decision making.
Civilian Crisis Management in the EU – Structural and Functional Aspects
Authors: Malešič Marjan
Published: January 2011

This article offers a general overview of civilian crisis management in the EU, its mechanisms and instruments, the nature of civil-military cooperation (coordination), and an overview of civilian crisis management missions. Particular attention will be paid to the EULEX Mission in Kosovo as a case-study of how participating civilian experts judge both the mission itself and the mission preparations (i.e. selection and training of personnel, mission strategy, mission related activities, the problems identified etc.). The article will argue that seemingly trivial operational details, such as personnel selection, the quality of pre-deployment training and advance preparation are important factors which, if not properly coordinated, could jeopardise EU goals in the field of crisis management. The author also presumes that unregulated civil-military cooperation and coordination can lead to the failure of crisis management operations.
Coherence and Coordination The Limits of the Comprehensive Approach
Authors: Coning Cedric de , Friis Karsten
Published: January 2011

This article explores why international actors assign such high importance to coherence. It argues that the assumptions on which the principle of coherence is based are flawed, and that the empirical and theoretical evidence indicates that there is much less room for coherence than generally acknowledged in the policy debate. It recommends that the international community should lower its expectations and adopt more realistic polices. The current approach tends to put pressure on all partners to adopt a maximal approach to coherence, regardless of their relations to each other and the operational context. Coherence should not be understood as an effort aimed equally at all, nor should all partners be expected to achieve the same level of unity of effort. Coherence should rather be understood as a scale of relationships, and the most appropriate and realistic level of coherence that can be achieved will depend on the exact constellation of organizations in an interdependent relationship in that specific operational context. This article offers a typology of the range of likely relationships, as well as an explanation of the circumstances that may determine the level of coherence that can be realistically expected to develop, depending on the context and the nature of the relationships among the partners.
Transnational Policing and International Human Development – A Rule of Law Perspective
Authors: Murney Tony , Crawford Sue-Ellen , Hider Andie
Published: January 2011

This study engages in an empirical analysis of the relationship between the rule of law and human development in the world order. Its goal is to determine whether lasting development can be achieved in emerging states without progress in the rule of law. The study relies on seven empirical models which plot seven separate human development indices against the rule of law index. Based on the empirical models, the study proposes a set of development paths for emerging nations which account for the possible ways in which emerging states achieve development. The study also recognises other development paths which take account of malignant development challenges occurring where there is specific resistance to development programs. Based on the evidence in the empirical models, the study concludes that the rule of law and human development are essential to one another to ensure development in emerging states and therefore police and other personnel working in these environments should modify their operational policies to implement this conclusion.
The rationalization of civil society
Authors: Papakostas Apostolis
Published: January 2011

Two ideas are almost universally accepted as reality in political sociology. One is that numbers are declining in nearly all membership associations. The usual interpretation of this phenomenon is that it occurs because of individualization. The other is that the character of collective action has changed. This idea, which stems from Touraine, Melucci and Castells, states that a new historical category of social action has emerged, one that resembles action in primary groups rather than in organizations and in some way is a victory over the iron law of oligarchy. This article questions both ideas. The author intends to show that another historical process is in play here, namely, a process of ‘inert rationalization’ in social movements, political parties and associations, which is taking place in Europe with different starting points and at different tempos. The result of this process can be summed up as ‘more organization with fewer people’. Domination, inherent in oligarchic organizations, is being transformed by the creation of a new organizational boundary between elite (or profession) and members. The point is that it is membership itself as a form for affiliation that is disappearing, not just members. The article argues that this is mainly because resource mobilization patterns have historically changed from the mobilization of resources drawn from members to the mobilization of resources drawn from other organizations. Finally, the article analyses the importance of the unstructured power fields (or open spaces) created by rationalization processes for social innovation and new social movements.
Deprofessionalization of a female occupation: Challenges for the sociology of professions
Authors: Andrews Therese Marie , Wærness Kari
Published: January 2011

This article argues that Norwegian public health nurses, after a long period of professionalization, have recently undergone a process of deprofessionalization. Public health nurses’ jurisdiction has become heavily circumscribed. They have lost duties linked with power and respect in the local community and they have lost monopoly on duties originally ascribed to the profession. Despite these changes, this study indicates a conspicuous lack of open disputes, conflicts or demands centred on jurisdiction and jurisdictional claims. In other words, the manner in which public health nurses cope with recent changes in their job structure does not seem to follow an easily explainable pattern in terms of prevailing sociological theories on professions. It is argued that the sociology of professions needs to develop theories that can explain why deprofessionalization sometimes occurs without resistance.
The impact of transnational migration on gender and marriage in sending communities of Vietnam
Authors: Bélanger Danièle , Tran Giang Linh
Published: January 2011

The recent, rapid increase in cross-border marriages between women from Southeast Asia and men from East Asia is creating a new international migration flow of ‘marriage migrants’ in the region. This article documents how marriage migration reconfigures gender power relations in three migrant-sending communities in Southern Vietnam. Analyses of data collected in 2007 indicate changes in the status of daughters and sons and a significant transformation of the marriage market. Emigrant daughters experienced enhanced status and power at home, mostly through remittances, to the extent that villagers expressed an increased preference for having girls rather than boys. Young women’s emigration has created a skewed marriage market, which gives village women and their families more bargaining power in marriage transactions. Getting married is difficult for many single men in the village due to the perceived greater value of foreign men, higher bride-prices and a shortage of potential brides. Overall, villagers view marriage migration as contributing to significant social transformations with respect to gender and power relations in households and in the marriage market.
Revisiting the Category of Fragile and Failed States in International Relations
Authors: Nuruzzaman Mohammed
Published: January 2011

International Relations scholars and policy-makers are increasingly paying greater attention to a new category of fragile and failed states across Asia, Africa, the Balkans, the Caucasus, Latin America and the Middle East. While effective policy responses are necessary to strengthen these politically fractured, economically collapsing and socially divided states, the category itself appears to be more politically and ideologically charged and less critically understood in the context of international relations. There is a general tendency to avoid examining how political and economic policies and military actions by the West contributed to the degeneration of these states. This article seeks to re-examine the causes of state fragility and failure, and critically reviews the current US strategies to rebuild the failed states of Afghanistan and Iraq. It argues that the US-led statebuilding strategies in both countries are based on a wrong diagnosis of the political and social problems, and the solutions offered are also ill-conceived. The article also contends that the Western liberal vision of the state, premised on the Weberian notion, commands less relevance to the fragile and failed states in the non-Western world.
Lebanese and Palestinian Perspectives on Suicide Bombings
Authors: Haddad Simon
Published: January 2011

While suicide terrorism has received tremendous attention from the general public, media and policy-makers in recent years, there are only a few studies that analyze public opinion on political violence in general and terrorism in particular. The article seeks to determine the correlates of support for suicide terrorism among the Lebanese and Palestinians living in South Lebanon and the Palestinian territories. Specifically, it examines the influence of religious and socio-economic factors on their attitudes towards suicide bombings. The analysis is based on four surveys conducted in Lebanon and the Palestinian territories in 2002, 2003 and 2007. The findings show that generally, militant religious view is the most important predictor of the respondents’ support for suicide terrorism.
Students With LD in Higher Education
Authors: Heiman Tali , Shemesh Dorit Olenik
Published: January 2011

This study examined the extent and patterns of usage of web courses, and their contribution to the academic and social perceptions of 964 undergraduate students with and without learning disabilities studying in higher education. Students were asked to complete four questionnaires examining the usage patterns of various adaptive technologies and their contribution to the student. The questionnaires assessed Perceptions of Learning through Online Usage; Accessibility of Campus Computing; Hope Scale and Subjective Well-being Scale. A detailed examination of the usage patterns of online courses revealed that, compared to the comparison group, students with LD log more often into the course sites, going into the forum more frequently and leaving significantly more messages on the forum than students in the comparison group. Findings indicated that students with LD are more familiar with assistive technology and use it more than the comparison group. Students with LD reported higher scores on the Hope scale, they felt an increased drive to find different pathways to attain their goals, as well as being motivated to pursue those goals, and their subjective well-being was higher that of the students in the comparison group.
Examining Agreement and Longitudinal Stability Among Traditional and RTI-Based Definitions of Reading Disability Using the Affected-Status Agreement Statistic
Authors: Brown Waesche Jessica S. , Schatschneider Christopher , Maner Jon K. , Ahmed Yusra , Wagner Richard K.
Published: January 2011

Rates of agreement among alternative definitions of reading disability and their 1- and 2-year stabilities were examined using a new measure of agreement, the affected-status agreement statistic. Participants were 288,114 first through third grade students. Reading measures were Dynamic Indicators of Basic Early Literacy Skills Oral Reading Fluency and Nonsense Word Fluency, and six levels of severity of poor reading were examined (25th, 20th, 15th, 10th, 5th, and 3rd percentile ranks). Four definitions were compared, including traditional unexpected low achievement and three response-to-intervention-based definitions: low achievement, low growth, and dual discrepancy. Rates of agreement were variable but only poor to moderate overall, with poorest agreement between unexpected low achievement and the other definitions. Longitudinal stability was poor, with poorest stability for the low growth definition. Implications for research and practice are discussed.
Studying performance of DEVS modeling and simulation environments using the DEVStone benchmark
Authors: Wainer Gabriel , Glinsky Ezequiel , Gutierrez-Alcaraz Marcelo
Published: January 2011

The Discrete Event System Specification (DEVS) formal modeling and simulation (M&S) framework (which supports hierarchical and modular model composition) has been widely used to understand, analyze and develop a variety of systems. Numerous DEVS simulators have been developed; nevertheless, evaluating the performance of such simulators is a complex process and it has been usually done using ad hoc methods. DEVStone, instead, is a synthetic benchmark that can be used to automate the evaluation of the performance of DEVS-based simulators. DEVStone generates a suite of models with varied structure and behavior automatically. To do so, it uses a standardized mechanism that can be the basis for comparisons between simulation software tools. As a proof of the concept, we present various tests in which DEVStone was used to study the efficiency of five different simulation engines. In this case, we compared various versions of the CD++ simulator, and then compared its performance with the ‘A Discrete Event System Simulator’ (ADEVS) M&S tool. This is the first effort in which these simulation tools have been thoroughly compared with a very demanding set of experiments. The use of DEVStone allowed a standardized and exhaustive method to compare different features of the simulation software. We show how the basic ideas used for DEVStone facilitates performance analysis for upgrades and updates of a given simulation engine, while also providing a common metric to compare different M&S environments.