bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine
Authors: Kempster Sarah L. , Belteki Gusztav , Forhead Alison J. , Fowden Abigail L. , Catalano Robert D. , Lam Brian Y. , McFarlane Ian , Charnock-Jones D. Stephen , Smith Gordon C. S.
Published: November 2010

The inflammasome is a multiprotein complex whose formation is triggered when a NOD-like receptor binds a pathogen ligand, resulting in activated caspase-1, which converts certain interleukins (IL-1β, IL-18, and IL-33) to their active forms. There is currently no information on regulation of this system around the time of birth. We employed transcript profiling of fetal rat intestinal and lung RNA at embryonic days 16 (E16) and 20 (E20) with out-of-sample validation using quantitative RT-PCR. Transcript profiling and quantitative RT-PCR demonstrated that transcripts of core components of the NOD-like receptor Nlrp6 inflammasome ( Nlrp6, Pycard, Caspase-1) and one of its substrates, IL-18, were increased at E20 compared with E16 in fetal intestine and not lung. Immunohistochemistry demonstrated increased Pycard in intestinal epithelium. Western blotting demonstrated that IL-18 was undetectable at E16, clearly detectable at E20 in its inactive form, and detectable postnatally in both its inactive and active form. Dramatic upregulation of IL-18 was also observed in the fetal sheep jejunum in late gestation ( P = 0.006). Transcription factor binding analysis of the rat array data revealed an overrepresentation of nuclear transcription factor binding sites peroxisome proliferator-activated receptor γ (PPAR-γ) and retinoid X receptor-α and chicken ovalbumin upstream promoter transcription factor 1 in the region 1,000 bp upstream of the transcription start site. Rosiglitazone, a PPAR-γ agonist, more than doubled levels of NLRP6 mRNA in human intestinal epithelial (Caco2) cells. These observations provide the first evidence, to our knowledge, linking activity of PPAR-γ to expression of a NOD-like receptor and adds to a growing body of evidence linking pattern recognition receptors of the innate immune system and intestinal colonization.
Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases
Authors: Ghishan Fayez K. , Kiela Pawel R.
Published: November 2010

Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1β, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammation-associated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD.
Effects of acute cold exposure on carotid and femoral wave intensity indexes: evidence for reflection coefficient as a measure of distal vascular resistance
Authors: Liu Jie , Yuan Li-Jun , Zhang Zuo-Ming , Duan Yun-You , Xue Jun-Hui , Yang Yi-Lin , Guo Qun , Cao Tie-Sheng
Published: November 2010

Our aim was to investigate the effects of acute cold pressor test (CPT) on augmentation index (AI) and wave intensity (WI) indexes from right common carotid artery (RCCA) and right common femoral artery (RCFA) and to test whether the reflection coefficient (RC) from wave intensity analysis can reflect the distal vascular resistance (DVR) accurately. Forty-three healthy males were randomly selected for measurements at baseline and 1 min after CPT at RCCA or RCFA. CPT induced similar increases of heart rate and blood pressure in RCCA and RCFA groups with their pulse pressures unchanged. The W2 (the second peak of WI) was too obscure in RCFA to be analyzed. The W1 (the first peak of WI) of both arteries, W1-W2 (interval between W1 and W2), and NA (negative area between W1 and W2, indicating reflected waves) of RCCA and the R-W1 (interval between the R wave of ECG and W1) of RCFA decreased obviously, whereas the W2 and R-W1 of RCCA and the RC (calculated as NA/W1) of RCFA increased with no changes in the RC of RCCA and the NA of RCFA during CPT compared with baseline. The AIs from both arteries increased significantly after CPT. These results suggested that acute CPT has opposing effects on cerebral and peripheral vascular resistances, with the former decreased and the latter increased. The RCs from RCCA and RCFA are more associated with the changes of cerebral and peripheral vascular resistances, respectively, than the NA and AI, and the RC is of guiding value in assessing DVR.
Influence of training and maturity status on the cardiopulmonary responses to ramp incremental cycle and upper body exercise in girls
Authors: McNarry Melitta A. , Welsman Joanne R. , Jones Andrew M.
Published: November 2010

It has been suggested that the potential for training to alter the physiological responses to exercise in children is related to a “maturational threshold”. To address this, we investigated the interaction of swim-training status and maturity on cardiovascular and metabolic responses to lower and upper body exercise. Twenty-one prepubertal [Pre: 11 trained (T), 10 untrained (UT)], 30 pubertal (Pub: 14 T, 16 UT), and 18 postpubertal (Post: 8 T, 10 UT) girls completed ramp incremental exercise on a cycle and an upper body ergometer. In addition to pulmonary gas exchange measurements, stroke volume and cardiac output were estimated by thoracic bioelectrical impedance, and muscle oxygenation status was assessed using near-infrared spectroscopy. All T girls had a higher peak O2uptake during cycle (Pre: T 49 ± 5 vs. UT 40 ± 4; Pub: T 46 ± 5 vs. UT 36 ± 4; Post: T 48 ± 5 vs. UT 39 ± 8 ml·kg−1·min−1; all P < 0.05) and upper body exercise (Pre: T 37 ± 6 vs. UT 32 ± 5; Pub: T 36 ± 5 vs. UT 28 ± 5; Post: T 39 ± 3 vs. UT 28 ± 7 ml·kg−1·min−1; all P < 0.05). T girls also had a higher peak cardiac output during both modalities, and this reached significance in Pub (cycle: T 21 ± 3 vs. UT 18 ± 3; upper body: T 20 ± 4 vs. UT 15 ± 4 l/min; all P < 0.05) and Post girls (cycle: T 21 ± 4 vs. UT 17 ± 2; upper body: T 22 ± 3 vs. UT 18 ± 2 l/min; all P < 0.05). None of the measured pulmonary, cardiovascular, or metabolic parameters interacted with maturity, and the magnitude of the difference between T and UT girls was similar, irrespective of maturity stage. These results challenge the notion that differences in training status in young people are only evident once a maturational threshold has been exceeded.
Breaking through a Plateau in Renal Cell Carcinoma Therapeutics: Development and Incorporation of Biomarkers
Authors: Pal Sumanta Kumar , Kortylewski Marcin , Yu Hua , Figlin Robert A.
Published: November 2010

With the Food and Drug Administration approval of 6 novel targeted agents since December 2005 and limited comparative trials to discern relative efficacy, the treatment of metastatic renal cell carcinoma (RCC) has become immensely complex. The research community must look to novel ways in which to identify appropriate candidates for selected targeted therapies; one potential strategy is the use of clinical and molecular biomarkers. A growing body of knowledge-related von Hippel Lindau-driven pathways in this disease has highlighted the potential role of hypoxia-inducible factor subtypes in distinguishing RCC patients clinically. Techniques applied in other malignancies, such as gene expression and proteomic profiling, may also ultimately allow for clinical stratification. An emerging understanding of immunologic phenomena that may affect cancer progression (i.e., tumor infiltration by CD68 lymphocytes, memory T-cells, etc.) has unveiled a number of other potential biomarkers of response. Several vascular endothelial growth factor receptor-directed therapies classically thought to function as antiangiogenics may also have complex effects upon the tumor microenvironment including the associated immune cell milieu. As such, immunologic parameters could potentially predict response to current therapies. Finally, clinical biomarkers, such as hypertension, may predict the efficacy of several currently available targeted agents, although implementation of such biomarkers remains challenging. Herein, the clinical relevance of putative RCC biomarkers is examined in detail. Mol Cancer Ther; 9(12); 3115–25. ©2010 AACR.
Serum Calcium Levels and Long-Term Mortality in Patients with Acute Stroke
Authors: Appel Shmuel A. , Molshatzki Noa , Schwammenthal Yvonne , Merzeliak Oleg , Toashi Maya , Sela Ben-Ami , Tanne David
Published: November 2010

Background: Calcium concentrations in serum are maintained within an exquisitely narrow range. Our aim was to examine the association between serum calcium and albumin-adjusted calcium (calciumadj) levels and stroke outcome in a cohort of unselected patients with acute stroke. Methods: Consecutive patients hospitalized due to acute stroke (ischemic or intracerebral hemorrhage) throughout a large medical center were systematically assessed and followed for 1 year. Baseline total calcium and calciumadj levels were collapsed into groups of low (<8.6 mg/dl), normal (8.7–9.9 mg/dl) and high (>10 mg/dl) levels and linear and quadratic relations with outcome were examined. Result: Among 784 patients (mean age 70.7 ± 12.5 years, 42.5% females), the mean ± SD total calcium level was 9.3 ± 0.6 mg/dl. For total calcium, the adjusted hazard ratio (HR) for all-cause death over 1 year was 1.83 [95% confidence interval (CI) 1.22–2.75] among patients with low versus normal levels. For calciumadj, the adjusted HR for all-cause death among women was over 3-fold higher among patients with high calciumadj levels versus those with normal levels (3.31; 95% CI 1.70–6.46), while no such associations were observed among men. In models developed to estimate the linear and quadratic relations, each unit increment in total calcium squared was associated with an increased adjusted HR of all-cause death over 1 year (p = 0.02) confirming nonlinear associations, and each unit increment in calciumadj squared was associated with an increased adjusted HR of all-cause death over 1 year among women (p < 0.001) but not among men (p = 0.70). Conclusions: Serum calcium concentrations are a marker of mortality in acute stroke patients, but the associations are not linear, increasing at both extremes of calcium levels. Our findings suggest that long-term survival is optimal in a distinct range of serum calcium levels.
The Bilirubin-Increasing Drug Atazanavir Improves Endothelial Function in Patients With Type 2 Diabetes Mellitus
Authors: Dekker Douwe , Dorresteijn Mirrin J. , Pijnenburg Margot , Heemskerk Suzanne , Rasing-Hoogveld Anja , Burger David M. , Wagener Frank A.D.T.G. , Smits Paul
Published: November 2010

Objective—

In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM.

Methods and Results—

In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 μmol/L (0.4 mg/dL) to 64 μmol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (
P
<0.001) and endothelium-dependent vasodilation (
P
=0.036) and a decrease in plasma von Willebrand factor (
P
=0.052) were observed.

Conclusion—

Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.
High-Mobility Group Box Protein 1 Neutralization Reduces Development of Diet-Induced Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Kanellakis Peter , Agrotis Alex , Kyaw Tin Soe , Koulis Christine , Ahrens Ingo , Mori Shuji , Takahashi Hideo K. , Liu Keyue , Peter Karlheinz , Nishibori Masahiro , Bobik Alex
Published: November 2010

Objective—

High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoE−/− mice.

Methods and Results—

Apolipoprotein E–deficient (ApoE−/−) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction. As with human atherosclerotic lesions, lesions in ApoE−/− mice expressed HMGB1. Treatment with the neutralizing antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43%, and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression was attenuated by 48% and 72%, respectively. CD11c+ dendritic cells were reduced by 65%, and the mature (CD83+) population was reduced by 60%. Treatment also reduced CD4+ cells by nearly 50%. mRNAs in lesions encoding tumor necrosis factor-α and interleukin-1β tended to be reduced. Mechanistically, HMGB1 stimulated macrophage migration in vitro and in vivo; in vivo, it markedly augmented the accumulation of F4/80+Gr-1(Ly-6C)+ macrophages and also increased F4/80+CD11b+ macrophage numbers.

Conclusion—

HMGB1 exerts proatherogenic effects augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells.
Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure
Authors: van Oort Ralph J. , McCauley Mark D. , Dixit Sayali S. , Pereira Laetitia , Yang Yi , Respress Jonathan L. , Wang Qiongling , De Almeida Angela C. , Skapura Darlene G. , Anderson Mark E. , Bers Donald M. , Wehrens Xander H.T.
Published: November 2010

Background

Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca
2+
release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca
2+
remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca
2+
/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias.

Methods and Results

Mice in which the S2814 Ca
2+
/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca
2+
release events, resulting in reduced sarcoplasmic reticulum Ca
2+
load on confocal microscopy. These Ca
2+
release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca
2+
/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery.

Conclusions

Our results suggest that Ca
2+
/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca
2+
release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.
Prevalence of Coronary Atherosclerosis in Patients With Cerebral Infarction
Authors: Amarenco Pierre , Lavallée Philippa C. , Labreuche Julien , Ducrocq Gregory , Juliard Jean-Michel , Feldman Laurent , Cabrejo Lucie , Meseguer Elena , Guidoux Celine , Adraï Valérie , Ratani Samina , Kusmierek Jérôme , Lapergue Bertrand , Klein Isabelle F. , Gongora-Rivera Fernando , Jaramillo Arturo , Mazighi Mikael , Touboul Pierre-Jean , Steg Philippe Gabriel
Published: November 2010

Background and Purpose—

There is an overlap between stroke and coronary heart disease, but the exact prevalence of coronary artery disease in patients with nonfatal cerebral infarction is unclear, particularly when there is no known history of coronary heart disease.

Methods—

We consecutively enrolled 405 patients presenting with acute cerebral infarction documented by neuroimaging who underwent carotid and femoral artery, thoracic, and abdominal aorta ultrasound examinations. Of the 342 patients with no known coronary heart disease, 315 underwent coronary angiography a median of 8 days (interquartile range, 6–11) after stroke onset.

Results—

Coronary plaques on angiography, regardless of stenosis severity, were present in 61.9% of patients (95% confidence interval [CI], 56.5–67.3) and coronary stenoses ≥50% were found in 25.7% (95% CI, 20.9–30.5). The overall prevalence of coronary plaque increased with the number of arterial territories (carotid or femoral arteries) involved, with an adjusted odds ratio of coronary artery disease of 1.25 (95% CI, 0.58–2.71) for presence of plaque in 1 territory, and 4.31 (95% CI, 1.92–9.68) for presence of plaque in both territories, compared with no plaque in either territory. The presence of plaque in both femoral and carotid arteries had an age- and sex-adjusted positive predictive value of 84% for presence of coronary plaque and a negative predictive value of 44%.

Conclusions—

There is a high burden of silent coronary artery disease in patients with nonfatal cerebral infarction and no known coronary heart disease, even in the absence of systemic atherosclerosis. The prevalence is even higher in patients with evidence of carotid and/or femoral plaque.
Delayed Anti-Nogo-A Therapy Improves Function After Chronic Stroke in Adult Rats
Authors: Tsai Shih-Yen , Papadopoulos Catherine M. , Schwab Martin E. , Kartje Gwendolyn L.
Published: November 2010

Background and Purpose—

We have shown that anti-Nogo-A immunotherapy to neutralize the neurite growth inhibitory protein Nogo-A results in functional improvement and enhanced plasticity after ischemic stroke in the adult rat. The present study investigated whether functional improvement and neuronal plasticity can be induced by this immunotherapy when administered to the chronic stroke-impaired rat.

Methods—

Adult rats were trained to perform the skilled forelimb reaching test, followed by permanent middle cerebral artery occlusion to impair the preferred forelimb. Nine weeks after stroke, animals showing a profound deficit were randomly distributed to 3 groups: no treatment, control antibody, or anti-Nogo-A antibody (11C7). Animals were tested weekly after stroke surgery and daily after antibody treatment until the end of the study. Biotin dextran amine tracing was injected into the nonlesioned forelimb motor cortex at the end of behavioral testing to determine axonal plasticity.

Results—

All rats showed similar forelimb impairment before treatment. Animals treated with anti-Nogo-A immunotherapy started to show improvement 3 weeks after treatment. Such improvement became significantly better than stroke-only control and control Ab-treated animals, and persisted to the end of the study. Biotin dextran amine-labeled axonal fiber analysis also showed significant enhanced corticorubral axonal sprouting from the contralesional forelimb motor cortex to the deafferented red nucleus in the anti-Nogo-A immunotherapy rats.

Conclusions—

These results indicate that improvement of chronic neurological deficits and enhancement of neuronal plasticity can be induced in the adult rat with anti-Nogo-A immunotherapy, and that this therapy may be used to restore function even when administered long after ischemic brain damage has occurred.
Can You Recognize an Effective Teacher When You Recruit One?
Authors: Rockoff Jonah E. , Jacob Brian A. , Kane Thomas J. , Staiger Douglas O.
Published: November 2010

Research on the relationship between teacher characteristics and teacher effectiveness has been underway for over a century, yet little progress has been made in linking teacher quality with factors observable at the time of hire. To extend this literature, we administered an in-depth survey to new math teachers in New York City and collected information on a number of nontraditional predictors of effectiveness, including teaching-specific content knowledge, cognitive ability, personality traits, feelings of self-efficacy, and scores on a commercially available teacher selection instrument. We find that only a few of these predictors have statistically significant relationships with student and teacher outcomes. However, the individual variables load onto two factors, which measure what one might describe as teachers' cognitive and noncognitive skills. We find that both factors have a moderately large and statistically significant relationship with student and teacher outcomes, particularly with student test scores.
Does Sector Matter? An Analysis of Planners’ Attitudes Regarding Politics and Competing Interests in the Planning Process
Authors: Read Dustin C. , Leland Suzanne M.
Published: November 2010

Both communicative planning theory and competing values models of public administration suggest attitudinal differences should exist between planners employed by private firms and those employed by government entities to the extent the perceptions of the former group are influenced by market forces to a greater degree than the latter. To test this, nine ordinal regression models were estimated using data collected from a national survey of 1,299 American Planning Association (APA) members. Planners employed in the public sector were found to be consistently more optimistic than private sector planners about government’s ability to manage political pressures and competing interests in the planning process. The results not only underscore the importance of existing planning and public administration theory but also offer a starting point to consider how sectoral differences in planners’ attitudes may influence outsourcing arrangements, public–private partnerships and other forms of cross-sector collaboration.
Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma
Authors: Sung Chang Ohk , Kim Sang Cheol , Karnan Sivasundaram , Karube Kennosuke , Shin Hyung Jin , Nam Do-Hyun , Suh Yeon-Lim , Kim Seok-Hyung , Kim Ji Yeon , Kim Seok Jin , Kim Won Seog , Seto Masao , Ko Young-Hyeh
Published: November 2010

Of the genetic changes in primary central nervous system lymphoma (PCNSL), little is known. To detect copy number alterations and differentially expressed genes in PCNSL, we analyzed a total of 12 PCNSL samples with high-resolution array-based comparative genomic hybridization and performed expression profiling in 7 of the 12 samples. The most frequent deletion found in 8 patients (66.7%) occurred in 9p21.3 containing CDKN2A. We compiled the top 96 genes (family-wise error rate, P < .05) showing the greatest differential expression between PCNSL and normal lymph node tissues. From these, we selected 8 candidate genes (NPFFR2, C4orf7, OSMR, EMCN, TPO, FNDC1, COL12A1, and MSC) in which expression changes were associated with copy number aberrations. All 8 genes showed both down-regulation in expression microarray and deletion in array-based comparative genomic hybridization analyses. These genes participate in cell signaling or cell adhesion. In addition, low mRNA expression of C4orf7 was significantly associated with poor survival (P = .0425). Using gene set enrichment analysis, we identified several signal transduction pathways, such as Janus kinase-signal transducers and activators of transcription pathway and adhesion-related pathways, which may be involved in pathogenesis of PCNSL. In conclusion, this study identified novel tumor suppressor genes that may serve as therapeutic targets of PCNSL.
A single mutation results in diploid gamete formation and parthenogenesis in a Drosophila yemanuclein-alpha meiosis I defective mutant
Authors: Meyer Régis E , Delaage Michèle , Rosset Roland , Capri Michèle , Aït-Ahmed Ounissa
Published: November 2010

Background

Sexual reproduction relies on two key events: formation of cells with a haploid genome (the gametes) and restoration of diploidy after fertilization. Therefore the underlying mechanisms must have been evolutionary linked and there is a need for evidence that could support such a model.

Results

We describe the identification and the characterization of yem

1
, the first yem-alpha mutant allele (V478E), which to some extent affects diploidy reduction and its restoration. Yem-alpha is a member of the Ubinuclein/HPC2 family of proteins that have recently been implicated in playing roles in chromatin remodeling in concert with HIRA histone chaperone. The yem

1
mutant females exhibited disrupted chromosome behavior in the first meiotic division and produced very low numbers of viable progeny. Unexpectedly these progeny did not display paternal chromosome markers, suggesting that they developed from diploid gametes that underwent gynogenesis, a form of parthenogenesis that requires fertilization.

Conclusions

We focus here on the analysis of the meiotic defects exhibited by yem

1
oocytes that could account for the formation of diploid gametes. Our results suggest that yem

1
affects chromosome segregation presumably by affecting kinetochores function in the first meiotic division.

This work paves the way to further investigations on the evolution of the mechanisms that support sexual reproduction.
A tritrophic signal that attracts parasitoids to host-damaged plants withstands disruption by non-host herbivores
Authors: Erb Matthias , Foresti Nicolas , Turlings Ted CJ
Published: November 2010

Background

Volatiles emitted by herbivore-infested plants are highly attractive to parasitoids and therefore have been proposed to be part of an indirect plant defense strategy. However, this proposed function of the plant-provided signals remains controversial, and it is unclear how specific and reliable the signals are under natural conditions with simultaneous feeding by multiple herbivores. Phloem feeders in particular are assumed to interfere with plant defense responses. Therefore, we investigated how attack by the piercing-sucking cicadellid Euscelidius variegatus influences signaling by maize plants in response to the chewing herbivore Spodoptera littoralis.

Results

The parasitoid Cotesia marginiventris strongly preferred volatiles of plants infested with its host S. littoralis. Overall, the volatile emissions induced by S. littoralis and E. variegatus were similar, but higher levels of certain wound-released compounds may have allowed the wasps to specifically recognize plants infested by hosts. Expression levels of defense marker genes and further behavioral bioassays with the parasitoid showed that neither the physiological defense responses nor the attractiveness of S. littoralis infested plants were altered by simultaneous E. variegatus attack.

Conclusions

Our findings imply that plant defense responses to herbivory can be more robust than generally assumed and that ensuing volatiles convey specific information about the type of herbivore that is attacking a plant, even in complex situations with multiple herbivores. Hence, the results of this study support the notion that herbivore-induced plant volatiles may be part of a plant's indirect defense stratagem.
Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen
Authors: Cimica Velasco , Smith Melissa E , Zhang Zhikai , Mathur Deepti , Mani Sridhar , Kalpana Ganjam V
Published: November 2010

Background

Rhabdoid Tumors (RTs) are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam) in order to reduce the concentration of flavopiridol needed for inhibition of RTs.

Methods

The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i) cell survival assays, ii) FACS analysis, iii) caspase activity assays, and iv) immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA) analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined.

Results

We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G2 arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G2 arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G2 arrest, but enhanced flavopiridol- (but not 4OH-Tam-) mediated apoptosis, by enhancing caspase 2 and 3 activities.

Conclusions

Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was enhanced by abrogation of p53. Our results warrant further studies investigating the combinatorial effects of flavopiridol and 4OH-Tam as a novel therapeutic strategy for RTs and other tumors that have been shown to respond to flavopiridol.
Determinants of delay in malaria treatment-seeking behaviour for under-five children in south-west Ethiopia: a case control study
Authors: Getahun Alemayehu , Deribe Kebede , Deribew Amare
Published: November 2010

Background

Prompt diagnosis and timely treatment of malaria within 24 hours after onset of first symptoms can reduce illness progression to severe stages and therefore, decrease mortality. The reason why mothers/caretakers delay in malaria diagnosis and treatment for under-five children is not well studied in Ethiopia. The objective of this study was to assess determinants of malaria treatment delay in under-five children in three districts of south-west Ethiopia.

Methods

A case control study was conducted from March 15 to April 20, 2010. Cases were under-five children who had clinical malaria and sought treatment after 24 hours of developing sign and symptom, and controls were under-five children who had clinical malaria and sought treatment within 24 hours of developing sign and symptom of malaria. Data were collected by trained enumerators using structured questionnaire. Data were entered in to Epi Info version 6.04 and analyzed using SPSS version 16.0. To identify determinants, multiple logistic regression was done.

Results

A total of 155 mothers of cases and 155 mothers of controls were interviewed. Mothers of children who were in a monogamous marriage (OR = 3.41, 95% CI: 1.39, 8.34), who complained about the side effects of anti-malarial drugs (OR = 4.96, 95% CI: 1.21, 20.36), who had no history of child death (OR = 3.50, 95% CI: 1.82, 6.42) and who complained about the higher cost of transportation to reach the health institutions (OR = 2.01, 95% CI: 1.17, 3.45) were more likely to be late for the treatment of malaria in under-five children.

Conclusion

Effective malaria control programmes should address reducing delayed presentation of children for treatment. Efforts to reduce delay should address transport cost, decentralization of services and increasing awareness of the community on early diagnosis and treatment.
Mammalian oocytes are targets for prostaglandin E2 (PGE2) action
Authors: Duffy Diane M , McGinnis Lynda K , VandeVoort Catherine A , Christenson Lane K
Published: November 2010

Background

The ovulatory gonadotropin surge increases synthesis of prostaglandin E2 (PGE2) by the periovulatory follicle. PGE2 actions on granulosa cells are essential for successful ovulation. The aim of the present study is to determine if PGE2 also acts directly at the oocyte to regulate periovulatory events.

Methods

Oocytes were obtained from monkeys and mice after ovarian follicular stimulation and assessed for PGE2 receptor mRNA and proteins. Oocytes were cultured with vehicle or PGE2 and assessed for cAMP generation, resumption of meiosis, and in vitro fertilization.

Results

Germinal vesicle intact (GV) oocytes from both monkeys and mice expressed mRNA for the PGE2 receptors EP2, EP3, and EP4. EP2 and EP4 proteins were detected by confocal microscopy in oocytes of both species. Monkey and mouse oocytes responded to PGE2 as well as agonists selective for EP2 and EP4 receptors with elevated cAMP, consistent with previous identification of EP2 and EP4 as Gαs/adenylyl cyclase coupled receptors. Incubation of mouse GV stage oocytes with PGE2 delayed oocyte nuclear maturation in vitro, but PGE2 treatment did not alter the percentage of mouse oocytes that fertilized successfully. PGE2 treatment also decreased the percentage of monkey oocytes that resumed meiosis in vitro. In contrast with mouse oocytes, the percentage of monkey oocytes which fertilized in vitro was lower after treatment with PGE2. Monkey oocytes with intact cumulus showed delayed nuclear maturation, but fertilization rate was not affected by PGE2 treatment.

Conclusions

Monkey and mouse oocytes express functional PGE2 receptors. PGE2 acts directly at mammalian oocytes to delay nuclear maturation. Surrounding cumulus cells modulate the effect of PGE2 to alter subsequent fertilization.
The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia
Authors: Ceulemans An-Gaëlle , Zgavc Tine , Kooijman Ron , Hachimi-Idrissi Said , Sarre Sophie , Michotte Yvette
Published: November 2010

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.
"pp65 antigenemia and real time polymerase chain reaction (PCR) based-study to determine the prevalence of human cytomegalovirus (HCMV) in kidney donors and recipients with follow-up studies."
Authors: Madhavan Hajib N , Samson Moses Y , Ishwarya Murali , Vijayakumar Ramanathan , Jambulingam Malathi
Published: November 2010

Background

The present study was undertaken to determine the rate of occurrence of Human cytomegalovirus (HCMV) among kidney transplant recipients and donors by application of direct detection methods and to understand HCMV infection/disease development among transplanted patients as a prospective study.

Results

Peripheral blood samples collected from 76 kidney donors and 76 recipients from September 2007 to August 2009 were subjected to pp65 antigenemia and Quantitative real-time PCR (qRT-PCR) assays. Data were analyzed under Group A, B and C. Group A was further divided into sub-groups I, II, III, IV, and V for better understanding. Three, one and two donors in sub-group I, III, IV of Group A tested positive for real time PCR respectively. One recipient from group III tested positive for HCMV by qRT- PCR prior transplantation and remained positive one month post-transplantation. Three other recipients, tested negative prior to transplantation became positive a month after transplantation. Group B consisted of 18 donor-recipient pairs and one of the donor tested positive for HCMV by qRT-PCR. Eight recipients tested positive for HCMV one month after transplantation. The pp65 positivity and HCMV DNA load was high among group C recipients who mostly had symptoms of active disease. Significantly high values of pp65 antigenemia were observed among recipients of sub-group II (non-parametric chi-square test p = 0.007). Positive correlation between pp65 antigenemia and qRT-PCR value was observed. Thirty three of the recipients with disease treated with Valgancyclovir showed improved clinical outcome.

Conclusion

Our study showed that a significant proportion of kidney recipients develop HCMV infection following renal transplantation in spite of the absence of HCMV among donors. pp65 antigenemia assay and qRT- PCR methods can be applied to detect HCMV among kidney donors and recipients to monitor development of disease and these assays were predicative of HCMV infection among them. Clinical resistant to valganciclovir was not observed.
Further developments towards a genome-scale metabolic model of yeast
Authors: Dobson Paul D , Smallbone Kieran , Jameson Daniel , Simeonidis Evangelos , Lanthaler Karin , Pir Pınar , Lu Chuan , Swainston Neil , Dunn Warwick B , Fisher Paul , Hull Duncan , Brown Marie , Oshota Olusegun , Stanford Natalie J , Kell Douglas B , King Ross D , Oliver Stephen G , Stevens Robert D , Mendes Pedro
Published: November 2010

Background

To date, several genome-scale network reconstructions have been used to describe the metabolism of the yeast Saccharomyces cerevisiae, each differing in scope and content. The recent community-driven reconstruction, while rigorously evidenced and well annotated, under-represented metabolite transport, lipid metabolism and other pathways, and was not amenable to constraint-based analyses because of lack of pathway connectivity.

Results

We have expanded the yeast network reconstruction to incorporate many new reactions from the literature and represented these in a well-annotated and standards-compliant manner. The new reconstruction comprises 1102 unique metabolic reactions involving 924 unique metabolites - significantly larger in scope than any previous reconstruction. The representation of lipid metabolism in particular has improved, with 234 out of 268 enzymes linked to lipid metabolism now present in at least one reaction. Connectivity is emphatically improved, with more than 90% of metabolites now reachable from the growth medium constituents. The present updates allow constraint-based analyses to be performed; viability predictions of single knockouts are comparable to results from in vivo experiments and to those of previous reconstructions.

Conclusions

We report the development of the most complete reconstruction of yeast metabolism to date that is based upon reliable literature evidence and richly annotated according to MIRIAM standards. The reconstruction is available in the Systems Biology Markup Language (SBML) and via a publicly accessible database http://www.comp-sys-bio.org/yeastnet/.
The nature and combination of subunits used in epitope-based Schistosoma japonicum vaccine formulations affect their efficacy
Authors: Wang Xuefeng , Zhang Lei , Chi Ying , Hoellwarth Jason , Zhou Sha , Wen Xiaoyun , He Lei , Liu Feng , Wu Calvin , Su Chuan
Published: November 2010

Background

Schistosomiasis remains a major public health problem in endemic countries and is caused by infections with any one of three primary schistosome species. Although there are no vaccines available to date, this strategy appears feasible since natural immunity develops in individuals suffering from repeated infection during a lifetime. Since vaccinations resulting in both Th1- and Th2-type responses have been shown to contribute to protective immunity, a vaccine formulation with the capacity for stimulating multiple arms of the immune response will likely be the most effective. Previously we developed partially protective, single Th- and B cell-epitope-based peptide-DNA dual vaccines (PDDV) (T3-PDDV and B3-PDDV, respectively) capable of eliciting immune responses against theSchistosoma japonicum22.6 kDa tegument antigen (Sj22.6) and a 62 kDa fragment of myosin (Sj62), respectively.

Results

In this study, we developed PDDV cocktails containing multiple epitopes ofS. japonicumfrom Sj22.6, Sj62 and Sj97 antigens by predicting cytotoxic, helper, and B-cell epitopes, and evaluated vaccine potentialin vivo. Results showed that mice immunized with a single-epitope PDDV elicited either Tc, Th, or B cell responses, respectively, and mice immunized with either the T3- or B3- single-epitope PDDV formulation were partially protected against infection. However, mice immunized with a multicomponent (3 PDDV components) formulation elicited variable immune responses that were less immunoprotective than single-epitope PDDV formulations.

Conclusions

Our data show that combining these different antigens did not result in a more effective vaccine formulation when compared to each component administered individually, and further suggest that immune interference resulting from immunizations with antigenically distinct vaccine targets may be an important consideration in the development of multicomponent vaccine preparations.
Systematic review and meta-analysis: the relationship between the Helicobacter pylori dupA gene and clinical outcomes
Authors: Shiota Seiji , Matsunari Osamu , Watada Masahide , Hanada Katsuhiro , Yamaoka Yoshio
Published: November 2010

Background

In 2005, the first disease-specific Helicobacter pylori virulence factor that induced duodenal ulcer and had a suppressive action on gastric cancer has been identified, and was named duodenal ulcer promoting gene (dupA). However, the importance of the dupA gene on clinical outcomes is conflicting in subsequent studies. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with dupA gene.

Methods

A meta-analysis of case-control studies which provided raw data on the infection rates with the dupA-positive H. pylori detected by polymerase chain reaction was performed.

Results

Seventeen studies with a total of 2,466 patients were identified in the search. Infection with the dupA-positive H. pylori increased the risk for duodenal ulcer by 1.41-fold (95% confidence interval [CI], 1.12-1.76) overall. Subgroup analysis showed that the summary odds ratio (OR) was 1.57 (95% CI, 1.19-2.06) in Asian countries and 1.09 (95% CI, 0.73-1.62) in Western countries. There was no association between the presence of the dupA gene and gastric cancer and gastric ulcer. Publication bias did not exist.

Conclusion

Our meta-analysis confirmed the importance of the presence of the dupA gene for duodenal ulcer, especially in Asian countries.
Prognostic Significance of Expression of a Single MicroRNA, miR-181a, in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Schwind Sebastian , Maharry Kati , Radmacher Michael D. , Mrózek Krzysztof , Holland Kelsi B. , Margeson Dean , Whitman Susan P. , Hickey Christopher , Becker Heiko , Metzeler Klaus H. , Paschka Peter , Baldus Claudia D. , Liu Shujun , Garzon Ramiro , Powell Bayard L. , Kolitz Jonathan E. , Carroll Andrew J. , Caligiuri Michael A. , Larson Richard A. , Marcucci Guido , Bloomfield Clara D.
Published: November 2010

Purpose

To evaluate the prognostic significance of expression levels of a single microRNA, miR-181a, in the context of established molecular markers in cytogenetically normal acute myeloid leukemia (CN-AML), and to gain insight into the leukemogenic role of miR-181a.

Patients and Methods

miR-181a expression was measured in pretreatment marrow using Ohio State University Comprehensive Cancer Center version 3.0 arrays in 187 younger (< 60 years) adults with CN-AML. Presence of other molecular prognosticators was assessed centrally. A gene-expression profile associated with miR-181a expression was derived using microarrays and evaluated by Gene-Ontology analysis.

Results

Higher miR-181a expression associated with a higher complete remission (CR) rate (P = .04), longer overall survival (OS; P = .01) and a trend for longer disease-free survival (DFS; P = .09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P = .009), and longer DFS (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥ 60 years) patients with CN-AML. A miR-181a-associated gene-expression profile was characterized by enrichment of genes usually involved in innate immunity.

Conclusion

To our knowledge, we provide the first evidence that the expression of a single microRNA, miR-181a, is associated with clinical outcome of patients with CN-AML and may refine their molecular risk classification. Targeted treatments that increase endogenous levels of miR-181a might represent novel therapeutic strategies.