bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol for a systematic review of the diagnostic and prognostic utility of tests currently available for the detection of aspirin resistance in patients with established cardiovascular or cerebrovascular disease
Authors: Raichand Smriti , Moore David , Riley Richard D , Lordkipanidzé Marie , Dretzke Janine , O’Donnell Jennifer , Jowett Sue , Bayliss Sue , Fitzmaurice David A
Published: February 2013

Background

The benefits of aspirin as an anti-platelet agent are well established; however, there has been much debate about the lack of uniformity in the efficacy of aspirin to inhibit platelet function. In some patients, aspirin fails to inhibit platelets even where compliance has been verified, a phenomenon which has been termed “aspirin resistance”. These patients may in turn be at a higher risk of future vascular events. The proportion of “resistant” patients identified depends on the type of platelet function test. Therefore, the aim of this systematic review is to determine which, if any, platelet function test has utility in terms of identifying patients with a high risk of vascular events. The review has been registered with PROSPERO (CRD42012002151).

Methods

Relevant studies will be sought from bibliographic databases. Trials registers will be searched for ongoing studies. Reference lists will be checked and subject experts contacted. There will be no date or language restrictions. Standard reviewing methodology to minimise bias will be employed. Any prospective studies in patients on aspirin therapy and assessing platelet function in relation to relevant clinical outcomes will be included, as will studies reporting prognostic models. Risk of bias assessment will be based on the Quality Assessment of Diagnostic Accuracy Studies guidelines, and suitable criteria for assessing quality of prognostic studies. Data on test accuracy measures, relative risks, odds or hazard ratios will be extracted and meta-analysed, where possible, using a random-effects model to account for between-study heterogeneity. Where appropriate, the causes of heterogeneity will be explored through meta-regression and sub-group or sensitivity analyses. If platelet function testing is demonstrated to have diagnostic/predictive utility in a specific population, the potential for a cost-effectiveness analysis will be considered and, if possible, an economic model constructed. This will be supported by a systematic review of existing economic evaluation studies.

Discussion

The results of the review could indicate if platelet function test(s) could lead to a reliable prediction of the risk of clinically important events in a defined population, and thus support investigations into adjustments to therapy in order to compensate for a predicted poor response to standard aspirin.
The quantitative proteomic response of Synechocystis sp. PCC6803 to phosphate acclimation
Authors: Fuszard Matthew A , Ow Saw Yen , Gan Chee Sian , Noirel Josseilin , Ternan Nigel G , McMullan Geoff , Biggs Catherine A , Reardon Kenneth F , Wright Phillip C
Published: February 2013

Background

Inorganic phosphate (Pi) is a critical nutrient for all life and is periodically limiting in marine and freshwater provinces, yet little is understood how organisms acclimate to fluctuations in Pi within their environment. To investigate whole cell adaptation, we grew Synechocystis sp. PCC6803, a model freshwater cyanobacterium, in 3%, and 0.3% inorganic phosphate (Pi) media. The cells were allowed to acclimate over 60 days, and cells were harvested for quantitative high throughput mass spectrometry-based proteomics using the iTRAQ™ labelling technology.

Results

In total, 120 proteins were identified, and 52 proteins were considered differentially abundant compared to the control. Alkaline phosphatase (APase) activities correlated significantly (p < 0.05) with observed relative PhoA abundances. PstS1 and PstS2 were both observed, yet PstS1 was not differentially more abundant than the control. Phycobilisome protein abundances appeared to be coordinated, and are significantly less abundant in 0.3% Pi than 3% Pi cultures. Also, the central metabolic cell function appears to have shifted towards the production of (NADPH) reducing energy and nucleotide sugars.

Conclusions

This acclimation response bears strong similarity to the previously reported response to nitrogen deprivation within Synechocystis sp. PCC 6803. However, it also demonstrates some characteristics of desiccation stress, such as the regulation of fatty acids and increased abundance of rehydrin in the 3% Pi culture.
The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age
Authors: Caorsi Roberta , Lepore Loredana , Zulian Francesco , Alessio Maria , Stabile Achille , Insalaco Antonella , Finetti Martina , Battagliese Antonella , Martini Giorgia , Bibalo Chiara , Martini Alberto , Gattorno Marco
Published: February 2013

Introduction

Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype.

Methods

13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation.

Results

seven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab.

Conclusions

The use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.
Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study
Authors: Scarmo Stephanie , Afanasyeva Yelena , Lenner Per , Koenig Karen L , Horst Ronald L , Clendenen Tess V , Arslan Alan A , Chen Yu , Hallmans Göran , Lundin Eva , Rinaldi Sabina , Toniolo Paolo , Shore Roy E , Zeleniuch-Jacquotte Anne
Published: February 2013

Introduction

Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent.

Methods

We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH)D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.

Results

No association was observed between circulating levels of 25(OH)D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH)D > 0.70). An inverse association between 25(OH)D levels and breast cancer risk was observed among women who were ≤ 45 years of age (ORQ5-Q1 = 0.48, 95% CI = 0.30-0.79, ptrend = 0.01) or premenopausal at enrollment (ORQ5-Q1 = 0.67, 95% CI = 0.48-0.92, ptrend = 0.03).

Conclusions

Circulating 25(OH)D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention.
Transcriptome analyses of primitively eusocial wasps reveal novel insights into the evolution of sociality and the origin of alternative phenotypes
Authors: Ferreira Pedro G , Patalano Solenn , Chauhan Ritika , Ffrench-Constant Richard , Gabaldón Toni , Guigó Roderic , Sumner Seirian
Published: February 2013

Background

Understanding how alternative phenotypes arise from the same genome is a major challenge in modern biology. Eusociality in insects requires the evolution of two alternative phenotypes - workers, who sacrifice personal reproduction, and queens, who realize that reproduction. Extensive work on honeybees and ants has revealed the molecular basis of derived queen and worker phenotypes in highly eusocial lineages, but we lack equivalent deep-level analyses of wasps and of primitively eusocial species, the latter of which can reveal how phenotypic decoupling first occurs in the early stages of eusocial evolution.

Results

We sequenced 20 Gbp of transcriptomes derived from brains of different behavioral castes of the primitively eusocial tropical paper wasp Polistes canadensis. Surprisingly, 75% of the 2,442 genes differentially expressed between phenotypes were novel, having no significant homology with described sequences. Moreover, 90% of these novel genes were significantly upregulated in workers relative to queens. Differential expression of novel genes in the early stages of sociality may be important in facilitating the evolution of worker behavioral complexity in eusocial evolution. We also found surprisingly low correlation in the identity and direction of expression of differentially expressed genes across similar phenotypes in different social lineages, supporting the idea that social evolution in different lineages requires substantial de novo rewiring of molecular pathways.

Conclusions

These genomic resources for aculeate wasps and first transcriptome-wide insights into the origin of castes bring us closer to a more general understanding of eusocial evolution and how phenotypic diversity arises from the same genome.
IL-12Rβ2 is critical for survival of primaryFrancisella tularensisLVS infection
Authors: Melillo Amanda A , Foreman Oded , Elkins Karen L
Published: February 2013

IL-12Rβ2 is critical in parenteral and mucosal host resistance to primary Francisella tularensis LVS infection, and controls liver damage.

Using a panel of vaccines that provided different degrees of protection, we previously identified the IL-12 receptor subunit β2 as a mediator, whose relative expression correlated with strength of protection against secondary lethal challenge of vaccinated mice with an intracellular bacterium, the LVS of Francisella tularensis. The present study therefore tested the hypothesis that IL-12Rβ2 is an important mediator in resistance to LVS by directly examining its role during infections. IL-12Rβ2 KO mice were highly susceptible to LVS primary infection, administered i.d. or i.n. The LD50 of LVS infection of KO mice were 2 logs lower than those of WT mice, regardless of route. Five days after infection with LVS, bacterial organ burdens were significantly higher in IL-12Rβ2 KO mice. IL-12Rβ2 KO mice infected with lethal doses of LVS had more severe liver pathology, including significant increases in the liver enzymes ALT and AST. Despite decreased levels of IFN-γ, LVS-vaccinated IL-12Rβ2 KO mice survived large lethal LVS secondary challenge. Consistent with in vivo protection, in vitro intramacrophage LVS growth was well-controlled in cocultures containing WT or IL-12Rβ2 KO LVS-immune splenocytes. Thus, survival of secondary LVS challenge was not strictly dependent on IL-12Rβ2. However, IL-12Rβ2 is important in parenteral and mucosal host resistance to primary LVS infection and in the ability of WT mice to clear LVS infection and serves to restrict liver damage.
Effects of Melatonin on Appetite and Other Symptoms in Patients With Advanced Cancer and Cachexia: A Double-Blind Placebo-Controlled Trial
Authors: Del Fabbro Egidio , Dev Rony , Hui David , Palmer Lynn , Bruera Eduardo
Published: February 2013

Purpose

Prior studies have suggested that melatonin, a frequently used integrative medicine, can attenuate weight loss, anorexia, and fatigue in patients with cancer. These studies were limited by a lack of blinding and absence of placebo controls. The primary purpose of this study was to compare melatonin with placebo for appetite improvement in patients with cancer cachexia.

Patients and Methods

We performed a randomized, double-blind, 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or GI cancer, appetite scores ≥ 4 on a 0 to 10 scale (10 = worst appetite), and history of weight loss ≥ 5%. Assessments included weight, symptoms by the Edmonton Symptom Assessment Scale, and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Differences between groups from baseline to day 28 were analyzed using one-sided, two-sample t tests or Wilcoxon two-sample tests. Interim analysis halfway through the trial had a Lan-DeMets monitoring boundary with an O'Brien-Fleming stopping rule. Decision boundaries were to accept the null hypothesis of futility if the test statistic z < 0.39 (P ≥ .348) and reject the null hypothesis if z > 2.54 (P ≤ .0056).

Results

After interim analysis of 48 patients, the study was closed for futility. There were no significant differences between groups for appetite (P = .78) or other symptoms, weight (P = .17), FAACT score (P = .95), toxicity, or survival from baseline to day 28.

Conclusion

In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo.
Temporal Trends in Mortality From Diseases of the Circulatory System After Treatment for Hodgkin Lymphoma: A Population-Based Cohort Study in Sweden (1973 to 2006)
Authors: Eloranta Sandra , Lambert Paul C. , Sjöberg Jan , Andersson Therese M.L. , Björkholm Magnus , Dickman Paul W.
Published: February 2013

Purpose

Hodgkin lymphoma (HL) survival in Sweden has improved dramatically over the last 40 years, but little is known about the extent to which efforts aimed at reducing long-term treatment-related mortality have contributed to the improved prognosis.

Methods

We used population-based data from Sweden to estimate the contribution of treatment-related mortality caused by diseases of the circulatory system (DCS) to temporal trends in excess HL mortality among 5,462 patients diagnosed at ages 19 to 80 between 1973 and 2006. Flexible parametric survival models were used to estimate excess mortality. In addition, we used recent advances in statistical methodology to estimate excess mortality in the presence of competing causes of death.

Results

Excess DCS mortality within 20 years after diagnosis has decreased continually since the mid-1980s and is expected to further decrease among patients diagnosed in the modern era. Age at diagnosis and sex were important predictors for excess DCS mortality, with advanced age and male sex being associated with higher excess DCS mortality. However, when accounting for competing causes of death, we found that excess DCS mortality constitutes a relatively small proportion of the overall mortality among patients with HL in Sweden.

Conclusion

Excess DCS mortality is no longer a common source of mortality among Swedish patients with HL. The main causes of death among long-term survivors today are causes other than HL, although other (non-DCS) excess mortality also persists for as long as 20 years after diagnosis, particularly among older patients.
Histomolecular Phenotypes and Outcome in Adenocarcinoma of the Ampulla of Vater
Authors: Chang David K. , Jamieson Nigel B. , Johns Amber L. , Scarlett Christopher J. , Pajic Marina , Chou Angela , Pinese Mark , Humphris Jeremy L. , Jones Marc D. , Toon Christopher , Nagrial Adnan M. , Chantrill Lorraine A. , Chin Venessa T. , Pinho Andreia V. , Rooman Ilse , Cowley Mark J. , Wu Jianmin , Mead R. Scott , Colvin Emily K. , Samra Jaswinder S. , Corbo Vincenzo , Bassi Claudio , Falconi Massimo , Lawlor Rita T. , Crippa Stefano , Sperandio Nicola , Bersani Samantha , Dickson Euan J. , Mohamed Mohamed A.A. , Oien Karin A. , Foulis Alan K. , Musgrove Elizabeth A. , Sutherland Robert L. , Kench James G. , Carter C. Ross , Gill Anthony J. , Scarpa Aldo , McKay Colin J. , Biankin Andrew V.
Published: February 2013

Purpose

Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies.

Patients and Methods

We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater.

Results

Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P < .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome.

Conclusion

Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Gonadal- and Sex-Chromosome-Dependent Sex Differences in the Circadian System
Authors: Kuljis Dika A. , Loh Dawn H. , Truong Danny , Vosko Andrew M. , Ong Margaret L. , McClusky Rebecca , Arnold Arthur P. , Colwell Christopher S.
Published: February 2013

Compelling reasons to study the role of sex in the circadian system include the higher rates of sleep disorders in women than in men and evidence that sex steroids modulate circadian control of locomotor activity. To address the issue of sex differences in the circadian system, we examined daily and circadian rhythms in wheel-running activity, electrical activity within the suprachiasmatic nucleus, and PER2::LUC-driven bioluminescence of gonadally-intact adult male and female C57BL/6J mice. We observed greater precision of activity onset in 12-hour light, 12-hour dark cycle for male mice, longer activity duration in 24 hours of constant darkness for female mice, and phase-delayed PER2::LUC bioluminescence rhythm in female pituitary and liver. Next, in order to investigate whether sex differences in behavior are sex chromosome or gonadal sex dependent, we used the 4 core genotypes (FCG) mouse model, in which sex chromosome complement is independent of gonadal phenotype. Gonadal males had more androgen receptor expression in the suprachiasmatic nucleus and behaviorally reduced photic phase shift response compared with gonadal female FCG mice. Removal of circulating gonadal hormones in adults, to test activational vs organizational effects of sex revealed that XX animals have longer activity duration than XY animals regardless of gonadal phenotype. Additionally, we observed that the activational effects of gonadal hormones were more important for regulating activity levels in gonadal male mice than in gonadal female FCG mice. Taken together, sex differences in the circadian rhythms of activity, neuronal physiology, and gene expression were subtle but provide important clues for understanding the pathophysiology of the circadian system.
Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh
Authors: Ferri Anna , Favaro Rebecca , Beccari Leonardo , Bertolini Jessica , Mercurio Sara , Nieto-Lopez Francisco , Verzeroli Cristina , La Regina Federico , De Pietri Tonelli Davide , Ottolenghi Sergio , Bovolenta Paola , Nicolis Silvia K.
Published: February 2013

The Sox2 transcription factor is active in stem/progenitor cells throughout the developing vertebrate central nervous system. However, its conditional deletion at E12.5 in mouse causes few brain developmental problems, with the exception of the postnatal loss of the hippocampal radial glia stem cells and the dentate gyrus. We deleted Sox2 at E9.5 in the telencephalon, using a Bf1-Cre transgene. We observed embryonic brain defects that were particularly severe in the ventral, as opposed to the dorsal, telencephalon. Important tissue loss, including the medial ganglionic eminence (MGE), was detected at E12.5, causing the subsequent impairment of MGE-derived neurons. The defect was preceded by loss of expression of the essential ventral determinants Nkx2.1 and Shh, and accompanied by ventral spread of dorsal markers. This phenotype is reminiscent of that of mice mutant for the transcription factor Nkx2.1 or for the Shh receptor Smo. Nkx2.1 is known to mediate the initial activation of ventral telencephalic Shh expression. A partial rescue of the normal phenotype at E14.5 was obtained by administration of a Shh agonist. Experiments in Medaka fish indicate that expression of Nkx2.1 is regulated by Sox2 in this species also. We propose that Sox2 contributes to Nkx2.1 expression in early mouse development, thus participating in the region-specific activation of Shh, thereby mediating ventral telencephalic patterning induction.
Matrix adhesion polarizes heart progenitor induction in the invertebrate chordate Ciona intestinalis
Authors: Norton Jennifer , Cooley James , Islam A. F. M. Tariqul , Cota Christina D. , Davidson Brad
Published: February 2013

Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous. Here, we employ the invertebrate chordate Ciona intestinalis to delineate an essential in vivo role for matrix adhesion in heart progenitor induction. In Ciona pre-cardiac founder cells, invasion of the underlying epidermis promotes localized induction of the heart progenitor lineage. We found that these epidermal invasions are associated with matrix adhesion along the pre-cardiac cell/epidermal boundary. Through targeted manipulations of RAP GTPase activity, we were able to manipulate pre-cardiac cell-matrix adhesion. Targeted disruption of pre-cardiac cell-matrix adhesion blocked heart progenitor induction. Conversely, increased matrix adhesion generated expanded induction. We were also able to selectively restore cell-matrix adhesion and heart progenitor induction through targeted expression of Ci-Integrin β2. These results indicate that matrix adhesion functions as a necessary and sufficient extrinsic cue for regional heart progenitor induction. Furthermore, time-lapse imaging suggests that cytokinesis acts as an intrinsic temporal regulator of heart progenitor adhesion and induction. Our findings highlight a potentially conserved role for matrix adhesion in early steps of vertebrate heart progenitor specification.
A membrane-associated β-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells
Authors: Faunes Fernando , Hayward Penelope , Descalzo Silvia Muñoz , Chatterjee Sujash S. , Balayo Tina , Trott Jamie , Christoforou Andrew , Ferrer-Vaquer Anna , Hadjantonakis Anna-Katerina , Dasgupta Ramanuj , Arias Alfonso Martinez
Published: February 2013

The maintenance of pluripotency in mouse embryonic stem cells (mESCs) relies on the activity of a transcriptional network that is fuelled by the activity of three transcription factors (Nanog, Oct4 and Sox2) and balanced by the repressive activity of Tcf3. Extracellular signals modulate the activity of the network and regulate the differentiation capacity of the cells. Wnt/β-catenin signaling has emerged as a significant potentiator of pluripotency: increases in the levels of β-catenin regulate the activity of Oct4 and Nanog, and enhance pluripotency. A recent report shows that β-catenin achieves some of these effects by modulating the activity of Tcf3, and that this effect does not require its transcriptional activation domain. Here, we show that during self-renewal there is negligible transcriptional activity of β-catenin and that this is due to its tight association with membranes, where we find it in a complex with Oct4 and E-cadherin. Differentiation triggers a burst of Wnt/β-catenin transcriptional activity that coincides with the disassembly of the complex. Our results establish that β-catenin, but not its transcriptional activity, is central to pluripotency acting through a β-catenin/Oct4 complex.
PUF-8 and TCER-1 are essential for normal levels of multiple mRNAs in theC. elegansgermline
Authors: Pushpa Kumari , Kumar Ganga Anil , Subramaniam Kuppuswamy
Published: February 2013

PUF family proteins are well-conserved regulators of cell proliferation in different developmental processes. They regulate target mRNAs by promoting degradation or by influencing translation through interaction with the translation initiation machinery. Here we show that Caenorhabditis elegans PUF-8 functions redundantly with the nuclear protein TCER-1 in the post-transcriptional maintenance of at least six germline mRNAs. The levels of spliced mRNAs in the puf-8(-) tcer-1(-) double mutant are only 10-30% of the wild type, whereas the unspliced forms increase by ∼2- to 3-fold compared with the wild type. These two proteins colocalise at the inner nuclear periphery, and their absence leads to reduced germ cell proliferation and to sterility. A yeast two-hybrid screen of 31 components of the nuclear pore complex and mRNA processing machineries identified seven proteins involved in mRNA export as potential partners of PUF-8. One of these, the nuclear cap-binding protein NCBP-2, colocalises with PUF-8 in the nucleus. A 50 amino acid N-terminal domain of PUF-8 is essential for interaction with NCBP-2 and for PUF-8 to function redundantly with TCER-1. These results reveal two important unexpected aspects of PUF proteins: that, in addition to the C-terminal PUF domain, the N-terminal domain is crucial for PUF function, and that PUF proteins have a novel role in mRNA maintenance. We propose that PUF proteins, in addition to their known cytoplasmic roles, participate in nuclear processing and/or export of mRNAs.
The ETS domain transcriptional repressor Anterior open inhibits MAP kinase and Wingless signaling to couple tracheal cell fate with branch identity
Authors: Caviglia Sara , Luschnig Stefan
Published: February 2013

Cells at the tips of budding branches in the Drosophila tracheal system generate two morphologically different types of seamless tubes. Terminal cells (TCs) form branched lumenized extensions that mediate gas exchange at target tissues, whereas fusion cells (FCs) form ring-like connections between adjacent tracheal metameres. Each tracheal branch contains a specific set of TCs, FCs, or both, but the mechanisms that select between the two tip cell types in a branch-specific fashion are not clear. Here, we show that the ETS domain transcriptional repressor anterior open (aop) is dispensable for directed tracheal cell migration, but plays a key role in tracheal tip cell fate specification. Whereas aop globally inhibits TC and FC specification, MAPK signaling overcomes this inhibition by triggering degradation of Aop in tip cells. Loss of aop function causes excessive FC and TC specification, indicating that without Aop-mediated inhibition, all tracheal cells are competent to adopt a specialized fate. We demonstrate that Aop plays a dual role by inhibiting both MAPK and Wingless signaling, which induce TC and FC fate, respectively. In addition, the branch-specific choice between the two seamless tube types depends on the tracheal branch identity gene spalt major, which is sufficient to inhibit TC specification. Thus, a single repressor, Aop, integrates two different signals to couple tip cell fate selection with branch identity. The switch from a branching towards an anastomosing tip cell type may have evolved with the acquisition of a main tube that connects separate tracheal primordia to generate a tubular network.
Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function
Authors: Guner-Ataman Burcu , Paffett-Lugassy Noelle , Adams Meghan S. , Nevis Kathleen R. , Jahangiri Leila , Obregon Pablo , Kikuchi Kazu , Poss Kenneth D. , Burns Caroline E. , Burns C. Geoffrey
Published: February 2013

Second heart field (SHF) progenitors perform essential functions during mammalian cardiogenesis. We recently identified a population of cardiac progenitor cells (CPCs) in zebrafish expressing latent TGFβ-binding protein 3 (ltbp3) that exhibits several defining characteristics of the anterior SHF in mammals. However, ltbp3 transcripts are conspicuously absent in anterior lateral plate mesoderm (ALPM), where SHF progenitors are specified in higher vertebrates. Instead, ltbp3 expression initiates at the arterial pole of the developing heart tube. Because the mechanisms of cardiac development are conserved evolutionarily, we hypothesized that zebrafish SHF specification also occurs in the ALPM. To test this hypothesis, we Cre/loxP lineage traced gata4+ and nkx2.5+ ALPM populations predicted to contain SHF progenitors, based on evolutionary conservation of ALPM patterning. Traced cells were identified in SHF-derived distal ventricular myocardium and in three lineages in the outflow tract (OFT). We confirmed the extent of contributions made by ALPM nkx2.5+ cells using Kaede photoconversion. Taken together, these data demonstrate that, as in higher vertebrates, zebrafish SHF progenitors are specified within the ALPM and express nkx2.5. Furthermore, we tested the hypothesis that Nkx2.5 plays a conserved and essential role during zebrafish SHF development. Embryos injected with an nkx2.5 morpholino exhibited SHF phenotypes caused by compromised progenitor cell proliferation. Co-injecting low doses of nkx2.5 and ltbp3 morpholinos revealed a genetic interaction between these factors. Taken together, our data highlight two conserved features of zebrafish SHF development, reveal a novel genetic relationship between nkx2.5 and ltbp3, and underscore the utility of this model organism for deciphering SHF biology.
Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3
Authors: Del Real Marissa Morales , Rothenberg Ellen V.
Published: February 2013

Hematopoiesis is a classic system with which to study developmental potentials and to investigate gene regulatory networks that control choices among alternate lineages. T-cell progenitors seeding the thymus retain several lineage potentials. The transcription factor PU.1 is involved in the decision to become a T cell or a myeloid cell, and the developmental outcome of expressing PU.1 is dependent on exposure to Notch signaling. PU.1-expressing T-cell progenitors without Notch signaling often adopt a myeloid program, whereas those exposed to Notch signals remain in a T-lineage pathway. Here, we show that Notch signaling does not alter PU.1 transcriptional activity by degradation/alteration of PU.1 protein. Instead, Notch signaling protects against the downregulation of T-cell factors so that a T-cell transcriptional network is maintained. Using an early T-cell line, we describe two branches of this network. The first involves inhibition of E-proteins by PU.1 and the resulting inhibition of Notch signaling target genes. Effects of E-protein inhibition can be reversed by exposure to Notch signaling. The second network is dependent on the ability of PU.1 to inhibit important T-cell transcription factor genes such as Myb, Tcf7 and Gata3 in the absence of Notch signaling. We show that maintenance of Gata3 protein levels by Myb and Notch signaling is linked to the ability to retain T-cell identity in response to PU.1.
Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window
Authors: Santoro Federica , Mayer Daniela , Klement Ruth M. , Warczok Katarzyna E. , Stukalov Alexey , Barlow Denise P. , Pauler Florian M.
Published: February 2013

The imprinted Airn macro long non-coding (lnc) RNA is an established example of a cis-silencing lncRNA. Airn expression is necessary to initiate paternal-specific silencing of the Igf2r gene, which is followed by gain of a somatic DNA methylation imprint on the silent Igf2r promoter. However, the developmental requirements for Airn initiation of Igf2r silencing and the role of Airn or DNA methylation in maintaining stable Igf2r repression have not been investigated. Here, we use inducible systems to control Airn expression during mouse embryonic stem cell (ESC) differentiation. By turning Airn expression off during ESC differentiation, we show that continuous Airn expression is needed to maintain Igf2r silencing, but only until the paternal Igf2r promoter is methylated. By conditionally turning Airn expression on, we show that Airn initiation of Igf2r silencing is not limited to one developmental ‘window of opportunity’ and can be maintained in the absence of DNA methylation. Together, this study shows that Airn expression is both necessary and sufficient to silence Igf2r throughout ESC differentiation and that the somatic methylation imprint, although not required to initiate or maintain silencing, adds a secondary layer of repressive epigenetic information.
ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue
Authors: Kuwajima Takaaki , Sitko Austen A. , Bhansali Punita , Jurgens Chris , Guido William , Mason Carol
Published: February 2013

We describe a clearing method for enhanced visualization of cell morphology and connections in neuronal and non-neuronal tissue. Using ClearT or ClearT2, which are composed of formamide or formamide/polyethylene glycol, respectively, embryos, whole mounts and thick brain sections can be rapidly cleared with minimal volume changes. Unlike other available clearing techniques, these methods do not use detergents or solvents, and thus preserve lipophilic dyes, fluorescent tracers and immunohistochemical labeling, as well as fluorescent-protein labeling.
tRNA residues evolved to promote translational accuracy
Authors: Shepotinovskaya Irina , Uhlenbeck Olke C.
Published: February 2013

The decoding properties of 22 structurally conservative base-pair and base-triple mutations in the anticodon hairpin and tertiary core of Escherichia coli tRNAAlaGGC were determined under single turnover conditions using E. coli ribosomes. While all of the mutations were able to efficiently decode the cognate GCC codon, many showed substantial misreading of near-cognate GUC or ACC codons. Although all the misreading mutations were present in the sequences of other E. coli tRNAs, they were never found among bacterial tRNAAlaGGC sequences. This suggests that the sequences of bacterial tRNAAlaGGC have evolved to avoid reading incorrect codons.
Methods of measurement and evaluation of natural antioxidant
capacity/activity (IUPAC Technical Report)
Authors: Apak Reşat , Gorinstein Shela , Böhm Volker , Schaich Karen M. , Özyürek Mustafa , Güçlü Kubilay
Published: February 2013

The chemical diversity of natural antioxidants (AOXs) makes it difficult to
separate, detect, and quantify individual antioxidants from a complex
food/biological matrix. Moreover, the total antioxidant power is often more
meaningful to evaluate health beneficial effects because of the cooperative
action of individual antioxidant species. Currently, there is no single
antioxidant assay for food labeling because of the lack of standard
quantification methods. Antioxidant assays may be broadly classified as the
electron transfer (ET)- and hydrogen atom transfer (HAT)-based assays. The
results obtained are hardly comparable because of the different mechanisms,
redox potentials, pH and solvent dependencies, etc. of various assays. This
project will aid the identification and quantification of properties and mutual
effects of antioxidants, bring a more rational basis to the classification of
antioxidant assays with their constraints and challenges, and make the results
more comparable and understandable. In this regard, the task group members
convey their own experiences in various methods of antioxidants measurement.
Are Multichannel Customers Really more Valuable? The Moderating Role of Product Category Characteristics
Authors: Kushwaha Tarun , Shankar Venkatesh
Published: February 2013

How does the monetary value of customer purchases vary by customer preference for purchase channels (e.g., traditional, electronic, multichannel) and product category? The authors develop a conceptual model and hypotheses on the moderating effects of two key product category characteristics—the utilitarian versus hedonic nature of the product category and perceived risk—on the channel preference–monetary value relationship. They test the hypotheses on a unique large-scale, empirically generalizable data set in the retailing context. Contrary to conventional wisdom that all multichannel customers are more valuable than single-channel customers, the results show that multichannel customers are the most valuable segment only for hedonic product categories. The findings reveal that traditional channel customers of low-risk categories provide higher monetary value than other customers. Moreover, for utilitarian product categories perceived as high (low) risk, web-only (catalog- or store-only) shoppers constitute the most valuable segment. The findings offer managers guidelines for targeting and migrating different types of customers for different product categories through different channels.
Walking through Dumbarton Oaks
Authors: Veder Robin
Published: February 2013

Walking through Dumbarton Oaks: Early Twentieth-century Bourgeois Bodily Techniques and Kinesthetic Experience of Landscape places landscape architect Beatrix Farrand’s design for rhythmic steps and landings at Dumbarton Oaks in Washington, D.C., into the contexts of early twentieth-century practices of walking and notions of aesthetic muscular response. Robin Veder argues that in this period kinesthesia was a recognized sixth sense and a significant aesthetic concern in landscape design and reception. The essay is structured to demonstrate methodologically how the history of the body can be employed to denaturalize and historicize phenomenology, and thus enrich explanations of built environments. Veder explores four frames for understanding the kinesthetic experience of walking through landscape. They are choreographic dictates for how designers wanted bodies to move, individual performances of movement through space, the clothing and muscular habits that constituted bodily techniques for walking, as well as the psychological and physiological aesthetics of kinesthetic empathy.
San Diego, Guardian of the American Pacific
Authors: Harrel John S.
Published: February 2013

San Diego did not easily become the home port of America’s Pacific fleet. It was two decades after the US acquisition of the Philippines, Guam, and Hawai‘i before a combination of imperialist naval strategy, Japanese expansionism, the Great White Fleet, unrest in Mexico and Central America, the completion of the Panama Canal, the Panama-California Exposition, a supportive congressman, and energetic civic leadership coalesced on the issue. Together, these factors led to the establishment of major naval facilities in this southern California city.
How Not to Arm a State
Authors: DeLay Brian
Published: February 2013

Today’s “Iron River of Guns” flowing from the United States into Mexico has a long backstory. From Mexico’s independence movement in the early nineteenth century through its early twentieth-century revolution, the international arms trade in general and arms transfers from the U.S. in particular have often confounded the project of national governance. The vagaries of global arms markets, the dangers of arming the state on credit, the difficulties of maintaining government arsenals, and the misfortune of sharing land borders with major arms producers all shaped Mexico’s first independent century in surprising and neglected ways. This history offers a fresh perspective on the contemporary crisis and the policy debate surrounding it.
In-Hospital Outcomes of Pedicled Bilateral Internal Mammary Artery Use in Diabetic and Nondiabetic Patients Undergoing Off-Pump Coronary Artery Bypass Grafting: Single-Surgeon, Single-Center Experience
Authors: Raja Shahzad G. , Salhiyyah Kareem , Rafiq Muhammad Umar , Navaratnarajah Manoraj , Chudasama Dimple , Walker Christopher P. , Amin Fouad , Amrani Mohamed
Published: February 2013

Objective: A common perception is that use of pedicled bilateral internal mammary arteries (BIMA) increases the risk of sternal wound complications in diabetic patients undergoing coronary artery bypass grafting (CABG). The purpose of this study was to compare the in-hospital outcomes of CABG using pedicled BIMA in diabetic and nondiabetic patients.

Methods: From September 1998 to September 2010, 390 consecutive diabetic patients and 519 nondiabetic patients underwent isolated off-pump CABG using pedicled BIMA. The 2 groups had comparable preoperative demographics except for a higher prevalence of acute myocardial infarction (18.9% versus 6.1%, P = .01), peripheral vascular disease (17.2% versus 2.7%, P = .001), an ejection fraction <30% (17.7% versus 8.5%, P = .02), and chronic renal failure (4.5% versus 0.9%, P = .01) in the diabetic patients.

Results: The operative mortality rate of the diabetic patients was comparable to that of the nondiabetic patients (2.8% versus 2.1%, P = .87). The in-hospital outcomes, including occurrence of superficial and deep sternal wound infections, were similar except for an increased occurrence of wound infection at the vein harvest site (6.6% versus 1.1%, P = .04) and a need for hemofiltration (11.8% versus 2.1%, P = .02) in the diabetic patients.

Conclusions: Pedicled BIMA use is associated with comparable incidences of sternal wound complications and other outcomes in diabetic patients and nondiabetic patients. Strict perioperative glycemic control, adherence to meticulous closure technique, and postoperative management of surgical wounds can make pedicled BIMA use a default strategy for diabetic patients.
Concomitant Off-Pump Coronary Artery Bypass Grafting Results in Improved In-Hospital Outcomes for Patients with Ischemic Mitral Regurgitation Undergoing Surgery
Authors: Raja Shahzad G. , Husain Mubassher , Salhiyyah Kareem , Navaratnarajah Manoraj , Chudasama Dimple , Walker Christopher P. , Amin Fouad , Amrani Mohamed
Published: February 2013

Objective: Surgical management of ischemic mitral regurgitation (IMR) has primarily consisted of revascularization with or without the addition of mitral valve repair or replacement. We hypothesize that performing off-pump coronary artery bypass (OPCAB) grafting before fixing MR improves in-hospital outcomes for patients with IMR undergoing surgery.

Methods: From January 2000 through December 2010, a total of 96 consecutive patients with moderate or severe IMR, as determined by preoperative echocardiography, underwent on-pump coronary artery bypass grafting (CABG) (n = 66) or OPCAB (n = 30) revascularization with concomitant mitral valve repair or replacement. A retrospective analysis of a prospectively collected cardiac surgery database (PATS; Dendrite Clinical Systems, Oxford, UK) was performed. In addition, medical notes and charts were reviewed for all study patients.

Results: The 2 groups had similar preoperative demographic and EuroSCORE risk-stratification characteristics. The operative mortality rate for the entire cohort was 9.4%. Patients who underwent OPCAB grafting had a lower operative mortality than those who underwent CABG (3.3% versus 12.1%; P = .006). The mean �SD cardiopulmonary bypass time (82.7 � 34.7 minutes versus 160.7 � 45.2 minutes; P < .001) and cross-clamp time (49.0 � 22.4 minutes versus 103.4 � 39.5 minutes; P < .001) were significantly shorter in the off-pump group than in the on-pump group. The OPCAB group also had significantly less in-hospital morbidity and shorter stays in the intensive care unit and the hospital.

Conclusion: Our analysis shows that OPCAB grafting (compared with conventional CABG) before repairing MR is associated with favorable in-hospital outcomes for patients undergoing surgery for IMR.
An Unusual Cause of Shortness of Breath: Hamman Syndrome
Authors: Asfour Victoria , Attia Rizwan
Published: February 2013

A 41-year-old primiparous low-risk woman developed dyspnea and generalized head and neck swelling after a normal delivery of a healthy neonate. A chest x-ray demonstrated surgical emphysema in the neck and a suggestion of pneumomediastinum (arrows, Figure panel A).
Mitral Paravalvular Leak: Caution in Percutaneous Occluder Device Deployment
Authors: Altarabsheh Salah Eldien , Deo Salil V. , Rihal Charanjit S. , Park Soon J.
Published: February 2013

A frail 70-year-old woman presented with symptomatic mitral paravalvular leak 2 months after undergoing a double valve replacement for mixed mitral and aortic valve disease. There was no evidence of prosthetic valve endocarditis. Percutaneous closure of the paravalvular leak was attempted as an alternative to a high-risk surgical procedure. This therapy was successful in reducing the regurgitation but resulted in severe intravascular hemolysis and acute renal failure requiring hemodialysis.

The development of new hemolysis and acute renal failure directed our attention to the Amplatzer device as a possible etiology for these complications. The assumption that her kidney injury was recent and likely reversible compelled us to think of the surgical method as a definitive option. A re-operative surgery was performed, which included retrieval of the occluder devices, pericardial patch repair, and re-replacement using a new biological prosthesis. The patient's urine output gradually improved, and the patient was dismissed with normal renal function.

We present this case as an unusual complication of percutaneous device closure. It also highlights the reversible nature of acute renal failure due to intravascular hemolysis and demonstrates the importance of early surgical intervention for this condition.