bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetic cardiomyopathy: An expression of stage B heart failure with preserved ejection fraction
Authors: Lam Carolyn SP
Published: April 2015

Heart failure is now recognized as a progressive disease in which patients transition through the stages of being at risk of heart failure (stage A), to asymptomatic structural heart disease (stage B), to clinical manifestations of heart failure (stage C) and finally end-stage or refractory heart failure (stage D). This review outlines the key role of diabetes mellitus as a stage A risk factor for heart failure with preserved ejection fraction, and asymptomatic diabetic cardiomyopathy, referring to the presence of left ventricular diastolic dysfunction in diabetic patients without coronary artery disease, hypertension or other potential aetiologies, as an expression of stage B heart failure with preserved ejection fraction at high risk of transitioning to symptomatic stage C heart failure with preserved ejection fraction. The data presented call for better recognition of the unique phenotype of diabetic cardiomyopathy with preserved ejection fraction and elevated diastolic stiffness as a manifestation of stage B heart failure with preserved ejection fraction that should be targeted for risk management and preventive strategies.
A Critical Discourse Analysis of Provincial Policies Impacting Shelter Service Delivery to Women Exposed to Violence
Authors: Burnett Camille , Ford-Gilboe Marilyn , Berman Helene , Ward-Griffin Cathy , Wathen Nadine
Published: April 2015

Shelters for abused women function within a broad context that includes intersecting social structures, policies, and resources, which may constrain and limit the options available to abused women and tacitly reinforce the cycle of abuse. This feminist, qualitative study combined in-depth interviews and focus groups conducted with 37 staff and four executive directors from four shelters in Ontario, Canada, along with a critical discourse analysis of salient policy texts. Together, the interviews and critical discourse analysis formed an integrated analysis of the dialectic between policy as written and enacted. The study findings illuminate the complexity of the system and its impact on women, shelters, and the community and highlight how specific types of social policies and various social system subsystems and structures, and system configuration, shape the day to day reality of shelter service delivery and impact outcomes for abused women and their children. Collectively, these findings offer direction regarding where these policies could be improved and provide a basis for shelters, policy makers, advocates, and the community to strengthen current services and policies, potentially enhancing outcomes for women.
Commercial Sexual Exploitation of Children and State Child Welfare Systems
Authors: Bounds Dawn , Julion Wrenetha A. , Delaney Kathleen R.
Published: April 2015

In several states, commercial sexual exploitation of children (CSEC) is now a reportable child abuse offense. Illinois has taken the lead in tackling the issue and the Illinois experience illuminates valuable lessons. This article delineates the protection, practice, and policy implications that evolve when CSEC falls under a state child welfare system. The specific aims are to (a) discuss CSEC, its victims, risks, harms, and challenges inherent in providing effective care; (b) use Illinois as an exemplar to explicate the consequences and implementation challenges of establishing a state reporting system that frames CSEC as a child welfare issue; (c) recommend strategies for developing effective state reporting models, and (d) demonstrate how nurses are well poised to advocate for victims of human trafficking on both state and national levels. Recommendations for improving the identification of CSEC victims and overcoming challenges to state implementation are offered.
Cytoskeletal prestress regulates nuclear shape and stiffness in cardiac myocytes
Authors: Lee Hyungsuk , Adams William J , Alford Patrick W , McCain Megan L , Feinberg Adam W , Sheehy Sean P , Goss Josue A , Parker Kevin Kit
Published: April 2015

Mechanical stresses on the myocyte nucleus have been associated with several diseases and potentially transduce mechanical stimuli into cellular responses. Although a number of physical links between the nuclear envelope and cytoplasmic filaments have been identified, previous studies have focused on the mechanical properties of individual components of the nucleus, such as the nuclear envelope and lamin network. The mechanical interaction between the cytoskeleton and chromatin on nuclear deformability remains elusive. Here, we investigated how cytoskeletal and chromatin structures influence nuclear mechanics in cardiac myocytes. Rapid decondensation of chromatin and rupture of the nuclear membrane caused a sudden expansion of DNA, a consequence of prestress exerted on the nucleus. To characterize the prestress exerted on the nucleus, we measured the shape and the stiffness of isolated nuclei and nuclei in living myocytes during disruption of cytoskeletal, myofibrillar, and chromatin structure. We found that the nucleus in myocytes is subject to both tensional and compressional prestress and its deformability is determined by a balance of those opposing forces. By developing a computational model of the prestressed nucleus, we showed that cytoskeletal and chromatin prestresses create vulnerability in the nuclear envelope. Our studies suggest the cytoskeletal–nuclear–chromatin interconnectivity may play an important role in mechanics of myocyte contraction and in the development of laminopathies by lamin mutations.
Exploring the mediating effects of trust on principal leadership and teacher professional learning in Hong Kong primary schools
Authors: Li Lijuan , Hallinger Philip , Walker Allan
Published: April 2015

This study attempted to identify effects of trust between principal leadership and teacher professional learning in Hong Kong primary schools. To verify the potential mediating effects of trust as a component of school capacity, survey data with a sample of 970 teachers from 32 local primary schools was used. Two questionnaires were combined to investigate principal leadership and school capacity in the schools. Baron and Kenny’s four-step causal process for mediation analysis was employed to have a preliminary inquiry. To compensate weaknesses of the orthodox regression based approach, significance of the mediating effects of trust were tested using the Sobel’s test and bootstrapping method. Next, the seven core sets of principal leadership practices were used as multiple predictors, and mediating effects of trust between them and teacher professional learning were also examined. The findings affirmed the role of faculty trust as a mediator between principal leadership and teacher professional learning in Hong Kong primary schools.
A new fuzzy model for determining risk level on the workplaces in manufacturing small and medium enterprises
Authors: Djapan Marko J , Tadic Danijela P , Macuzic Ivan D , Dragojovic Predrag Dj
Published: April 2015

Crucial part of the reduction and prevention of workplace injuries and maintaining occupational safety and health system takes risk assessment model, which appears as one of the most important. Frequent advances in all fields cause changes in risk assessment models in relation to the traditional approach. This article is focused on providing reliable assessment tool that will enable suitable and easy usage of methodology for risk evaluation in the workplaces in manufacturing small and medium enterprises. For that purpose, three groups of factors are introduced and their hierarchical structures are defined. Pre-defined linguistic expressions are used to describe relative importance of factors, sub-factors and values of sub-factors. Fuzzy set theory is used for modeling of existing uncertainties. The levels of identified risks are given by exact way, using fuzzy logic. The proposed model is tested with real-life data from manufacturing small and medium enterprises.
An improved monocyte activation test using cryopreserved pooled human mononuclear cells
Authors: Solati Shabnam , Aarden Lucien , Zeerleder Sacha , Wouters Diana
Published: April 2015

The monocyte activation test (MAT) is a promising replacement of the currently used rabbit pyrogen test to detect the presence of pyrogens in injectable drugs. In the MAT, drugs are incubated with a source of human monocytes and production of pyrogenic cytokines used as readout. The best results are obtained with human mononuclear cells (MNC). However, donor variation requires testing on four different donors, and for most laboratories access to fresh MNCs is a problem. The current study shows how to overcome these problems using frozen pooled MNCs. The MAT is performed by thawing pooled MNC and co-culture overnight with a test substance, LPS or non-endotoxin pyrogens, with IL-6 production as the readout. The study demonstrates that fresh and frozen pooled MNC have comparable sensitivity. The reproducibility of the MAT performed with different batches of frozen pooled MNC was excellent. Different non-endotoxin pyrogens induce IL-6, confirming the ability of the MAT to detect a variety of pyrogens. In conclusion, the MAT using frozen pooled MNC is a highly sensitive, specific and reproducible pyrogen test, able to detect and quantify endotoxin and non-endotoxin pyrogenic contaminations in parenteral pharmaceuticals.
Current approaches to atherosclerotic obstructive renal artery stenosis
Authors: Juncos Luis I. , Textor Stephen
Published: April 2015

Increased lifespan in the last few decades has substantially changed the scenario for renal artery stenosis. Indeed, because older populations show a higher prevalence of atherosclerotic disease, the incidence of atheromatous renal artery stenosis has also increased. Intuitively, one could surmise that stenosis removal should void both the hypertension and the kidney damage resulting from the obstructive stenosis. Surprisingly, a number of important clinical trials have failed to show the reversion seen in experimental models. The reasons for these differences may be linked to chronicity and inflammation associated with the atherosclerotic lesion. However, the failure to obtain a favorable response may also be related to abnormalities in the contralateral kidney. Indeed, this apparently normal kidney should work to compensate the hemodynamic effects of the ipsilateral stenosed kidney. Instead, structure and function in the contralateral kidney can be altered in renal artery stenosis to the point that this nonstenotic kidney may sustain both, hypertension and progressive kidney disease. Certainly, comparing the effects of clip removal in the Goldblatt model to angioplasty in clinical settings with atherosclerotic lesions may be totally inappropriate. Nevertheless, there remain certain clinical situations such as bilateral renal arterial disease, congestive heart failure, and progressive renal failure, where angioplasty may be an alternative. These approaches however are yet to be tested.
Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid hemangioendothelioma
Authors: Lau Augustine , Malangone Steve , Green Myke , Badari Ambuga , Clarke Kathryn , Elquza Emad
Published: April 2015

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed vascular neoplasm with clinical behaviors that range from indolent to highly aggressive. Even when the appropriate diagnosis is achieved, the best treatment for HEHE has not been defined or standardized, further complicating the care of these patients. We present a diagnostically challenging case of HEHE where we utilized capecitabine and bevacizumab as another novel treatment option.
Do Incoming First-Year College Students Who Think of Themselves as Adults Drink More Responsibly After Starting College?
Authors: Rinker Dipali Venkataraman , Walters Scott T. , Wyatt Todd M. , DeJong William
Published: April 2015

First-year college students are at particular risk for problem drinking, especially around the time when they first begin college. The purpose of this study was to examine whether self-perception of adulthood (SPOA) was prospectively associated with drinking behaviors, the use of different types of protective behavioral strategies (PBS), and negative alcohol-related consequences in a large sample of incoming first-year college students. Participants were a national sample of 8,230 entering first-year college students required to complete a web-based alcohol education program that included a baseline survey prior to the start of the fall term and a follow-up survey one month later, after classes had started. Relevant measures included SPOA, drinking behaviors, use of PBS, and negative alcohol-related consequences. Results indicated that SPOA negatively predicted peak blood alcohol concentration (BAC) and number of heavy drinking episodes while positively predicting PBS. Implications for interventions and future research are discussed.
Metastasizing Bronchopulmonary Leiomyosarcoma
Authors: Livieratos Speros , Fatakhov Eddie , Ammar Ali , Dillard Thomas , Davis Bruce
Published: April 2015

An otherwise healthy 55-year-old female, nonsmoker, was seen in pulmonary consultation for progressively worsening shortness of breath. She had undergone a complete hysterectomy 7 years prior for bleeding leiomyomas. On presentation, her initial chest X-ray showed a large right-sided pleural effusion with multiple pulmonary nodules. Two thoracenteses failed to reveal any cytologic abnormalities. Bronchoscopy revealed smooth, round, endobronchial lesions. Histologic examination showed features consistent with leiomyosarcoma. We present a rare case of a patient that initially had possible leiomyomas of the uterus surgically removed and years later presented with bronchopulmonary leiomyosarcoma.
Teaching Children With Disabilities
Authors: VanWeelden Kimberly , Meehan Laura
Published: April 2015

The purpose of this study was to determine the types and frequency of music and special education workshops held at state music educators association (MEA) conferences. Specifically, the researchers sought to determine the following within the past 10 years: (a) states that offered music and special education workshops at their MEA conferences, (b) frequency of music and special education workshops at each MEA conference, (c) frequency of music and special education workshops by music classroom type or IDEA disability category, and (d) significant differences in frequency of music and special education workshops between state MEAs with and state MEAs without a Special Learners Chair. There were 226 conference programs obtained from 2004 to 2013, of which 33 states (73%) provided at least one conference program and 12 states (27%) provided all programs. Within the provided conference programs, there were 300 music and special education sessions listed. Furthermore, most sessions were those that gave special education information without being specific to an individual music area or disability ( n = 149 or 50%). When the data were analyzed by music area or individual disability category, sessions pertaining to general music ( n = 43.5 or 14.5%) or autism ( n = 36.5 or 12%) were most frequent. Furthermore, results are discussed within the article.
Gardner's Syndrome Revisited: A Clinical Case and Overview of the Literature
Authors: Seehra Jadbinder , Patel Shruti , Bryant Catherine
Published: April 2015

Gardner's syndrome (GS), a variant of familial adenomatous polyposis (FAP), remains a life-threatening condition of significant dental relevance. Clinicians can play an important role in the identification of this condition as the dental manifestations often precede the development of intestinal polyposis. This article describes a clinical case in which identification of the dental features of GS during routine orthodontic assessment resulted in the early diagnosis of this condition, which was previously unrecognised in a young female patient.
In Situ Patch-Clamp Recordings from Merkel Cells in Rat Whisker Hair Follicles, an Experimental Protocol for Studying Tactile Transduction in Tactile-End Organs
Authors: Ikeda Ryo , Ling Jennifer , Cha Myeounghoon , Gu Jianguo G
Published: April 2015

Mammals use tactile end-organs to perform sensory tasks such as environmental exploration, social interaction, and tactile discrimination. However, cellular and molecular mechanisms underlying tactile transduction in tactile end-organs remain poorly understood. The patch-clamp recording technique may be the most valuable approach for detecting and studying tactile transduction in tactile end-organs, but it is technically challenging because tactile transduction elements in an end-organ are normally inaccessible by patch-clamp recording electrodes. Here we describe an in situ patch-clamp recording protocol for the study of tactile transduction in Merkel cells of rat whisker hair follicles, one of the most sensitive tactile end-organs in mammals. This technique offers an opportunity to explore the identities and properties of ion channels that are involved in tactile transduction in whisker hair follicles, and it may also lend a useful tool for researchers to study other tactile end-organs. The experimental protocol describes procedures for 1) tissue dissection and whisker hair follicle preparation, 2) device setup and steps for performing patch-clamp recordings from Merkel cells in a whisker hair follicle, 3) methods of delivering mechanical stimuli, and 4) intra-follicle microinjection for receptor knockdown in whisker hair follicles. The main procedures in this protocol, from tissue preparation to whole-cell patch-clamp recordings, can be completed in a few hours.
Impact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study
Authors: Wieske Luuk , Dettling-Ihnenfeldt Daniela S , Verhamme Camiel , Nollet Frans , van Schaik Ivo N , Schultz Marcus J , Horn Janneke , van der Schaaf Marike
Published: April 2015

Introduction

ICU-acquired weakness is thought to mediate physical impairments in survivors of critical illness, but few studies have investigated this thoroughly. The purpose was to investigate differences in post-ICU mortality and physical functioning between patients with and without ICU-acquired weakness at 6 months after ICU discharge.

Method

ICU patients, mechanically ventilated ≥2 days, were included in a single-center prospective observational cohort study. ICU-acquired weakness was diagnosed when the average Medical Research Council score was <4 in awake and attentive patients. Post-ICU mortality was recorded until 6 months after ICU discharge; in surviving patients, physical functioning was assessed using the Short-Form Health Survey physical functioning domain. The independent effect of ICU-acquired weakness on post-ICU mortality was analyzed using a multivariable Cox proportional hazards model. The independent effect of ICU-acquired weakness on the physical functioning domain score was analyzed using a multivariable linear regression model.

Results

Of the 156 patients included, 80 had ICU-acquired weakness. Twenty-three patients died in the ICU (20 with ICU-acquired weakness); during 6 months follow-up after ICU discharge another 25 patients died (17 with ICU-acquired weakness). Physical functioning domain scores were available for 96 survivors (39 patients with ICU-acquired weakness). ICU-acquired weakness was independently associated with an increase in post-ICU mortality (hazard ratio 3.6, 95% confidence interval, 1.3 to 9.8; P = 0.01) and with a decrease in physical functioning (β: -16.7 points; 95% confidence interval, -30.2 to -3.1; P = 0.02).

Conclusion

ICU-acquired weakness is independently associated with higher post-ICU mortality and with clinically relevant lower physical functioning in survivors at 6 months after ICU discharge.
An investigation of the lead tin yellows type I and II and their use in Bohemian panel paintings from the Gothic period
Authors: Šefců Radka , Chlumská Štěpánka , Hostašová Alena
Published: April 2015

Background

Presented article summarizes the results of a broad-based survey on painting techniques used during the High and Late Gothic period in the Bohemian panel paintings located in the collections of the National Gallery in Prague. The work is focused on the specific use of yellow pigments – lead tin yellow type I and type II in the panel painting from the period around 1340–1550. In the scientific investigation supplementary microscopic and spectral analyses were made. A representative range of 57 micro-samples collected from the 36 panel paintings of the 21 Masters and their workshops was investigated by the methods of optical microscopy on polarizing microscope (OM). Molecular analysis of both types of yellow was performed using Raman micro-spectroscopy (RMS). The use of this technique was crucial for the nondestructive differentiation between each type of lead-tin yellow.

Results

Thanks to the Raman spectroscopy it was possible for the first time to map the usage of lead tin yellow type I and II in such a broad range. Combination of the analytical techniques brought the knowledge about the morphology of the grains and variability of the use of the lead tin yellows in the Bohemian panel paintings.

Conclusions

The contribution offers a systematic view on the outcomes and in a synoptic way consults the results of respective scientific methods. It clearly confirms both the temporally and locally specific use of both types of lead tin yellows. The presented facts are the results of interdisciplinary collaboration among the scientists and the art historian.
Marginal Figures and the Ethos of the Global Novel
Authors: Haley Madigan
Published: April 2015

This essay approaches the global as an ethos emergent within contemporary fiction, taking J. M. Coetzee's Disgrace (1999) as its primary example. Recent accounts of global or world literature have generally considered these solely as spheres of circulation, while dominant accounts of the novel's ethics have been predicated upon its capacity to circulate otherness. Departing from these models, the essay revisits Erich Auerbach's claim that the contemporary novel would bear reference to “a common life.” And it considers alternative accounts of the ethics of culture in Lukács's and Heidegger's thought in order to propose that the potential for supranational circulation impinges upon the novel's mimesis: specifically, how figurations of character, action, and event relate to a larger social or communal horizon—the work's ethos. Attending to the problem of ethos in Disgrace clarifies the political scandal of its representation of postapartheid South Africa and draws out how the novel figures compelling ways of being and acting not limited to a South African horizon. Tracing this potential of figure in Disgrace's famous last scene, and through reference to Auerbach's early essay “Figura” (1938), the essay concludes by showing how fiction by Teju Cole and W. G. Sebald similarly respond to historical injustice by opening up an ethical horizon delimited by the work's trajectory rather than by given cultural and political formations. In this way, it argues for contemporary fiction's capacity to manifest an ethical notion of globality that does not simply reflect the workings of neoliberal globalization or other global processes.
The Media, Democracy, and Spectacle
Authors: Kellner Douglas
Published: April 2015

In this essay, I document shifts in the political mediascape of the United States during the past fifteen years, focusing on the rise of partisan television networks and radio shows of the Left and the Right and the rise of alternative media and social networking that provided a wide diversity of opinion and critique of the dominant political and corporate order. I argue that this shift in the US mediascape helped elect Barack Obama, which in turn intensified contestation for and against Obama and the Democrats within contemporary US politics. I then indicate how Barack Obama used the media and media spectacle to successfully win the 2008 and 2012 US presidential elections. I conclude with a discussion of how new and alternative media can help to promote genuine democratic debate and help disseminate the full range of information and ideas necessary to have a robustly democratic social order.
Smart Dust and Remote Sensing
Authors: Bishop Ryan
Published: April 2015

Remote sensing using nanosensors continue a long trajectory of multisensory teletechnologies devised by the military for surveillance and weapons verification at a distance. These remote-sensing systems form the basis of current military and corporate plans to monitor all elements of the earth in real time. Because these systems provide extensions of human senses and are also autonomous, they simultaneously extend and delimit the power and imaginary of the human subject as actor and political agent. By thinking through these multiple large-scale interrelated remote-sensing systems and offering a meditation on the autonomous (as a combination of the terms auto and nomos), the article explores the profound ramifications for imagining the political subject as agent and, further, for the conditions of thinking the autonomous as concept, subject, or technology.
ALS mutant FUS proteins are recruited into stress granules in induced Pluripotent Stem Cells (iPSCs) derived motoneurons
Authors: Lenzi Jessica , De Santis Riccardo , de Turris Valeria , Morlando Mariangela , Laneve Pietro , Calvo Andrea , Caliendo Virginia , Chiò Adriano , Rosa Alessandro , Bozzoni Irene
Published: April 2015

Patient-derived induced Pluripotent Stem Cells (iPSCs) provide an opportunity to study human diseases mainly in those cases where no suitable model systems are available. Here we have taken advantage of in vitro iPSCs derived from patients affected by Amyotrophic Lateral Sclerosis and carrying mutations in the RNA-binding proteins FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUSR514S and FUSR521C patients’ fibroblasts, while in the case of the severe FUSP525L mutation, where fibroblasts were not available, a heterozygous and a homozygous iPSC lines were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, nicely correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.
Sphingolipids inhibit vimentin-dependent cell migration
Authors: Hyder Claire L. , Kemppainen Kati , Isoniemi Kimmo O. , Imanishi Susumu Y. , Goto Hidemasa , Inagaki Masaki , Fazeli Elnaz , Eriksson John E. , Törnquist Kid
Published: April 2015

The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial–mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid–vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration.
SUMOylation regulates ciliary localization of olfactory signaling proteins
Authors: McIntyre Jeremy C. , Joiner Ariell M. , Zhang Lian , Iñiguez-Lluhí Jorge , Martens Jeffrey R.
Published: April 2015

Cilia are evolutionarily conserved organelles found on many mammalian cell types, including neuronal populations. Although neuronal cilia, including those on olfactory sensory neurons (OSNs), are often delineated by localization of adenylyl cyclase 3 (AC3, also known as ADCY3), the mechanisms responsible for targeting integral membrane proteins are largely unknown. Post-translational modification by small ubiquitin-like modifier (SUMO) proteins plays an important role in protein localization processes such as nuclear–cytosolic transport. Here, we identified through bioinformatic analysis that adenylyl cyclases harbor conserved SUMOylation motifs, and show that AC3 is a substrate for SUMO modification. Functionally, overexpression of the SUMO protease SENP2 prevented ciliary localization of AC3, without affecting ciliation or cilia maintenance. Furthermore, AC3-SUMO mutants did not localize to cilia. To test whether SUMOylation is sufficient for cilia entry, we compared localization of ANO2, which possesses a SUMO motif, and ANO1, which lacks SUMOylation sites and does not localize to cilia. Introduction of SUMOylation sites into ANO1 was not sufficient for ciliary entry. These data suggest that SUMOylation is necessary but not sufficient for ciliary trafficking of select constituents, further establishing the link between ciliary and nuclear import.
Protection ofDrosophilachromosome ends through minimal telomere capping
Authors: Dubruille Raphaëlle , Loppin Benjamin
Published: April 2015

In Drosophila, telomere-capping proteins have the remarkable capacity to recognize chromosome ends in a sequence-independent manner. This epigenetic protection is essential to prevent catastrophic ligations of chromosome extremities. Interestingly, capping proteins occupy a large telomere chromatin domain of several kilobases; however, the functional relevance of this to end protection is unknown. Here, we investigate the role of the large capping domain by manipulating HOAP (encoded by caravaggio) capping-protein expression in the male germ cells, where telomere protection can be challenged without compromising viability. We show that the exhaustion of HOAP results in a dramatic reduction of other capping proteins at telomeres, including K81 [encoded by ms(3)K81], which is essential for male fertility. Strikingly however, we demonstrate that, although capping complexes are barely detected in HOAP-depleted male germ cells, telomere protection and male fertility are not dramatically affected. Our study thus demonstrates that efficient protection of Drosophila telomeres can be achieved with surprisingly low amounts of capping complexes. We propose that these complexes prevent fusions by acting at the very extremity of chromosomes, reminiscent of the protection conferred by extremely short telomeric arrays in yeast or mammalian systems.
GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway
Authors: Menon Deepthi , Coll Rebecca , O'Neill Luke A. J. , Board Philip G.
Published: April 2015

Macrophages mediate innate immune responses that recognise foreign pathogens, and bacterial lipopolysaccharide (LPS) recruits a signalling pathway through Toll-like receptor 4 (TLR4) to induce pro-inflammatory cytokines and reactive oxygen species (ROS). LPS activation also skews the metabolism of macrophages towards a glycolytic phenotype. Here, we demonstrate that the LPS-triggered glycolytic switch is significantly attenuated in macrophages deficient for glutathione transferase omega-1 (GSTO1, note that GSTO1-1 refers to the dimeric molecule with identical type 1 subunits). In response to LPS, GSTO1-1-deficient macrophages do not produce excess lactate, or dephosphorylate AMPK, a key metabolic stress regulator. In addition, GSTO1-1-deficient cells do not induce HIF1α, which plays a key role in maintaining the pro-inflammatory state of activated macrophages. The accumulation of the TCA cycle intermediates succinate and fumarate that occurs in LPS-treated macrophages was also blocked in GSTO1-1-deficient cells. These data indicate that GSTO1-1 is required for LPS-mediated signalling in macrophages and that it acts early in the LPS–TLR4 pro-inflammatory pathway.
Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes
Authors: McKenna Sarah , Wright Clyde J.
Published: April 2015

Multiple mediators of septic shock are regulated by the transcription factor nuclear factor κB (NFκB). However, complete NFκB inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NFκB inhibitors specifically attenuates lipopolysaccharide (LPS)-induced IκBβ degradation and the expression of a select subset of target genes (encoding IL1β, IL6, IL12β). Gain- and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NFκB family member IκBβ (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from IκBβ overexpressing mice demonstrate attenuated LPS-induced IκBβ–NFκB signaling and IL1β, IL6 and IL12β expression. Further confirming the role of IκBβ and its NFκB subunit binding partner cRel in LPS-induced gene expression, pre-treatment of wild-type mouse embryonic fibroblasts with a cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression. We prove that LPS-induced IκBβ–NFκB signaling can be selectively modulated to attenuate the expression of select pro-inflammatory target genes, thus providing therapeutic insights for patients exposed to systemic inflammatory stress.
The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins
Authors: Ibuka Souji , Matsumoto Shinji , Fujii Shinsuke , Kikuchi Akira
Published: April 2015

Epithelial tubular structures are essential units in various organs. Here, we used rat intestinal epithelial IEC6 cells to investigate tubulogenesis and we found that tubular formation was induced by a combination of Wnt3a and EGF signaling during three-dimensional culture. Wnt3a and EGF induced the expression of the P2Y2 receptor (P2Y2R, also known as P2RY2), and knockdown of P2Y2R suppressed tubular formation. A P2Y2R mutant that lacks nucleotide responsiveness rescued the phenotypes resulting from P2Y2R knockdown, suggesting that nucleotide-dependent responses are not required for P2Y2R functions in tubular formation. The Arg-Gly-Asp (RGD) sequence of P2Y2R has been shown to interact with integrins, and a P2Y2R mutant lacking integrin-binding activity was unable to induce tubular formation. P2Y2R expression inhibited the interaction between integrins and fibronectin, and induced cell morphological changes and proliferation. Inhibition of integrin and fibronectin binding by treatment with the cyclic RGD peptide and fibronectin knockdown induced tubular formation in the presence of EGF alone, but a fibronectin coat suppressed Wnt3a- and EGF-induced tubular formation. These results suggest that Wnt3a- and EGF-induced P2Y2R expression causes tubular formation by preventing the binding of integrins and fibronectin rather than by mediating nucleotide responses.
The cost of digestion in the fish-eating myotis (Myotis vivesi)
Authors: Welch Kenneth C. , Otálora-Ardila Aída , Herrera M. L. Gerardo , Flores-Martínez José Juan
Published: April 2015

Flying vertebrates, such as bats, face special challenges with regards to the throughput and digestion of food. On the one hand, as potentially energy-limited organisms, bats must ingest and assimilate energy efficiently in order to satisfy high resting and active metabolic demands. On the other hand, the assimilation of nutrients must be accomplished using a digestive tract that is, compared with that of similarly sized non-flying vertebrates, significantly shorter. Despite these competing demands, and the relative breadth of dietary diversity among bats, little work has been done describing the cost of digestion, termed ‘specific dynamic action’ (SDA). Here, we provide the first systematic assessment of the SDA response in a bat, the fish-eating myotis (Myotis vivesi). Given the shorter digestive tract and the relatively higher resting and active metabolic rates of bats in general, and based on anecdotal published evidence, we hypothesized that the SDA response in fish-eating myotis would be dependent on meal size and both significantly more brief and intense than in small, non-flying mammals. In agreement with our hypothesis, we found that the peak metabolic rate during digestion, relative to rest, was significantly higher in these bats compared with any other mammals or vertebrates, except for some infrequently eating reptiles and amphibians. Additionally, we found that the magnitude and duration of the SDA response were related to meal size. However, we found that the duration of the SDA response, while generally similar to reported gut transit times in other small bats, was not substantially shorter than in similarly sized non-flying mammals.
A meta-analysis ofin vivovertebrate cardiac performance: implications for cardiovascular support in the evolution of endothermy
Authors: Hillman Stanley S. , Hedrick Michael S.
Published: April 2015

Endothermy in birds and mammals is associated with high body temperatures, and high rates of metabolism that are aerobically supported by elevated rates of cardiovascular O2 transport. The purpose of this meta-analysis was to examine cardiovascular data from ectothermic and endothermic vertebrates, at rest and during exercise, with the goal of identifying key variables that may have contributed to the role of the cardiovascular system in supporting high rates of O2 transport associated with endothermy. Vascular conductance, cardiac power and stroke work were summarized and calculated from a variety of studies at rest and during exercise for five classes of vertebrates where data were available. Conductance and cardiac power were linearly related to cardiac output from rest to exercise and also interspecifically. Exercise cardiac power and stroke work were greater in the endothermic species, owing to increased flow resulting from increased heart rate and increased pressure. Increased relative ventricle mass (RVM) was related to increased stroke volume in both groups. However, the increased RVM of endotherms was related to the increased pressure, as stroke work per gram of ventricle during exercise was equivalent between the groups. Cardiac power was linearly related to aerobic metabolic power, with 158 mW aerobic power output achieved per mW of cardiac power input. This analysis indicates that the greatly increased heart rate and cardiac stroke work leading to increased blood flow rate and blood pressure was necessary to support the metabolic requirements of endothermy.
Western and Clark's grebes use novel strategies for running on water
Authors: Clifton Glenna T. , Hedrick Tyson L. , Biewener Andrew A.
Published: April 2015

Few vertebrates run on water. The largest animals to accomplish this feat are western and Clark's grebes (Aechmophorus occidentalis and Aechmophorus clarkii). These birds use water running to secure a mate during a display called rushing. Grebes weigh an order of magnitude more than the next largest water runners, basilisk lizards (Basilicus basiliscus), and therefore face a greater challenge to support their body weight. How do these birds produce the hydrodynamic forces necessary to overcome gravity and sustain rushing? We present the first quantitative study of water running by grebes. High-speed video recordings elucidate the hindlimb movements of grebes rushing in the wild. We complement these findings with laboratory experiments using physical models and a preserved grebe foot to estimate how slapping the water surface contributes to weight support. Our results indicate that grebes use three novel tactics to successfully run on water. First, rushing grebes use exceptionally high stride rates, reaching 10 Hz. Second, grebe foot size and high water impact speed allow grebes to generate up to 30–55% of the required weight support through water slap alone. Finally, flattened foot bones reduce downward drag, permitting grebes to retract each foot from the water laterally. Together, these mechanisms outline a water-running strategy qualitatively different from that of the only previously studied water runner, the basilisk lizard. The hydrodynamic specializations of rushing grebes could inform the design of biomimetic appendages. Furthermore, the mechanisms underlying this impressive display demonstrate that evolution can dramatically alter performance under sexual selection.
Metabolic fates and effects of nitrite in brown trout under normoxic and hypoxic conditions: blood and tissue nitrite metabolism and interactions with branchialNOS,Na+/K+-ATPaseandhsp70expression
Authors: Jensen Frank B. , Gerber Lucie , Hansen Marie N. , Madsen Steffen S.
Published: April 2015

Nitrite secures essential nitric oxide (NO) bioavailability in hypoxia at low endogenous concentrations, whereas it becomes toxic at high concentrations. We exposed brown trout to normoxic and hypoxic water in the absence and presence of added ambient nitrite to decipher the cellular metabolism and effects of nitrite at basal and elevated concentrations under different oxygen regimes. We also tested hypotheses concerning influences of nitrite on branchial nitric oxide synthase (NOS), Na+/K+-ATPase (nka) and heat shock protein (hsp70) mRNA expression. Basal plasma and erythrocyte nitrite levels were higher in hypoxia than normoxia, suggesting increased NOS activity. Nitrite exposure strongly elevated nitrite concentrations in plasma, erythrocytes, heart tissue and white muscle, which was associated with an extensive metabolism of nitrite to nitrate and to iron-nitrosylated and S-nitrosated compounds. Nitrite uptake was slightly higher in hypoxia than normoxia, and high internal nitrite levels extensively converted blood hemoglobin to methemoglobin and nitrosylhemoglobin. Hypoxia increased inducible NOS (iNOS) mRNA levels in gills, which was overruled by a strong inhibition of iNOS expression by nitrite in both normoxia and hypoxia, suggesting negative feedback regulation of iNOS gene expression by nitrite. A similar inhibition was absent for neuronal NOS. Branchial NKA activity stayed unchanged, but mRNA levels of the NKA α1a subunit increased with hypoxia and nitrite, which may have countered an initial NKA inhibition. Nitrite also increased hsp70 gene expression, probably contributing to cytoprotective effects of nitrite at low concentrations. Nitrite displays a concentration-dependent switch between positive and negative effects resembling other signaling molecules.
Oxidative stress as an indicator of the costs of reproduction among free-ranging rhesus macaques
Authors: Georgiev Alexander V. , Thompson Melissa Emery , Mandalaywala Tara , Maestripieri Dario
Published: April 2015

Sex differences in longevity may reflect sex-specific costs of intra-sexual competition and reproductive effort. As male rhesus macaques experience greater intrasexual competition and die younger, we predicted males would experience greater oxidative stress than females, and that oxidative stress would reflect sex-specific measures of reproductive effort. Males, relative to females, had higher 8-OHdG and malondialdehyde concentrations, markers of DNA oxidative damage and lipid peroxidation, respectively. Older macaques had lower 8-OHdG levels than younger ones, suggesting oxidative stress decreases in parallel with known age-related declines in reproductive investment. Among males, a recent period of social instability affected oxidative status: males who attacked others at higher rates had higher 8-OHdG levels. Multiparous lactating females with daughters had higher 8-OHdG levels than those with sons. No differences in antioxidant capacity were found. These results lend initial support for using oxidative stress markers to assess trade-offs between reproductive effort and somatic maintenance in primates.
Recent Advances in Copper-mediated Direct Biaryl Coupling
Authors: Hirano Koji , Miura Masahiro
Published: April 2015

Copper salts and complexes have recently received significant attention as less expensive, abundant, and unique alternatives to noble transition-metal catalysts such as palladium, rhodium, and ruthenium, in the research field of C–H activation. This highlight review focuses on recent advances in copper-mediated biaryl coupling via aromatic C–H cleavage, and the scope and limitations are briefly summarized.
Funding source and primary outcome changes in clinical trials registered on ClinicalTrials.gov are associated with the reporting of a statistically significant primary outcome: a cross-sectional study
Authors: Ramagopalan Sreeram V , Skingsley Andrew P. , Handunnetthi Lahiru , Magnus Daniel , Klingel Michelle , Pakpoor Julia , Goldacre Ben
Published: April 2015

Background: We and others have shown a significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. The objectives of this study were to investigate whether changes made to primary outcomes are associated with the likelihood of reporting a statistically significant primary outcome on ClinicalTrials.gov.

Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 20 November 2014 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date.

Findings: 13,238 completed interventional trials were registered with ClinicalTrials.gov that also had study results posted on the website. 2555 (19.3%) had one or more statistically significant primary outcomes. Statistical analysis showed that registration year, funding source and primary outcome change after trial completion were associated with reporting a statistically significant primary outcome.

Conclusions: Funding source and primary outcome change after trial completion are associated with a statistically significant primary outcome report on clinicaltrials.gov.
Algorithm for the anesthetic management of cesarean delivery in patients with unsatisfactory labor epidural analgesia
Authors: Vaida Sonia , Cattano Davide , Hurwitz Debra , Mets Berend
Published: April 2015

The management of a patient presenting with unsatisfactory labor epidural analgesia poses a severe challenge for the anesthetist wanting to provide safe anesthetic care for a cesarean delivery. Early recognition of unsatisfactory labor analgesia allows for replacement of the epidural catheter. The decision to convert labor epidural analgesia to anesthesia for cesarean delivery is based on the urgency of the cesarean delivery, airway examination, and the existence of a residual sensory and motor block.  We suggest an algorithm which is implemented in our department, based on the urgency of the cesarean delivery.