bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydroxyl Fasudil, an Inhibitor of Rho Signaling, Improves Erectile Function in Diabetic Rats: A Role for Neuronal ROCK
Authors: Sezen Sena F. , Lagoda Gwen , Musicki Biljana , Burnett Arthur L.
Published: June 2014

Introduction

The pathogenesis of diabetic erectile dysfunction (ED) includes neuropathy, but the molecular basis for neurogenic ED is incompletely understood. The RhoA/ROCK pathway has been implicated in diabetic neuropathy and in ED, but its role in diabetic neurogenic ED is not known.

Aims

The aim of this study was to determine whether hydroxyl fasudil, a ROCK inhibitor, affects diabetic neuropathy-related ED.

Methods

Type 1 diabetes mellitus was induced in male rats by streptozotocin (75 mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10 mg/kg/day, intraperitoneally) or vehicle, for 4 weeks. Age-matched control, nondiabetic, rats were treated intraperitoneally for 4 weeks with saline. At week 12, after a 2 day washout, neuro-stimulated erectile function was evaluated. Major pelvic ganglia (MPG) were collected for Western blot analysis of RhoA, ROCK-1, ROCK-2, phospho (P)-AKT (Ser473), and P-phosphatase and tensin homolog (P-PTEN) (Ser380/Thr382/383).

Main Outcome Measures

Effect of ROCK inhibitor hydroxyl fasudil on erectile function and ROCK/P-AKT/P-PTEN pathway in the MPG of diabetic rats.

Results

Erectile response was significantly (P < 0.05) reduced in diabetic rats compared with nondiabetic rats and was preserved (P < 0.05) in diabetic rats treated with hydroxyl fasudil. In diabetic rats, RhoA and ROCK-2 protein expressions in MPG were increased (P < 0.05) and remained increased in hydroxyl fasudil-treated rats. P-AKT (Ser473) expression was decreased (P < 0.05), whereas P-PTEN (Ser380/Thr382/383) expression was increased (P < 0.05) in MPG of diabetic rats compared with nondiabetic rats, and both were reversed (P < 0.05) in diabetic rats treated with hydroxyl fasudil.

Conclusion

Improved erectile function and restored P-AKT and P-PTEN in the MPG with hydroxyl fasudil treatment suggest the role of Rho signaling via PTEN/AKT pathway in neurogenic diabetic ED.
A comprehensive hepatitis C virus risk factors meta‐analysis (1989–2013); Do they differ in Egypt?
Authors: El‐Ghitany Engy Mohamed , Abdel Wahab Moataza M. , Abd El‐Wahab Ekram W. , Hassouna Safaa , Farghaly Azza G.
Published: June 2014

Background & Aims

The prevention and control of HCV infection is complex and challenging in terms of describing risk factors and modes of transmission. This meta‐analysis was conducted to summarize the best available data on HCV risk factors worldwide and in Egypt.

Methods

Through exhaustive literature searches (1989–2013) of HCV risk factors, 357 original eligible articles were included in this study.

Results

The highest detected risk was intravenous drug users (IDUs) (OR = 9.6) followed by HIV infection (OR = 4.9), having an IDU partner (OR = 4.1), HBV infection (OR = 3.5), Caesarean section (CS) (OR = 3.35), blood transfusion (OR = 3.2) and having an HCV+ partner (OR = 3). Organ transplantation, hospital admission, haemodialysis and having a sexually transmitted infection carry 2.96, 2.4, 2.18 and 2 risks of having HCV respectively. Other significant risk factors included poor education, older age, sharing sharp or blunt objects, MSM, tattooing, hijama, body piercing, minor operations and medical procedures. Some risks showed a decrease over the previous decade, including blood transfusion, organ transplantation, IDUs, IDU partner and CS. Others showed rising risks, including having an HCV+ partner, MSM and suffering from STI. In Egypt, male gender, rural residence, acupuncture and receiving parenteral antischistosomal treatment were significant risks, while neither HIV nor HBV were found to carry a risk of HCV infection.

Conclusion

Blood transfusion, organ transplantation, CS, IDUs, haemodialysis, minor operations and medical procedures are established risk factors. Attention and urgent intervention should be given to the sexual route of transmission, as well as that through minor operations and medical procedures.
Stardust Interstellar Preliminary Examination X: Impact speeds and directions of interstellar grains on the Stardust dust collector
Authors: Sterken Veerle J. , Westphal Andrew J. , Altobelli Nicolas , Grün Eberhard , Hillier Jon K. , Postberg Frank , Srama Ralf , Allen Carlton , Anderson David , Ansari Asna , Bajt Saša , Bastien Ron S. , Bassim Nabil , Bechtel Hans A. , Borg Janet , Brenker Frank E. , Bridges John , Brownlee Donald E. , Burchell Mark , Burghammer Manfred , Butterworth Anna L. , Changela Hitesh , Cloetens Peter , Davis Andrew M. , Doll Ryan , Floss Christine , Flynn George , Frank David , Gainsforth Zack , Heck Philipp R. , Hoppe Peter , Hudson Bruce , Huth Joachim , Hvide Brit , Kearsley Anton , King Ashley J. , Lai Barry , Leitner Jan , Lemelle Laurence , Leroux Hugues , Leonard Ariel , Lettieri Robert , Marchant William , Nittler Larry R. , Ogliore Ryan , Ong Wei Ja , Price Mark C. , Sandford S. A. , Tresseras Juan‐Angel Sans , Schmitz Sylvia , Schoonjans Tom , Silversmit Geert , Simionovici Alexandre , Solé Vicente A. , Stephan Thomas , Stodolna Julien , Stroud Rhonda M. , Sutton Steven , Trieloff Mario , Tsou Peter , Tsuchiyama Akira , Tyliszczak Tolek , Vekemans Bart , Vincze Laszlo , Korff Joshua Von , Wordsworth Naomi , Zevin Daniel , Zolensky Michael E. ,   > 30,000 Stardust@home dusters
Published: June 2014

On the basis of an interstellar dust model compatible with Ulysses and Galileo observations, we calculate and predict the trajectories of interstellar dust (ISD) in the solar system and the distribution of the impact speeds, directions, and flux of ISD particles on the Stardust Interstellar Dust Collector during the two collection periods of the mission. We find that the expected impact velocities are generally low (<10 km s−1) for particles with the ratio of the solar radiation pressure force to the solar gravitational force β > 1, and that some of the particles will impact on the cometary side of the collector. If we assume astronomical silicates for particle material and a density of 2 g cm−3, and use the Ulysses measurements and the ISD trajectory simulations, we conclude that the total number of (detectable) captured ISD particles may be on the order of 50. In companion papers in this volume, we report the discovery of three interstellar dust candidates in the Stardust aerogel tiles. The impact directions and speeds of these candidates are consistent with those calculated from our ISD propagation model, within the uncertainties of the model and of the observations.
De Lubac, Grace, and the Pure Nature Debate
Authors: Grumett David
Published: June 2014

Henri de Lubac's doctrine of grace and nature emerged out of the pastoral and sacramental context of confession. Although recent critics have assumed a Thomist setting, a close reading shows that the doctrine is rooted in de Lubac's critical engagement with Augustinianism. In the form of Jansenism and drawing especially on Augustine's late, anti‐Pelagian writings, this sensibility pervaded modern French theology. Notwithstanding its distorted conceptions of grace's mode of operation and of human nature, Jansenism provoked de Lubac into developing new understandings of the relation between belief and knowledge, and of theological anthropology. In advocating for the continuity of Augustine's theology, de Lubac made an important contribution to Augustine scholarship. His resulting doctrine of grace and nature, in which the person of Adam is central, has wider, abiding theological salience.
Elevational disease distribution in a natural plant–pathogen system: insights from changes across host populations and climate
Authors: Abbate Jessica L. , Antonovics Janis
Published: June 2014

Understanding the factors determining the distribution of parasites and pathogens in natural systems is essential for making predictions about the spread of emerging infectious disease. Here, we report the distribution of the fungal anther‐smut disease, caused by Microbotryum spp., on populations of the European wildflower Silene vulgaris over a range of elevations. A survey of several geographically distinct mountains in the southern French alps found that anther‐smut disease was restricted to high elevations, rarely observed below 1300 m despite availability of hosts below this elevation. Anther smut causes host‐sterility, and is recognized as a model system for natural host–pathogen interactions, sharing common features with vector‐borne and sexually‐transmitted disease in animals. In such systems, many biotic and abiotic factors likely to change over ecological gradients can influence disease epidemiology, including host spatial structure, pathogen infectivity, host resistance, and vector behavior. Here, we tested whether host population size, density, or connectivity also declined across elevation, and whether these epidemiologically relevant factors explained the observed disease distribution. We found that while none of these factor means changed across elevation, disease was significantly more likely to occur at both higher elevations and in larger populations, the majority of which were found above 1300 m. The break in disease incidence was also associated with an apparent scarcity of these larger host populations between 1000 and 1300 m in elevation. Examining variation in climatic factors among host populations, we also showed that the probability of disease was higher in areas with historically colder, wetter, and more stable conditions. The restricted distribution of anther‐smut disease in high‐elevation S. vulgaris provides an opportunity for empirical study on range limits and disease distribution in natural alpine communities that are considered particularly sensitive to the effects of climate change.
First‐year seedlings and climate change: species‐specific responses of 15 North American tree species
Authors: Fisichelli Nicholas , Wright Alexandra , Rice Karen , Mau Alida , Buschena Cindy , Reich Peter B.
Published: June 2014

Species will respond individually to climate change and this poses a challenge for modeling climate–vegetation dynamics using broader taxonomic or biogeographical classifications. Additionally, responses to climate and environmental conditions may shift with ontogeny, further complicating efforts to understand the likely rates and directions of vegetation change. We measured emergence, leaf‐out rate, growth, and survival of first‐year seedlings in response to warming, precipitation regime shifts, and seedbed condition (leaf litter presence/absence). We grouped species into three levels of organization (species‐specific, biome‐level and broad taxonomic group) and hypothesized that most metrics of seedling performance would be best described by species‐specific models, as even similar species may respond in vastly different ways to global change. Results showed that the species‐specific model was the best fit for emergence and development rates, whereas growth and survival could be captured through broader groupings, with the broadleaf temperate group exhibiting the greatest growth and conifers the shortest survival times. The sign and magnitude of response to climate and seedbed condition varied with treatment combinations and metric of performance. For example, seedlings grew more in response to warming, but conditions too dry or too wet limited this positive response. Also, warmer temperatures generally increased emergence, development, and growth, but decreased survival, whereas leaf litter presence decreased emergence and slowed development, but increased survival. The results presented here are for first‐year seedlings and in many cases the responses are different from other studies using older plants. Future research and climate vegetation modeling needs to assess performance at multiple development stages and determine where key bottleneck phases for population growth occur for individual species.
Filaggrin Gene Mutations in African Americans with Both Ichthyosis Vulgaris and Atopic Dermatitis
Authors: Polcari Ingrid , Becker Lauren , Stein Sarah L. , Smith Marilyn S. , Paller Amy S.
Published: June 2014

Atopic dermatitis (AD) and ichthyosis vulgaris (IV) are two common disorders of epidermal homeostasis resulting in dry skin. The profilaggrin gene, located on chromosome 1q22, encodes a keratin filament aggregating protein (filaggrin) that is essential to forming the epidermal barrier and maintaining hydration. Null mutations in filaggrin have been found to underlie IV and are common in patients with AD, but the minority of African Americans with AD or IV show these mutations in filaggrin. We have selectively studied African Americans with both AD and IV to maximize the possibility of finding filaggrin null mutations in this population. DNA was collected using buccal swabs from 18 African American children with both AD and IV and 17 African American controls without either of these diseases. Purified genomic DNA was amplified using polymerase chain reaction from three regions of the filaggrin gene, exon 3, including R501X, 2282del4, E2554X, R2447X, 1249insG, R826X, 2767insT, and E2422X. Of the African American children with both AD and IV, 22.2% were heterozygous for filaggrin null mutations. Out of the control group, one carried a null mutation and was later discovered to have a history of asthma. Null mutations found in this population included R501X (n = 1), 2282del4 (n = 2), and R826X (n = 2, including the control patient). Our data demonstrate a prevalence of filaggrin mutations in the African American population that exceeds previously published data, although the overall prevalence is still lower than in other populations. It is likely that factors other than known FLG mutations are involved in African American patients.
Recent Advances in the Genetics and Management of Harlequin Ichthyosis
Authors: Ahmed Hera , O'Toole Edel A.
Published: June 2014

Harlequin ichthyosis (HI) is the most severe and devastating form of the autosomal recessive congenital ichthyoses (ARCIs). Mutations in the ABCA12 gene result in disruption of intercellular lipid deposition in the stratum corneum and a major skin barrier defect. Patients present at birth, often premature, with cutaneous thick, yellow, hyperkeratotic plates with deep erythematous fissures, causing a typical facial appearance. Harlequin ichthyosis has often been considered to be fatal, and management tends to be palliative, but follow‐up of 45 affected infants has shown that with good neonatal care and early introduction of oral retinoids, survival rates are improving. Because ABCA12 mutations have been identified, known carriers are able to undergo preventative preimplantation and prenatal genetic testing. Experimental studies have shown recovery of lipid secretion in lamellar granules using corrective gene therapy. Further research is needed to develop alternative therapies to retinoids in HI.
B‐type natriuretic peptide trends after pediatric heart transplantation
Authors: Sparks Joshua D. , Boston Umar , Eghtesady Pirooz , Canter Charles E.
Published: June 2014

BNP is increasingly utilized in the management of pediatric HT recipients. Performing a retrospective single‐center chart review, we sought to describe BNP changes during the first year after HT and identify factors that affect its trend. After exclusion for rejection, 316 BNP levels from 50 patients were evaluated. BNP underwent an exponential decline 120 days after HT followed by a plateau. Log10BNP decline strongly correlated with time (r = −0.70, p < 0.0001). Initial BNP was less in pretransplant VAD (p = 0.0016) and lower post‐HT inotrope use (p = 0.0043). Infant recipients, IT >4 h, and those bridged medically were associated with higher plateau BNP. Multivariable logistic regression demonstrated IT >4 h independently predicted plateau BNP in the upper quartile (OR 7.1, p = 0.02). No significant change in BNP coincided with rejection (N = 6 patients) without severe hemodynamic compromise. BNP correlated modestly with right atrial pressure (r = 0.4652, p < 0.0001) and pulmonary capillary wedge pressure (r = 0.2660, p < 0.001), but poorly with echocardiogram (r = −0.18, p = 0.003). Trending BNP could help provide insight into how the graft recovers after HT and IT >4 h independently predicted higher plateau BNP and may reflect subtle changes in graft performance.
Balloon‐occluded retrograde transvenous obliteration for recurrent fundal gastric variceal bleeding in an adolescent
Authors: Rosen Danya , Chu Jaime , Patel Rahul , Moon Jang , Iyer Kishore , Arnon Ronen
Published: June 2014

Gastric variceal bleeding is associated with high morbidity and mortality. Balloon‐occluded retrograde transvenous obliteration is a relatively new treatment used to control bleeding gastric varices that involves transvenous sclerosis of gastric varices through a spontaneous gastrorenal shunt. Here, we report on a 14‐yr‐old patient that underwent balloon‐occluded retrograde transvenous obliteration for refractory bleeding fundal varices in the setting of esophageal varices and cirrhosis, which did not respond to medical management or endoscopic injection. This case report serves as a reminder that balloon‐occluded retrograde transvenous obliteration can successfully control fundal variceal bleeding in pediatric patients and may serve as a bridge to liver transplantation.
Risk‐Cost‐Benefit Analysis for Transportation Corridors with Interval Uncertainties of Heterogeneous Data
Authors: Xu Junrui , Lambert James H.
Published: June 2014

Access management, which systematically limits opportunities for egress and ingress of vehicles to highway lanes, is critical to protect trillions of dollars of current investment in transportation. This article addresses allocating resources for access management with incomplete and partially relevant data on crash rates, travel speeds, and other factors. While access management can be effective to avoid crashes, reduce travel times, and increase route capacities, the literature suggests a need for performance metrics to guide investments in resource allocation across large corridor networks and several time horizons. In this article, we describe a quantitative decision model to support an access management program via risk‐cost‐benefit analysis under data uncertainties from diverse sources of data and expertise. The approach quantifies potential benefits, including safety improvement and travel time savings, and costs of access management through functional relationships of input parameters including crash rates, corridor access point densities, and traffic volumes. Parameter uncertainties, which vary across locales and experts, are addressed via numerical interval analyses. This approach is demonstrated at several geographic scales across 7,000 kilometers of highways in a geographic region and several subregions. The demonstration prioritizes route segments that would benefit from risk management, including (i) additional data or elicitation, (ii) right‐of‐way purchases, (iii) restriction or closing of access points, (iv) new alignments, (v) developer proffers, and (vi) etc. The approach ought to be of wide interest to analysts, planners, policymakers, and stakeholders who rely on heterogeneous data and expertise for risk management.
Rethinking Vulnerability Analysis and Governance with Emphasis on a Participatory Approach
Authors: Rossignol Nicolas , Delvenne Pierre , Turcanu Catrinel
Published: June 2014

This article draws on vulnerability analysis as it emerged as a complement to classical risk analysis, and it aims at exploring its ability for nurturing risk and vulnerability governance actions. An analysis of the literature on vulnerability analysis allows us to formulate a three‐fold critique: first, vulnerability analysis has been treated separately in the natural and the technological hazards fields. This separation prevents vulnerability from unleashing the full range of its potential, as it constrains appraisals into artificial categories and thus already closes down the outcomes of the analysis. Second, vulnerability analysis focused on assessment tools that are mainly quantitative, whereas qualitative appraisal is a key to assessing vulnerability in a comprehensive way and to informing policy making. Third, a systematic literature review of case studies reporting on participatory approaches to vulnerability analysis allows us to argue that participation has been important to address the above, but it remains too closed down in its approach and would benefit from embracing a more open, encompassing perspective. Therefore, we suggest rethinking vulnerability analysis as one part of a dynamic process between opening‐up and closing‐down strategies, in order to support a vulnerability governance framework.
Effects of a multimodality blood conservation schema toward improvement of intraoperative hemoglobin levels and off‐pump transfusions in coronary artery bypass graft surgery
Authors: Tran Minh‐Ha , Lin David M. , Wilcox Tanya , Schiro Dana , Cannesson Maxime , Milliken Jeffrey
Published: June 2014

Background

Cardiothoracic surgery places significant demands on blood bank resources. Measures aimed at reducing intraoperative hemodilution were initiated as part of a blood conservation program.

Study Design and Methods

We initiated a series of measures aimed at reducing hemodilution volume: 1) reduction of intravenous fluid (IVF) volume, 2) reduction of circuit size, and 3) use of autologous priming techniques. All sources and volumes of IVF were obtained from the medical record. Intraoperative hematocrit (Hct) measurements were performed at the following intervals: first in operating room (OR), lowest on‐pump, last on‐pump, after protamine reversal, and immediately before discharge from OR. Red blood cell (RBC) transfusions were recorded. Intraoperative IVF, Hct levels, and transfusions were analyzed by cardiopulmonary bypass phase (prepump, on‐pump, and off‐pump), comparing preimplementation and postimplementation periods.

Results

Total intraoperative IVF volume was reduced by 973.7 mL (95% confidence interval, 671.6‐1275.9 mL; p < 0.001) leading to a mean on‐pump Hct improvement of more than 2% (p < 0.004). This contributed to a reduction in off‐pump RBC transfusions by 20.6% (p = 0.014). A significant degree of heterogeneity in transfusion practice was noted between anesthesiologists.

Conclusions

Blood conservation efforts in cardiac surgery should include efforts aimed at reducing hemodilution. Potential improvements are blunted by variation in transfusion practice.
Community Sport for Development: Perceptions From Practice in Southern Africa
Authors: Marshall Sara K. , Barry Paul
Published: June 2014

Development practitioners and agencies consider sport to play a valuable role in social development; however, the emerging evidence does not yet adequately describe sport’s contribution to social development. Lyras (2009, 2012a) proposed a sport for development theory (SFDT) as a specific model to increase understanding of the processes and conditions involved in sport for development (SFD) programs. In our study, SFD practitioners of the Kicking AIDS Out Network were interviewed to identify project elements perceived as significant for achieving development objectives, and their perceptions were examined in relation to SFDT to test its applicability to their particular development context. The findings suggest SFDT offers an appropriate framework to enhance project design and delivery that integrates the features of sport, education, life skills development, use of leaders as change agents, and participation that are key to Kicking AIDS Out programs and other community sport programs promoting behavior and social change.
Detecting nonlocality in many-body quantum states
Authors: Tura J. , Augusiak R. , Sainz A. B. , Vértesi T. , Lewenstein M. , Acín A.
Published: June 2014

Testing nonlocality for many particles

Distant parts of a quantum-mechanical system can be correlated in ways that cannot be described classically—a concept known as nonlocality. Tura
et al.
propose a simple test for nonlocality in systems with multiple particles. The test involves quantities that should readily be measurable in, for example, cold atom experiments. This is an improvement over currently available tests, which are difficult to implement experimentally.

Science
, this issue p.
1256
Evidence for mesothermy in dinosaurs
Authors: Grady John M. , Enquist Brian J. , Dettweiler-Robinson Eva , Wright Natalie A. , Smith Felisa A.
Published: June 2014

Not too fast, not too slow, somewhere in between

In early depictions, dinosaurs lumbered slowly, dragging their tails. More recently, we have imagined them lifting their tails and running. The question boils down to whether dinosaurs had energetic systems closer to those of rapidly metabolizing mammals and birds, or to those of slower reptiles that do not internally regulate their body temperature. However, determining the metabolic rate of extinct organisms is no easy task. Grady
et al.
analyzed a huge data set on growth rate in both extinct and living species, using a method that considers body temperature and body size. Dinosaur metabolism seems to have been neither fast nor slow, but somewhere in the middle—so, dinosaurs did not fully regulate their internal temperature but they were also not entirely at the whim of the environment; neither slow goliaths nor supercharged reptiles.

Science
, this issue p.
1268
It helps to be well connected
Authors: Duffy Meghan A.
Published: June 2014

Highly connected populations of the weedy plant
Plantago
are less likely to be colonized by a fungal pathogen

[Also see Report by

Jousimo
et al.

]
A salty start to modern ocean circulation
Authors: Filippelli Gabriel
Published: June 2014

Water flow out of the Mediterranean is linked to large-scale ocean circulation patterns

[Also see Research Article by

Hernández-Molina
et al.

]
Time to speak up for research
Authors: Porter John Edward
Published: June 2014

As U.S. National Institutes of Health (NIH) Director Francis Collins stated in recent testimony to Congress, “Our nation has never witnessed a time of greater promise for advances in medicine.” Researchers are moving closer to developing a universal flu vaccine, cancer immunotherapy (harnessing the immune system to attack tumor cells) is on the horizon, and the public/private BRAIN initiative will provide deeper knowledge of billions of nerve cells to advance research on Alzheimer's disease, autism, and other braindisorders. Yet the general public, and in particular elected officials, have failed to embrace the promise of cutting-edge science as a means to improve health and the economy.
Carbon-mapping satellite will monitor plants' faint glow
Authors: Hand Eric
Published: June 2014

Launch of Orbiting Carbon Observatory-2 promises precise mapping of chlorophyll fluorescence from space.
Polio eradicators struggle to prevent the next outbreak
Authors: Roberts Leslie
Published: June 2014

A new “Red List” identifies the countries where the virus may strike next.
Racing for disaster?
Authors: Gibbons Ann
Published: June 2014

Breeding thoroughbreds for speed may harm their health.
STAP cells succumb to pressure
Authors: Normile Dennis , Vogel Gretchen
Published: June 2014

Retraction plans for easy stem cell recipe leave scientists wondering how the papers came to be published.
Mission to MERS
Authors: Enserink Martin
Published: June 2014

A massive study in Qatar is yielding the most detailed data yet on how a new virus spreads between camels—and how it jumps to humans.
A touch of the random
Authors: Macilwain Colin
Published: June 2014

As researchers seek ever-larger supercomputers to crunch climate models of baffling complexity, some are calling for a fresh, statistics-based approach.
An explosion of bioinformatics careers
Authors: Levine Alaina G.
Published: June 2014

Big data is everywhere, and its influence and practical omnipresence across multiple industries will just continue to grow. For life scientists with expertise and an interest in bioinformatics, computer science, statistics, and related skill sets, the job outlook couldn’t be rosier. Big pharma, biotech, and software companies are clamoring to hire professionals with experience in bioinformatics and the identification, compilation, analysis, and visualization of huge amounts of biological and health care information. With the rapid development of new tools to make sense of life science research and outcomes, spurred by innovative research in bioinformatics itself, scientists who are entranced by data can pursue more career options than ever before.
RNAi Therapies: Drugging the Undruggable
Authors: Wu Sherry Y. , Lopez-Berestein Gabriel , Calin George A. , Sood Anil K.
Published: June 2014

New strategies are required to make RNA interference therapeutics a viable tool for cancer management.
WANTED: Natural-Born Sickler
Authors: Lemaire Mathieu
Published: June 2014

Sixty-five years after Pauling discovered the molecular basis of sickle cell anemia, the lipid S1P is found to be a critical player.
Antimicrobial Drug Resistance in All Four Corners of the Earth
Authors: Tsalik Ephraim L.
Published: June 2014

Antibiotic resistance genes exist in multiple environmental and biological sources worldwide.
Role for Gr-1+Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG
Authors: Panas Michael W. , Letvin Norman L.
Published: June 2014

Mycobacterium bovisbacillus Calmette-Guérin (BCG) is an attractive target for development as a live vaccine vector delivering transgenic antigens from HIV and other pathogens. Most studies aimed at defining the clearance of BCG have been performed at doses between 102and 104CFU. Interestingly, however, recombinant BCG (rBCG) administered at doses of >106CFU effectively generates antigen-specific T-cell responses and primes for heterologous boost responses. Thus, defining clearance at high doses might aid in the optimization of rBCG as a vector. In this study, we used bioluminescence imaging to examine the kinetics of rBCG transgene expression and clearance in mice immunized with 5 × 107CFU rBCG expressing luciferase. Similar to studies using low-dose rBCG, our results demonstrate that the adaptive immune response is necessary for long-term control of rBCG beginning 9 days after immunizing mice. However, in contrast to these reports, we observed that the majority of mycobacterial antigen was eliminated prior to day 9. By examining knockout and antibody-mediated depletion mouse models, we demonstrate that the rapid clearance of rBCG occurs in the first 24 h and is mediated by Gr-1+cells. As Gr-1+granulocytes have been described as having no impact on BCG clearance at low doses, our results reveal an unappreciated role for Gr-1+neutrophils and inflammatory monocytes in the clearance of high-dose rBCG. This work demonstrates the potential of applying bioluminescence imaging to rBCG in order to gain an understanding of the immune response and increase the efficacy of rBCG as a vaccine vector.
PCR-Based Detection and Molecular Characterization of Shiga Toxin-Producing Escherichia coli Strains in a Routine Microbiology Laboratory over 16 years
Authors: Haugum K. , Brandal L. T. , Lindstedt B.-A. , Wester A. L. , Bergh K. , Afset J. E.
Published: June 2014

Shiga toxin-producing
Escherichia coli
(STEC) is a heterogeneous group of bacteria causing disease ranging from asymptomatic carriage and mild infection to hemolytic uremic syndrome (HUS). Here, we describe patients with STEC infection and characterize the STEC strains detected in our laboratory by use of PCR for
stx
1
,
stx
2
, and
eae
from 1996 through 2011. Patient information was collected from referral forms and from the Norwegian Surveillance System for Communicable Diseases. STEC isolates were characterized with respect to serogroup or serotype, selected potential virulence genes, and multilocus variable-number tandem-repeat analysis (MLVA) genotype. STEC strains were isolated from 138 (1.09%) of 12,651 patients tested. STEC strains of serogroups O26, O103, O121, O145, and O157 were the most frequent. These serogroups, except non-sorbitol-fermenting O157, were also the most frequent among the 11 patients (all ≤5 years old) who developed HUS. Twenty-four STEC strains were classified as being HUS associated based on an epidemiological link to a HUS case, including an MLVA genotype identical to that of the STEC strain. The age of the patient (≤5 years) and the genes
eae
and
stx
2a
were significantly associated with HUS-associated STEC (
P
< 0.05 for each parameter), while
stx
1
was associated with non-HUS-associated STEC (
P
< 0.05). All of the potential virulence genes analyzed, except
ehxA
, were significantly more frequent among HUS-associated than non-HUS-associated strains (
P
< 0.05 for each gene). However, these genes were also present in some non-HUS-associated STEC strains and could therefore not reliably differentiate between HUS-associated and non-HUS-associated STEC strains.
Multidrug-Resistant Nontuberculous Mycobacteria Isolated from Cystic Fibrosis Patients
Authors: Cândido Pedro Henrique Campanini , Nunes Luciana de Souza , Marques Elizabeth Andrade , Folescu Tânia Wrobel , Coelho Fábrice Santana , de Moura Vinicius Calado Nogueira , da Silva Marlei Gomes , Gomes Karen Machado , Lourenço Maria Cristina da Silva , Aguiar Fábio Silva , Chitolina Fernanda , Armstrong Derek T. , Leão Sylvia Cardoso , Neves Felipe Piedade Gonçalves , Mello Fernanda Carvalho de Queiroz , Duarte Rafael Silva
Published: June 2014

Worldwide, nontuberculous mycobacteria (NTM) have become emergent pathogens of pulmonary infections in cystic fibrosis (CF) patients, with an estimated prevalence ranging from 5 to 20%. This work investigated the presence of NTM in sputum samples of 129 CF patients (2 to 18 years old) submitted to longitudinal clinical supervision at a regional reference center in Rio de Janeiro, Brazil. From June 2009 to March 2012, 36 NTM isolates recovered from 10 (7.75%) out of 129 children were obtained. Molecular identification of NTM was performed by using PCR restriction analysis targeting the
hsp65
gene (PRA-
hsp65
) and sequencing of the
rpoB
gene, and susceptibility tests were performed that followed Clinical and Laboratory Standards Institute recommendations. For evaluating the genotypic diversity, pulsed-field gel electrophoresis (PFGE) and/or enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) was performed. The species identified were
Mycobacterium abscessus
subsp.
bolletii
(
n
= 24),
M. abscessus
subsp.
abscessus
(
n
= 6),
Mycobacterium fortuitum
(
n
= 3),
Mycobacterium marseillense
(
n
= 2), and
Mycobacterium timonense
(
n
= 1). Most of the isolates presented resistance to five or more of the antimicrobials tested. Typing profiles were mainly patient specific. The PFGE profiles indicated the presence of two clonal groups for
M. abscessus
subsp.
abscessus
and five clonal groups for
M. abscesssus
subsp.
bolletii
, with just one clone detected in two patients. Given the observed multidrug resistance patterns and the possibility of transmission between patients, we suggest the implementation of continuous and routine investigation of NTM infection or colonization in CF patients, including countries with a high burden of tuberculosis disease.
Hypertrophic Adenoid Is a Major Infection Site of Human Bocavirus 1
Authors: Proenca-Modena J. L. , Paula F. E. , Buzatto G. P. , Carenzi L. R. , Saturno T. H. , Prates M. C. , Silva M. L. , Delcaro L. S. , Valera F. C. P. , Tamashiro E. , Anselmo-Lima W. T. , Arruda E.
Published: June 2014

Human bocavirus 1 (HBoV1) is associated with respiratory infections worldwide, mainly in children. Similar to other parvoviruses, it is believed that HBoV1 can persist for long periods of time in humans, probably through maintaining concatemers of the virus single-stranded DNA genome in the nuclei of infected cells. Recently, HBoV-1 was detected in high rates in adenoid and palatine tonsils samples from patients with chronic adenotonsillar diseases, but nothing is known about the virus replication levels in those tissues. A 3-year prospective hospital-based study was conducted to detect and quantify HBoV1 DNA and mRNAs in samples of the adenoids (AD), palatine tonsils (PT), nasopharyngeal secretions (NPS), and peripheral blood (PB) from patients undergoing tonsillectomy for tonsillar hypertrophy or recurrent tonsillitis. HBoV1 was detected in 25.3% of the AD samples, while the rates of detection in the PT, NPS, and PB samples were 7.2%, 10.5%, and 1.7%, respectively. The viral loads were higher in AD samples, and 27.3% of the patients with HBoV had mRNA detectable in this tissue. High viral loads and detectable mRNA in the AD were associated with HBoV1 detection in the other sample sites. The adenoids are an important site of HBoV1 replication and persistence in children with tonsillar hypertrophy. The adenoids contain high HBoV1 loads and are frequently positive for HBoV mRNA, and this is associated with the detection of HBoV1 in secretions.
Sumoylation of Influenza A Virus Nucleoprotein Is Essential for Intracellular Trafficking and Virus Growth
Authors: Han Qinglin , Chang Chong , Li Li , Klenk Christoph , Cheng Jinke , Chen Yixin , Xia Ningshao , Shu Yuelong , Chen Ze , Gabriel Gülsah , Sun Bing , Xu Ke
Published: June 2014

Viruses take advantage of host posttranslational modifications for their own benefit. It was recently reported that influenza A virus proteins interact extensively with the host sumoylation system. Thereby, several viral proteins, including NS1 and M1, are sumoylated to facilitate viral replication. However, to what extent sumoylation is exploited by influenza A virus is not fully understood. In this study, we found that influenza A virus nucleoprotein (NP) is a bona fide target of sumoylation in both NP-transfected cells and virus-infected cells. We further found that NP is sumoylated at the two most N-terminal residues, lysines 4 and 7, and that sumoylation at lysine 7 of NP is highly conserved across different influenza A virus subtypes and strains, including the recently emerged human H7N9 virus. While NP stability and polymerase activity are little affected by sumoylation, the NP sumoylation-defective WSN-NP
K4,7R
virus exhibited early cytoplasmic localization of NP. The growth of the WSN-NP
K4,7R
virus was highly attenuated compared to that of the wild-type WSN virus, and the lysine residue at position 7 is indispensable for the virus's survival, as illustrated by the rapid emergence of revertant viruses. Thus, sumoylation of influenza A virus NP is essential for intracellular trafficking of NP and for virus growth, illustrating sumoylation as a crucial strategy extensively exploited by influenza A virus for survival in its host.

IMPORTANCE
Host posttranslational modifications are heavily targeted by viruses for their own benefit. We and others previously reported that influenza A virus interacts extensively with the host sumoylation system. However, the functional outcomes of viral sumoylation are not fully understood. Here we found that influenza A virus nucleoprotein (NP), an essential component for virus replication, is a new target of SUMO. This is the first study to find that NP from different influenza A viruses, including recently emerged H7N9, is sumoylated at conserved lysine 7. Our data further illustrated that sumoylation of influenza A virus NP is essential for intracellular trafficking of NP and virus growth, indicating that influenza A virus relies deeply on sumoylation to survive in host cells. Strategies to downregulate viral sumoylation could thus be a potential antiviral treatment.
Modulation of Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Function by Hypoxia-Upregulated Protein 1
Authors: Giffin Louise , Yan Feng , Major M. Ben , Damania Blossom
Published: June 2014

Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV expresses several proteins that modulate host cell signaling pathways. One of these proteins is viral interleukin-6 (vIL-6), which is a homolog of human IL-6 (hIL-6). vIL-6 is able to prevent apoptosis and promote proinflammatory signaling, angiogenesis, and cell proliferation. Although it can be secreted, vIL-6 is mainly an intracellular protein that is retained in the endoplasmic reticulum (ER). We performed affinity purification and mass spectrometry to identify novel vIL-6 binding partners and found that a cellular ER chaperone, hypoxia-upregulated protein 1 (HYOU1), interacts with vIL-6. Immunohistochemical staining reveals that both PEL and KS tumor tissues express significant amounts of HYOU1. We also show that HYOU1 increases endogenous vIL-6 protein levels and that HYOU1 facilitates vIL-6-induced JAK/STAT signaling, migration, and survival in endothelial cells. Furthermore, our data suggest that HYOU1 also modulates vIL-6's ability to induce CCL2, a chemokine involved in cell migration. Finally, we investigated the impact of HYOU1 on cellular hIL-6 signaling. Collectively, our data indicate that HYOU1 is important for vIL-6 function and may play a role in the pathogenesis of KSHV-associated cancers.

IMPORTANCE
KSHV vIL-6 is detectable in all KSHV-associated malignancies and promotes tumorigenesis and inflammation. We identified a cellular protein, called hypoxia-upregulated protein 1 (HYOU1), that interacts with KSHV vIL-6 and is present in KSHV-infected tumors. Our data suggest that HYOU1 facilitates the vIL-6-induced signaling, migration, and survival of endothelial cells.
The Hop-Like Stress-Induced Protein 1 Cochaperone Is a Novel Cell-Intrinsic Restriction Factor for Mitochondrial Tombusvirus Replication
Authors: Xu Kai , Lin Jing-Yi , Nagy Peter D.
Published: June 2014

Recent genome-wide screens reveal that the host cells express an arsenal of proteins that inhibit replication of plus-stranded RNA viruses by functioning as cell-intrinsic restriction factors of viral infections. One group of cell-intrinsic restriction factors against tombusviruses contains tetratricopeptide repeat (TPR) domains that directly interact with the viral replication proteins. In this paper, we find that the TPR domain-containing Hop-like stress-inducible protein 1 (Sti1p) cochaperone selectively inhibits the mitochondrial membrane-based replication of
Carnation Italian ringspot tombusvirus
(CIRV). In contrast, Sti1/Hop does not inhibit the peroxisome membrane-based replication of the closely related
Tomato bushy stunt virus
(TBSV) or
Cucumber necrosis virus
(CNV) in a yeast model or in plants. Deletion of
STI1
in yeast leads to up to a 4-fold increase in CIRV replication, and knockdown of the orthologous Hop cochaperone in plants results in a 3-fold increase in CIRV accumulation. Overexpression of Sti1p derivatives in yeast reveals that the inhibitory function depends on the TPR1 domain known to interact with heat shock protein 70 (Hsp70), but not on the TPR2 domain interacting with Hsp90.
In vitro
CIRV replication studies based on isolated mitochondrial preparations and purified recombinant proteins has confirmed that Sti1p, similar to the TPR-containing Cyp40-like Cpr7p cyclophilin and the Ttc4 oncogene-like Cns1 cochaperone, is a strong inhibitor of CIRV replication. Sti1p interacts and colocalizes with the CIRV replication proteins in yeast. Our findings indicate that the TPR-containing Hop/Sti1 cochaperone could act as a cell-intrinsic virus restriction factor of the mitochondrial CIRV, but not against the peroxisomal tombusviruses in yeast and plants.

IMPORTANCE
The host cells express various cell-intrinsic restriction factors that inhibit the replication of plus-stranded RNA viruses. In this paper, the authors find that the Hop-like stress-inducible protein 1 (Sti1p) cochaperone selectively inhibits the mitochondrial membrane-based replication of
Carnation Italian ringspot tombusvirus
(CIRV) in yeast. Deletion of
STI1
in yeast or knockdown of the orthologous Hop cochaperone in plants leads to increased CIRV replication. In addition, overexpression of Sti1p derivatives in yeast reveals that the inhibitory function depends on the TPR1 domain known to interact with heat shock protein 70 (Hsp70), but not on the TPR2 domain interacting with Hsp90.
In vitro
CIRV replication studies based on isolated mitochondrial preparations and purified recombinant proteins have confirmed that Sti1p is a strong inhibitor of CIRV replication. The authors' findings reveal that the Hop/Sti1 cochaperone could act as a cell-intrinsic restriction factor against the mitochondrial CIRV, but not against the related peroxisomal tombusviruses.
Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+Epitope Immunogenicity in HIV-1 Envelope Glycoprotein
Authors: Li Tingfeng , Steede N. Kalaya , Nguyen Hong-Nam P. , Freytag Lucy C. , McLachlan James B. , Mettu Ramgopal R. , Robinson James E. , Landry Samuel J.
Published: June 2014

Helper T-cell epitope dominance in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is not adequately explained by peptide binding to major histocompatibility complex (MHC) proteins. Antigen processing potentially influences epitope dominance, but few, if any, studies have attempted to reconcile the influences of antigen processing and MHC protein binding for all helper T-cell epitopes of an antigen. Epitopes of gp120 identified in both humans and mice occur on the C-terminal flanks of flexible segments that are likely to be proteolytic cleavage sites. In this study, the influence of gp120 conformation on the dominance pattern in gp120 from HIV strain 89.6 was examined in CBA mice, whose MHC class II protein has one of the most well defined peptide-binding preferences. Only one of six dominant epitopes contained the most conserved element of the I-Akbinding motif, an aspartic acid. Destabilization of the gp120 conformation by deletion of single disulfide bonds preferentially enhanced responses to the cryptic I-Akmotif-containing sequences, as reported by T-cell proliferation or cytokine secretion. Conversely, inclusion of CpG in the adjuvant with gp120 enhanced responses to the dominant CD4+T-cell epitopes. The gp120 destabilization affected secretion of some cytokines more than others, suggesting that antigen conformation could modulate T-cell functions through mechanisms of antigen processing.

IMPORTANCECD4+helper T cells play an essential role in protection against HIV and other pathogens. Thus, the sites of helper T-cell recognition, the dominant epitopes, are targets for vaccine design; and the corresponding T cells may provide markers for monitoring infection and immunity. However, T-cell epitopes are difficult to identify and predict. It is also unclear whether CD4+T cells specific for one epitope are more protective than T cells specific for other epitopes. This work shows that the three-dimensional (3D) structure of an HIV protein partially determines which epitopes are dominant, most likely by controlling the breakdown of HIV into peptides. Moreover, some types of signals from CD4+T cells are affected by the HIV protein 3D structure; and thus the protectiveness of a particular peptide vaccine could be related to its location in the 3D structure.