bluuebunny/crossref_metadata_2025 huggingface dataset:
A Sport-Specific Upper-Body Ergometer Test for Evaluating Submaximal and Maximal Parameters in Elite Rock Climbers
Authors: Michailov Michail Lubomirov , Morrison Audry , Ketenliev Mano Mitkov , Pentcheva Boyanka Petkova
Published: September 2014

Traditional treadmill or bicycle ergometry neglects the upper-body musculature that predominantly limits or terminates rock-climbing performance (ie, the inability to continually pull up one’s body mass or “hang on”).

Purpose:

To develop an incremental maximal upper-body ergometer test (UBT) to evaluate climbers’ aerobic fitness and sport-specific work capacity and to compare these results with a traditional treadmill protocol.

Methods:

Eleven elite sport climbers (best redpoint grade Fr.8b) performed a UBT on a vertically mounted rowing ergometer and, on a separate occasion, performed a maximal incremental treadmill test (TMT). Cardiorespiratory parameters were measured continuously. Lactate (La) samples were collected.

Results:

Peak oxygen consumption (VO2peak) and heart rate in UBT and TMT were 34.1 ± 4.1 vs 58.3 ± 2.6 mL · min−1 · kg−1 and 185 ± 8 vs 197 ± 8 beats/min, respectively, and both variables were of significantly lower magnitude during UBT (P < .001). End-of-test La levels for UBT (11.9 ± 1.7 mmol/L) and TMT (12.3 ± 2.5 mmol/L) were similar (P = .554). Treadmill VO2peak was not correlated with either upper-body (UB) VO2peak (P = .854) or redpoint and on-sight climbing grade ability (P > .05). UB VO2peak and peak power output per kg body mass were both strongly correlated (P < .05) with climbing grade ability. The highest correlation coefficient was calculated between current on-sight grade and UB VO2peak (r = .85, P = .001).

Conclusion:

UBT aerobic- and work-capacity results were strongly correlated to climbing-performance variables and reflected sport-specific fatigue, and TMT results were not. UBT is preferred to TMT to test and monitor dedicated and elite rock climbers’ training status.
Morality in everyday life
Authors: Hofmann Wilhelm , Wisneski Daniel C. , Brandt Mark J. , Skitka Linda J.
Published: September 2014

Moral homeostasis in real life vs. the lab

Individuals who witnessed a moral deed are more likely than nonwitnesses to perform a moral deed themselves and are also more likely to allow themselves to act immorally. Hofmann
et al.
asked smartphone users to report their encounters with morality (see the Perspective by Graham). Most moral judgment experiments are lab-based and don't allow for conclusions based on what people experience in their daily lives. This field experiment revealed that people experience moral events frequently in daily life. A respondent's ideology influenced the kind of event reported and the frequency, which is consistent with moral foundations theory.

Science
, this issue p.
1340
; see also p.
1242
Biogeographic patterns in ocean microbes emerge in a neutral agent-based model
Authors: Hellweger Ferdi L. , van Sebille Erik , Fredrick Neil D.
Published: September 2014

Patterns of life in the ocean wave

The open ocean is not uniform. The seas teem with unseen life that has evolved distinctive patterns of species distribution, much as the land-bound world contains a spectrum of biological provinces. Taking data from genome studies, Hellweger
et al.
devised a model showing how marine bacteria diversified throughout the world's oceans into stable geographic provinces independently of natural selection (see the Perspective by Giovannoni and Nemergut). All that is needed to create these distributions are mutations and ocean currents.

Science
, this issue p.
1346
; see also p.
1246
A global strategy for protecting vulnerable coastal populations
Authors: Barbier Edward B.
Published: September 2014

Short-term emergency response and long-run investments are needed
Intersection of population variation and autoimmunity genetics in human T cell activation
Authors: Ye Chun Jimmie , Feng Ting , Kwon Ho-Keun , Raj Towfique , Wilson Michael T. , Asinovski Natasha , McCabe Cristin , Lee Michelle H. , Frohlich Irene , Paik Hyun-il , Zaitlen Noah , Hacohen Nir , Stranger Barbara , De Jager Philip , Mathis Diane , Regev Aviv , Benoist Christophe
Published: September 2014

Response to pathogens is in the genes

T cells are important in mounting immune responses to a host of pathogens, and they have also been implicated in autoimmune disease. By examining the variability in gene expression in stimulated T cells over time from a multi-ethnic cohort of healthy humans, Ye
et al.
identified specific genetic polymorphisms that explain differences among individuals in response to pathogens. Furthermore, a candidate gene approach led to the identification of a single-nucleotide polymorphism that controls the response of the autoimmune-associated IL2RA gene. This study helps us understand the degree to which immune responses are driven by the environment or by an individual's physiological or genetic factors.

Science
, this issue
10.1126/science.1254665
Legislators learning to interpret evidence for policy
Authors: Cockcroft Anne , Masisi Mokgweetsi , Thabane Lehana , Andersson Neil
Published: September 2014

Training for making health policy that has the best impact on a population
How to transform the practice of engineering to meet global health needs
Authors: Niemeier Deb , Gombachika Harry , Richards-Kortum Rebecca
Published: September 2014

More of the world’s population has access to cell phones than to basic sanitation facilities, a gap that can only be closed if the engineering and international aid communities adopt new approaches to design for scarcity and scalability.
Creating a global observatory for health R&D
Authors: Terry Robert F. , Salm José F. , Nannei Claudia , Dye Christopher
Published: September 2014

A global map of health R&D activity would improve the coordination of research and help to match limited resources with public health priorities, such as combating antimicrobial resistance. The challenges of R&D mapping are large because there are few standards for research classification and governance and limited capacity to report on R&D data, especially in low-income countries. Nevertheless, based on developments in semantic classification, and with better reporting of funded research though the Internet, it is now becoming feasible to create a global observatory for health R&D.
Putting women and girls at the center of development
Authors: French Gates Melinda
Published: September 2014

The development field needs to be more serious about gender inequities and women’s empowerment. By ignoring gender inequities, many development projects fail to achieve their objective. And when development organizations do not focus on women’s empowerment, they neglect the fact that empowered women have the potential to transform their societies. I also review the Gates Foundation’s record on gender and propose some approaches to improve it.
Changing behaviors to prevent noncommunicable diseases
Authors: Chokshi Dave A. , Farley Thomas A.
Published: September 2014

Altering physical and social environments can change behaviors to improve population health
Ebola's perfect storm
Authors: Piot Peter
Published: September 2014

The devastating Ebola epidemic in West Africa is the result of a perfect storm: dysfunctional health services as the result of decades of war, low public trust in government and Western medicine, traditional beliefs and even denials about the cause or existence of the virus, and burial practices that involve contact with contagious Ebola-infected corpses. There are now five affected West African countries: Guinea, Liberia, Nigeria, Sierra Leone, and most recently, Senegal. Ebola has killed around 2000 and infected more than 3500, with over 40% of cases occurring within the past few weeks. The World Health Organization (WHO) predicts that 20,000 may become infected. This fast pace of Ebola's spread is a grim reminder that epidemics are a global threat and that the only way to get this virus under control is through a rapid response at a massive global scale—much stronger than the current efforts.
Ebola: ‘Wow, that is really tough’
Authors: Roberts Leslie
Published: September 2014

WHO's Bruce Aylward says international action is needed right now.
Young blood
Authors: Hall Stephen S.
Published: September 2014

Young animals' blood holds rejuvenating powers. Amy Wagers wants to know why.
After the windfall
Authors: Enserink Martin
Published: September 2014

Plateauing budgets for global health sharpen the focus on what really works.
As cholera goes, so goes Haiti
Authors: Kean Sam
Published: September 2014

The West's poorest nation confronts a new disease.
Zambia fights to sustain its malaria success
Authors: Kupferschmidt Kai
Published: September 2014

A model for malaria interventions is at risk as funding flattens and the disease smolders on.
Response to Pathogens Is in the Genes
Authors: Zahn Laura
Published: September 2014

Profiles of T cell responses display genetically influenced interindividual variation.
From Amyloid to ATF4, Axons Mediate Neuron Loss
Authors: Ferrarelli Leslie K.
Published: September 2014

Retrograde transport of a transcription factor from hippocampal axons exposed to amyloid β triggers neurodegeneration.
EbpA vaccine antibodies block binding of
Enterococcus faecalis
to fibrinogen to prevent catheter-associated bladder infection in mice
Authors: Flores-Mireles Ana L. , Pinkner Jerome S. , Caparon Michael G. , Hultgren Scott J.
Published: September 2014

Binding to host fibrinogen is a critical event in
Enterococcus faecalis
pathogenesis in catheter-associated urinary tract infections in mice.
Broadly neutralizing antibodies abrogate established hepatitis C virus infection
Authors: de Jong Ype P. , Dorner Marcus , Mommersteeg Michiel C. , Xiao Jing W. , Balazs Alejandro B. , Robbins Justin B. , Winer Benjamin Y. , Gerges Sherif , Vega Kevin , Labitt Rachael N. , Donovan Bridget M. , Giang Erick , Krishnan Anuradha , Chiriboga Luis , Charlton Michael R. , Burton Dennis R. , Baltimore David , Law Mansun , Rice Charles M. , Ploss Alexander
Published: September 2014

HCV-specific neutralizing antibodies protect humanized mice from challenge and suppress established infections.
Comment on “The placenta harbors a unique microbiome”
Authors: Kliman Harvey J.
Published: September 2014

Microbiota found in the placenta may actually be bacteria or bacterial fragments in maternal blood.
The Fringe Benefits of Cloning Cancer
Authors: Kyprianou Natasha
Published: September 2014

A new approach to monitor tumor clone dynamics (Carreira
et al
., this issue) uses sequential biopsies and circulating DNA to help optimize treatment in metastatic prostate cancer.
Lights, Microscope, Action!
Authors: White Nathan J.
Published: September 2014

Fine-needle tissue biopsies take center stage with real-time live confocal microscopy.
Comparison of Three Luminescent Immunoassays for Hepatitis B Virus Surface Antigen Quantification during the Natural History of Chronic Hepatitis B Virus Infection
Authors: Cheng Xiao-Dong , Song Liu-Wei , Fang Lin-Lin , Yang Lin , Wu Yong , Ge Sheng-Xiang , Yuan Quan , Zhang Jun , Xia Ning-Shao , Hao Xiao-Ke
Published: September 2014

Hepatitis B surface antigen (HBsAg) quantification has garnered attention because of its high predictive value in determining treatment responses. The HBsAg quantification assays, such as Architect and Elecsys, are commercially available, and more assays are in development. We aimed to compare the results of the Architect and Elecsys assays with those of a new assay, WTultra. The WTultra HBsAg assay is a sandwich chemiluminescent microplate enzyme immunoassay and provides an alternative choice which is more cost-effective and potentially applicable in developing or resource-constrained countries and areas. A total of 411 serum samples were collected from patients during various phases of chronic hepatitis B (CHB) infection. The samples were assessed using the three assays, and the results were compared and analyzed. The results for the Architect, Elecsys, and WTultra assays were well correlated according to the overall results for the samples (correlation coefficients,rArchitect versus WTultra= 0.936,rArchitect versus Elecsys= 0.952, andrWTultra versus Elecsys= 0.981) and the various infection phases (rArchitect versus WTultraranging from 0.67 to 0.975,rArchitect versus Elecsysranging from 0.695 to 0.982, andrWTultra versus Elecsysranging from 0.877 to 0.99). Additionally, consistent results were observed according to genotype (genotype B:rArchitect versus WTultra= 0.976,rArchitect versus Elecsys= 0.978, andrWTultra versus Elecsys= 0.979; genotype C:rArchitect versus WTultra= 0.950,rArchitect versus Elecsys= 0.963, andrWTultra versus Elecsys= 0.981) and hepatitis B virus (HBV) DNA levels (rArchitect= 0.540,rWTultra= 0.553, andrElecsys= 0.580). In conclusion, the Elecsys and WTultra assays were well correlated with the Architect assay, irrespective of the CHB infection phase or genotype. All of these assays are reliable for HBsAg quantification.
To Add or Not To Add Polysorbate 80: Impact on Colistin MICs for Clinical Strains of Enterobacteriaceae and Pseudomonas aeruginosa and Quality Controls
Authors: Sutherland Christina A. , Nicolau David P.
Published: September 2014

Colistin adherence to plastics can be diminished by adding a surfactant, i.e., polysorbate 80. Incorporating polysorbate 80 resulted in 3 twofold and 2 twofold modal MIC decreases for
Enterobacteriaceae
and
Pseudomonas aeruginosa
, respectively. The reproducibility of the quality controls (QCs) with and without polysorbate 80 supports the use of
Escherichia coli
strain 25922 and
P. aeruginosa
strain 27853.
Evaluation of the Automated Vitek 2 System for Detection of Various Mechanisms of Macrolide and Lincosamide Resistance in Staphylococcus aureus
Authors: Filippin Lorenzo , Roisin Sandrine , Nonhoff Claire , Vandendriessche Stien , Heinrichs Amélie , Denis Olivier
Published: September 2014

We evaluated the performance of the automated Vitek 2 system against disk diffusion for susceptibility testing of
Staphylococcus aureus
strains showing various resistance mechanisms to macrolides and lincosamides (ML). The Vitek 2 system showed 100% concordance with the D-zone test in detection of the most common resistance mechanisms to ML, including methylase and efflux systems.
Broad Protection against Avian Influenza Virus by Using a Modified Vaccinia Ankara Virus Expressing a Mosaic Hemagglutinin Gene
Authors: Kamlangdee Attapon , Kingstad-Bakke Brock , Anderson Tavis K. , Goldberg Tony L. , Osorio Jorge E.
Published: September 2014

A critical failure in our preparedness for an influenza pandemic is the lack of a universal vaccine. Influenza virus strains diverge by 1 to 2% per year, and commercially available vaccines often do not elicit protection from one year to the next, necessitating frequent formulation changes. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. We have constructed a recombinant modified vaccinia virus Ankara (MVA) that expresses an H5N1 mosaic hemagglutinin (H5M) (MVA-H5M). This mosaic was generated
in silico
using 2,145 field-sourced H5N1 isolates. A single dose of MVA-H5M provided 100% protection in mice against clade 0, 1, and 2 avian influenza viruses and also protected against seasonal H1N1 virus (A/Puerto Rico/8/34). It also provided short-term (10 days) and long-term (6 months) protection postvaccination. Both neutralizing antibodies and antigen-specific CD4
+
and CD8
+
T cells were still detected at 5 months postvaccination, suggesting that MVA-H5M provides long-lasting immunity.

IMPORTANCE
Influenza viruses infect a billion people and cause up to 500,000 deaths every year. A major problem in combating influenza is the lack of broadly effective vaccines. One solution from the field of human immunodeficiency virus vaccinology involves a novel
in silico
mosaic approach that has been shown to provide broad and robust protection against highly variable viruses. Unlike a consensus algorithm which picks the most frequent residue at each position, the mosaic method chooses the most frequent T-cell epitopes and combines them to form a synthetic antigen. These studies demonstrated that a mosaic influenza virus H5 hemagglutinin expressed by a viral vector can elicit full protection against diverse H5N1 challenges as well as induce broader immunity than a wild-type hemagglutinin.
Occurrence and Reassortment of Avian Influenza A (H7N9) Viruses Derived from Coinfected Birds in China
Authors: Liu Wei , Fan Hang , Raghwani Jayna , Lam Tommy Tsan-Yuk , Li Jing , Pybus Oliver G. , Yao Hong-Wu , Wo Ying , Liu Kun , An Xiao-Ping , Pei Guang-Qian , Li Hao , Wang Hong-Yu , Zhao Jian-Jun , Jiang Tao , Ma Mai-Juan , Xia Xian , Dong Yan-De , Zhao Tong-Yan , Jiang Jia-Fu , Yang Yin-Hui , Guan Yi , Tong Yigang , Cao Wu-Chun
Published: September 2014

Over the course of two waves of infection, H7N9 avian influenza A virus has caused 436 human infections and claimed 170 lives in China as of July 2014. To investigate the prevalence and genetic diversity of H7N9, we surveyed avian influenza viruses in poultry in Jiangsu province within the outbreak epicenter. We found frequent occurrence of H7N9/H9N2 coinfection in chickens. Molecular clock phylogenetic analysis confirms coinfection by H7N9/H9N2 viruses and also reveals that the identity of the H7N9 outbreak lineage is confounded by ongoing reassortment between outbreak viruses and diverse H9N2 viruses in domestic birds. Experimental inoculation of a coinfected sample in cell culture yielded two reassortant H7N9 strains with polymerase segments from the original H9N2 strain. Ongoing reassortment between the H7N9 outbreak lineage and diverse H9N2 viruses may generate new strains with the potential to infect humans, highlighting the need for continued viral surveillance in poultry and humans.

IMPORTANCE
We found frequent occurrence of H7N9/H9N2 coinfection in chickens. The H7N9 outbreak lineage is confounded by ongoing reassortment between H7N9 and H9N2 viruses. The importance of H9N2 viruses as the source of novel avian influenza virus infections in humans requires continuous attention.
Characterization of pH-Sensitive Molecular Switches That Trigger the Structural Transition of Vesicular Stomatitis Virus Glycoprotein from the Postfusion State toward the Prefusion State
Authors: Ferlin Anna , Raux Hélène , Baquero Eduard , Lepault Jean , Gaudin Yves
Published: September 2014

Vesicular stomatitis virus (VSV; the prototype rhabdovirus) fusion is triggered at low pH and mediated by glycoprotein G, which undergoes a low-pH-induced structural transition. A unique feature of rhabdovirus G is that its conformational change is reversible. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. The crystal structures of G pre- and postfusion states have been elucidated, leading to the identification of several acidic amino acid residues, clustered in the postfusion trimer, as potential pH-sensitive switches controlling the transition back toward the prefusion state. We mutated these residues and produced a panel of single and double mutants whose fusion properties, conformational change characteristics, and ability to pseudotype a virus lacking the glycoprotein gene were assayed. Some of these mutations were also introduced in the genome of recombinant viruses which were further characterized. We show that D268, located in the segment consisting of residues 264 to 273, which refolds into postfusion helix F during G structural transition, is the major pH sensor while D274, D395, and D393 have additional contributions. Furthermore, a single passage of recombinant virus bearing the mutation D268L (which was demonstrated to stabilize the G postfusion state) resulted in a pseudorevertant with a compensatory second mutation, L271P. This revealed that the propensity of the segment of residues 264 to 273 to refold into helix F has to be finely tuned since either an increase (mutation D268L alone) or a decrease (mutation L271P alone) of this propensity is detrimental to the virus.

IMPORTANCE
Vesicular stomatitis virus enters cells via endocytosis. Endosome acidification induces a structural transition of its unique glycoprotein (G), which mediates fusion between viral and endosomal membranes. G conformational change is reversible upon increases in pH. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. We mutated five acidic residues, proposed to be pH-sensitive switches controlling the structural transition back toward the prefusion state. Our results indicate that residue D268 is the major pH sensor, while other acidic residues have additional contributions, and reveal that the propensity of the segment consisting of residues 264 to 273 to adopt a helical conformation is finely regulated. This segment might be a good target for antiviral compounds.
Circulating Clinical Strains of Human Parainfluenza Virus Reveal Viral Entry Requirements for
In Vivo
Infection
Authors: Palmer Samantha G. , DeVito Ilaria , Jenkins Stephen G. , Niewiesk Stefan , Porotto Matteo , Moscona Anne
Published: September 2014

Human parainfluenza viruses (HPIVs) cause widespread respiratory infections, with no vaccines or effective treatments. We show that the molecular determinants for HPIV3 growth
in vitro
are fundamentally different from those required
in vivo
and that these differences impact inhibitor susceptibility. HPIV infects its target cells by coordinated action of the hemagglutinin-neuraminidase receptor-binding protein (HN) and the fusion envelope glycoprotein (F), which together comprise the molecular fusion machinery; upon receptor engagement by HN, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. Peptides derived from key regions of F can potently inhibit HPIV infection at the entry stage, by interfering with the structural transition of F. We show that clinically circulating viruses have fusion machinery that is more stable and less readily activated than viruses adapted to growth in culture. Fusion machinery that is advantageous for growth in human airway epithelia and
in vivo
confers susceptibility to peptide fusion inhibitors in the host lung tissue or animal, but the same fusion inhibitors have no effect on viruses whose fusion glycoproteins are suited for growth
in vitro
. We propose that for potential clinical efficacy, antivirals should be evaluated using clinical isolates in natural host tissue rather than lab strains of virus in cultured cells. The unique susceptibility of clinical strains in human tissues reflects viral inhibition
in vivo
.

IMPORTANCE
Acute respiratory infection is the leading cause of mortality in young children under 5 years of age, causing nearly 20% of childhood deaths worldwide each year. The paramyxoviruses, including human parainfluenza viruses (HPIVs), cause a large share of these illnesses. There are no vaccines or drugs for the HPIVs. Inhibiting entry of viruses into the human cell is a promising drug strategy that blocks the first step in infection. To develop antivirals that inhibit entry, it is critical to understand the first steps of infection. We found that clinical viruses isolated from patients have very different entry properties from those of the viruses generally studied in laboratories. The viral entry mechanism is less active and more sensitive to fusion inhibitory molecules. We propose that to interfere with viral infection, we test clinically circulating viruses in natural tissues, to develop antivirals against respiratory disease caused by HPIVs.
Matrix Proteins of Nipah and Hendra Viruses Interact with Beta Subunits of AP-3 Complexes
Authors: Sun Weina , McCrory Thomas S. , Khaw Wei Young , Petzing Stephanie , Myers Terrell , Schmitt Anthony P.
Published: September 2014

Paramyxoviruses and other negative-strand RNA viruses encode matrix proteins that coordinate the virus assembly process. The matrix proteins link the viral glycoproteins and the viral ribonucleoproteins at virus assembly sites and often recruit host machinery that facilitates the budding process. Using a co-affinity purification strategy, we have identified the beta subunit of the AP-3 adapter protein complex, AP3B1, as a binding partner for the M proteins of the zoonotic paramyxoviruses Nipah virus and Hendra virus. Binding function was localized to the serine-rich and acidic Hinge domain of AP3B1, and a 29-amino-acid Hinge-derived polypeptide was sufficient for M protein binding in coimmunoprecipitation assays. Virus-like particle (VLP) production assays were used to assess the relationship between AP3B1 binding and M protein function. We found that for both Nipah virus and Hendra virus, M protein expression in the absence of any other viral proteins led to the efficient production of VLPs in transfected cells, and this VLP production was potently inhibited upon overexpression of short M-binding polypeptides derived from the Hinge region of AP3B1. Both human and bat (
Pteropus alecto
) AP3B1-derived polypeptides were highly effective at inhibiting the production of VLPs. VLP production was also impaired through small interfering RNA (siRNA)-mediated depletion of AP3B1 from cells. These findings suggest that AP-3-directed trafficking processes are important for henipavirus particle production and identify a new host protein-virus protein binding interface that could become a useful target in future efforts to develop small molecule inhibitors to combat paramyxoviral infections.

IMPORTANCE
Henipaviruses cause deadly infections in humans, with a mortality rate of about 40%. Hendra virus outbreaks in Australia, all involving horses and some involving transmission to humans, have been a continuing problem. Nipah virus caused a large outbreak in Malaysia in 1998, killing 109 people, and smaller outbreaks have since occurred in Bangladesh and India. In this study, we have defined, for the first time, host factors that interact with henipavirus M proteins and contribute to viral particle assembly. We have also defined a new host protein-viral protein binding interface that can potentially be targeted for the inhibition of paramyxovirus infections.
The HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity
Authors: Lemaître Cécile , Harper Francis , Pierron Gérard , Heidmann Thierry , Dewannieux Marie
Published: September 2014

Endogenous retroviruses are the remnants of past retroviral infections that are scattered within mammalian genomes. In humans, most of these elements are old degenerate sequences that have lost their coding properties. The HERV-K(HML2) family is an exception: it recently amplified in the human genome and corresponds to the most active proviruses, with some intact open reading frames and the potential to encode viral particles. Here, using a reconstructed consensus element, we show that HERV-K(HML2) proviruses are able to inhibit Tetherin, a cellular restriction factor that is active against most enveloped viruses and acts by keeping the viral particles attached to the cell surface. More precisely, we identify the Envelope protein (Env) as the viral effector active against Tetherin. Through immunoprecipitation experiments, we show that the recognition of Tetherin is mediated by the surface subunit of Env. Similar to Ebola glycoprotein, HERV-K(HML2) Env does not mediate Tetherin degradation or cell surface removal; therefore, it uses a yet-undescribed mechanism to inactivate Tetherin. We also assessed all natural complete alleles of endogenous HERV-K(HML2) Env described to date for their ability to inhibit Tetherin and found that two of them (out of six) can block Tetherin restriction. However, due to their recent amplification, HERV-K(HML2) elements are extremely polymorphic in the human population, and it is likely that individuals will not all possess the same anti-Tetherin potential. Because of Tetherin's role as a restriction factor capable of inducing innate immune responses, this could have functional consequences for individual responses to infection.

IMPORTANCE
Tetherin, a cellular protein initially characterized for its role against HIV-1, has been proven to counteract numerous enveloped viruses. It blocks the release of viral particles from producer cells, keeping them tethered to the cell surface. Several viruses have developed strategies to inhibit Tetherin activity, allowing them to efficiently infect and replicate in their host. Here, we show that human HERV-K(HML2) elements, the remnants of an ancient retroviral infection, possess an anti-Tetherin activity which is mediated by the envelope protein. It is likely that this activity was an important factor that contributed to the recent, human-specific amplification of this family of elements. Also, due to their recent amplification, HERV-K(HML2) elements are highly polymorphic in the human population. Since Tetherin is a mediator of innate immunity, interindividual variations among HERV-K(HML2) Env genes may result in differences in immune responses to infection.
Adenovirus E1A Targets the DREF Nuclear Factor To Regulate Virus Gene Expression, DNA Replication, and Growth
Authors: Radko Sandi , Koleva Maria , James Kris M. D. , Jung Richard , Mymryk Joe S. , Pelka Peter
Published: September 2014

The adenovirus E1A gene is the first gene expressed upon viral infection. E1A remodels the cellular environment to maximize permissivity for viral replication. E1A is also the major transactivator of viral early gene expression and a coregulator of a large number of cellular genes. E1A carries out its functions predominantly by binding to cellular regulatory proteins and altering their activities. The unstructured nature of E1A enables it to bind to a large variety of cellular proteins and form new molecular complexes with novel functions. The C terminus of E1A is the least-characterized region of the protein, with few known binding partners. Here we report the identification of cellular factor DREF (ZBED1) as a novel and direct binding partner of E1A. Our studies identify a dual role for DREF in the viral life cycle. DREF contributes to activation of gene expression from all viral promoters early in infection. Unexpectedly, it also functions as a growth restriction factor for adenovirus as knockdown of DREF enhances virus growth and increases viral genome copy number late in the infection. We also identify DREF as a component of viral replication centers. E1A affects the subcellular distribution of DREF within PML bodies and enhances DREF SUMOylation. Our findings identify DREF as a novel E1A C terminus binding partner and provide evidence supporting a role for DREF in viral replication.

IMPORTANCE
This work identifies the putative transcription factor DREF as a new target of the E1A oncoproteins of human adenovirus. DREF was found to primarily localize with PML nuclear bodies in uninfected cells and to relocalize into virus replication centers during infection. DREF was also found to be SUMOylated, and this was enhanced in the presence of E1A. Knockdown of DREF reduced the levels of viral transcripts detected at 20 h, but not at 40 h, postinfection, increased overall virus yield, and enhanced viral DNA replication. DREF was also found to localize to viral promoters during infection together with E1A. These results suggest that DREF contributes to activation of viral gene expression. However, like several other PML-associated proteins, DREF also appears to function as a growth restriction factor for adenovirus infection.
Virus-Mediated Compartmentalization of the Host Translational Machinery
Authors: Desmet Emily A. , Anguish Lynne J. , Parker John S. L.
Published: September 2014

Viruses require the host translational apparatus to synthesize viral proteins. Host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. Here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (VF). VF are the sites of reovirus replication and assembly but were thought not to contain ribosomes. It was assumed viral mRNAs exited the VF to undergo translation by the cellular machinery, and proteins reentered the factory to participate in assembly. Here, we used ribopuromycylation to visualize active translation in infected cells. These studies revealed that active translation occurs within VF and that ribosomal subunits and proteins required for translation initiation, elongation, termination, and recycling localize to the factory. Interestingly, we observed components of the 43S preinitiation complex (PIC) concentrating primarily at factory margins, suggesting a spatial and/or dynamic organization of translation within the VF. Similarly, the viral single-stranded RNA binding protein σNS localized to the factory margins and had a tubulovesicular staining pattern that extended a short distance from the margins of the factories and colocalized with endoplasmic reticulum (ER) markers. Consistent with these colocalization studies, σNS was found to associate with both eukaryotic translation initiation factor 3 subunit A (eIF3A) and the ribosomal subunit pS6R. Together, these findings indicate that σNS functions to recruit 43S PIC machinery to the primary site of viral translation within the viral factory. Pathogen-mediated compartmentalization of the translational apparatus provides a novel mechanism by which viruses might avoid host translational suppression.

IMPORTANCE
Viruses lack biosynthetic capabilities and depend upon the host for protein synthesis. This dependence requires viruses to evolve mechanisms to coerce the host translational machinery into synthesizing viral proteins in the face of ongoing cellular stress responses that suppress global protein synthesis. Reoviruses replicate and assemble within cytoplasmic inclusions called viral factories. However, synthesis of viral proteins was thought to occur in the cytosol. To identify the site(s) of viral translation, we undertook a microscopy-based approach using ribopuromycylation to detect active translation. Here, we report that active translation occurs within viral factories and that translational factors are compartmentalized within factories. Furthermore, we find that the reovirus nonstructural protein σNS associates with 43S preinitiation complexes at the factory margins, suggesting a role for σNS in translation. Together, virus-induced compartmentalization of the host translational machinery represents a strategy for viruses to spatiotemporally couple viral protein synthesis with viral replication and assembly.
Limited infant exposure to benznidazole through breast milk during maternal treatment for Chagas disease
Authors: García-Bournissen Facundo , Moroni Samanta , Marson Maria Elena , Moscatelli Guillermo , Mastrantonio Guido , Bisio Margarita , Cornou Laura , Ballering Griselda , Altcheh Jaime
Published: September 2014

Background

Benznidazole (BNZ) is safe and effective for the treatment of paediatric Chagas disease. Treatment of adults is also effective in many cases, but discouraged in breastfeeding women because no information on BNZ transfer into breast milk is available. We aimed to evaluate the degree of BNZ transfer into breast milk in lactating women with Chagas disease.

Patients and methods

Prospective cohort study of lactating women with Chagas disease treated with BNZ administered for 30 days. Patients and their breastfed infants were evaluated at admission, the 7th and 30th day of treatment (and monthly thereafter, for 6 months). BNZ was measured in plasma and milk by high performance liquid chromatography. The protocol was registered in ClinicalTrials.gov (#NCT01547533).

Results

12 lactating women with chronic Chagas disease were enrolled (median age 28.5 years, range 20–34). Median BNZ dose was 5.65 mg/kg/day twice daily. Five mothers had adverse drug events (45%), but no adverse drug reactions or any untoward outcomes were observed in the breastfed infants. Median milk BNZ concentration was 3.8 mg/L (range 0.3–5.9) and 6.26 mg/L (range 0.3–12.6) in plasma. Median BNZ milk to plasma ratio was 0.52 (range 0.3–2.79). Median relative BNZ dose received by the infant (assuming a daily breast milk intake of 150 mL/kg/day) was 12.3% of the maternal dose per kg (range 5.5%–17%).

Conclusions

The limited transference of BNZ into breast milk and the reassuring normal clinical evaluation of the breastfed babies suggest that maternal BNZ treatment for Chagas disease during breast feeding is unlikely to present a risk for the breastfed infant.

Trial registration number

ClinicalTrials.gov NCT01547533.
The ECG of high-level junior soccer players: comparing the ESC vs the Seattle criteria
Authors: Bessem B , de Bruijn M C , Nieuwland W
Published: September 2014

Introduction

Sudden cardiac death in young athletes is a devastating event. The screening and detection of potentially life-threatening cardiac pathology by ECG is difficult due to high numbers of false-positive results, especially in the very young. The Seattle ECG criteria (2013) were introduced to decrease false-positive results. We compared the Seattle ECG criteria with the European Society of Cardiology (ESC) ECG criteria of 2005 and 2010 for cardiac screening in high-level junior soccer players.

Methods

During the 2012–2013 season, all data from cardiovascular screenings performed on the youth division of two professional soccer clubs were collected. The total study population consisted of 193 male adolescent professional soccer players, aged 10–19 years. Five players dropped out of this study.

Results

Applying the ESC criteria of 2005 and 2010 to our population resulted in a total of 89 (47%) and 62 (33%) abnormal ECGs. When the Seattle ECG criteria were applied, the number of abnormal ECGs was 6 (3%). The reduction was mainly due to a reclassification of the long QT cut-off value and the exclusion of right atrial enlargement criteria. All ECG abnormalities using the Seattle criteria related to T-wave inversion criteria.

Conclusion

The Seattle ECG criteria seem very promising for decreasing false-positive screening results for high-level junior soccer players.
Effect of specific exercise strategy on need for surgery in patients with subacromial impingement syndrome: randomised controlled study
Authors: Holmgren Theresa , Hallgren Hanna Björnsson , Öberg Birgitta , Adolfsson Lars , Johansson Kajsa
Published: September 2014

STUDY QUESTION

Can a specific exercise strategy improve shoulder function and pain in patients with subacromial impingement syndrome, thereby decreasing the need for arthroscopic subacromial decompression?

SUMMARY ANSWER

Compared with a control exercise group, patients in the specific exercise group had significantly greater improvements in shoulder function and pain and fewer patients needed surgery at the three month assessment.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Different exercise programmes are used as first line treatment in patients with subacromial impingement syndrome, but conclusive evidence to support the efficacy for these programmes is lacking. This specific exercise strategy proved effective in improving shoulder function and pain in patients in whom earlier conservative treatment had failed.
Statin use and risk of liver cancer: an update meta-analysis
Authors: Shi Meng , Zheng Huiling , Nie Biao , Gong Wei , Cui Xiaobing
Published: September 2014

Objective

Statins are commonly prescribed cholesterol-lowering drugs. Preclinical studies suggest that statins may possess cancer preventive properties. The primary objective of this meta-analysis was to determine the association between statin use and risk of liver cancer.

Design

Meta-analysis.

Setting

International.

Participants

A comprehensive literature search of PubMed, BIOSIS Previews, Web of Science, EMBASE, EBSCO and Cochrane Library was conducted through March 2014. The effect estimate was reported as pooled relative risk (RR) with 95% CIs, using the random-effects model.

Results

A total of 12 studies (1 individual patient data analysis of 22 randomised controlled trials, 5 cohorts and 6 case–controls) were qualified for this meta-analysis, involving 5 640 313 participants including 35 756 liver cancer cases. Our results indicated a significant risk reduction of liver cancer among all statin users (RR=0.58, 95% CIs 0.51 to 0.67). The difference of the study designs can partly explain the significant heterogeneity found in the overall analysis (I2=65%, p=0.0006). No evidence of publication bias was observed in this meta-analysis. Similar risk reductions were found in the subgroups analysis of Western and Asian countries, lipophilic and hydrophilia statins. There was a trend towards more risk reductions in subgroups with higher baseline risk, inadequate adjustment and higher cumulative dosage of statin use.

Conclusions

This meta-analysis suggests that statin is associated with a significant risk reduction of liver cancer when taken daily for cardiovascular event prevention. However, this preventive effect might be overestimated due to the exposure period, the indication and contraindication of statins and other confounders. Statins might be considered as an adjuvant in the treatment of liver cancer.
Acupuncture for neurogenic bladder due to spinal cord injury: a systematic review protocol
Authors: Zhang Tao , Liu Huilin , Liu Zhishun , Wang Linpeng
Published: September 2014

Introduction

Neurogenic bladder is one of the most common complications following spinal cord injury (SCI). In China, acupuncture therapy is a common treatment for neurogenic bladder due to SCI, but its effects and safety remain uncertain. A protocol is described for a systematic review to investigate the beneficial effects and safety of acupuncture for neurogenic bladder due to SCI.

Methods and analysis

Eight databases will be searched from their inception: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the China National Knowledge Infrastructure (CNKI), the VIP database, the Wanfang database, the China Doctoral Dissertations Full-text Database (CDFD) and the China Master's Theses Full-text Database (CMFD). Any clinical randomised controlled trials (RCTs) and the first period of randomised cross-over studies related to acupuncture for neurogenic bladder due to SCI will be included. Outcomes will include change in urinary symptoms, urodynamic tests, clinical assessment and quality of life (QoL). The incidence of adverse events will be assessed as the safety outcome. Study selection, data extraction and quality assessment will be performed independently by two reviewers. Assessment of risk of bias, data synthesis and subgroup analysis will be carried out using Review Manager software.

Ethics and dissemination

Ethics approval is not required as this is a protocol for a systematic review. The findings of this systematic review will be disseminated via peer-reviewed publications and conference presentations.

Trial registration number

PROSPERO (CRD42014010448).
Personalised physician learning intervention to improve hypertension and lipid control: randomised trial comparing two methods of physician profiling
Authors: O'Connor Patrick J , Magid David J , Sperl-Hillen JoAnn M , Price David W , Asche Stephen E , Rush William A , Ekstrom Heidi L , Brand David W , Tavel Heather M , Godlevsky Olga V , Johnson Paul E , Margolis Karen L
Published: September 2014

Purpose

To assess the impact of personalised physician learning (PPL) interventions using simulated learning cases on control of hypertension and dyslipidaemia in primary care settings.

Methods

A total of 132 primary care physicians, 4568 eligible patients with uncontrolled hypertension, and 15 392 eligible patients with uncontrolled dyslipidaemia were cluster-randomised to one of three conditions: (a) no intervention, (b) PPL-electronic medical record (EMR) intervention in which 12 PPL cases were assigned to each physician based on observed patterns of care in the EMR in the previous year, or (c) PPL-ASSESS intervention in which 12 PPL cases were assigned to each physician based on their performance on four standardised assessment cases. General and generalised linear mixed models were used to account for clustering and to model differences in patient outcomes in the study arms.

Results

Among patients with uncontrolled hypertension at baseline, 49.1%, 46.6% and 47.3% (p=0.43) achieved blood pressure (BP) targets at follow-up. Among patients with uncontrolled dyslipidaemia at baseline, 37.5%, 37.3% and 38.1% (p=0.72) achieved low density lipoprotein cholesterol targets at follow-up in PPL-EMR, PPL-ASSESS and the control group, respectively. Although systolic (BP) (p<0.001) and lipid (p<0.001) values significantly improved during the study, the group-by-time interaction term showed no differential change in systolic BP values (p=0.51) or lipid values (p=0.61) among the three study arms. No difference in intervention effect was noted when comparing the PPL-EMR with the PPL-ASSESS intervention (p=0.47).

Conclusions

The two PPL interventions tested in this study did not lead to improved control of hypertension or dyslipidaemia in primary care clinics during a mean 14-month follow-up period. This null result may have been due in part to substantial overall improvement in BP and lipid control at the study sites during the study.

Trial registration number

NCT00903071.
Experience of propofol sedation in a UK ERCP practice: lessons for service provision
Authors: Joshi D , Paranandi B , El Sayed G , Down J , Johnson G J , Chapman M H , Pereira S P , Webster G J M
Published: September 2014

Objective

Endoscopic retrograde cholangiopancreatography (ERCP) in the UK has been historically performed under conscious sedation. However, given the increasing complexity of cases, the role of propofol-assisted ERCP (propERCP) is increasing. We describe our experience of propERCP and highlight the importance of this service.

Design

Our prospective ERCP database was interrogated between January 2013 and January 2014. Data collection included procedural information, patient demographics, American Association of Anaesthesiologists (ASA) status, Cotton grade of endoscopic difficulty and endoscopic and anaesthetic complications. Comparison was made with patients undergoing conscious sedation ERCP (sedERCP).

Results

744 ERCPs were performed in 629 patients (53% male). 161 ERCPs were performed under propofol. PropERCP patients were younger compared with the sedERCP group (54 vs 66 years, p<0.0001) but ASA grade 1–2 status was similar (84% vs 78%, p=0.6). An increased number of Cotton grade 3–4 ERCPs were performed in the propERCP group (64% vs 34%, p<0.0001). Indications for propERCP included sphincter of Oddi manometry (27%), previously poorly tolerated sedERCP (26%), cholangioscopy (21%) and patient request (8%). 77% of cases were elective, 12% were urgent day-case transfers and 11% were urgent inpatients. 59% of cases were tertiary referrals. ERCP was completed successfully in 95% of cases. Anaesthetic and endoscopic complications were comparable between the two groups (5% and 7% vs 3% and 5%). Where sedERCP had been unsuccessful due to patient intolerance, the procedure was completed successfully using propofol.

Conclusions

PropERCP is safe and is associated with high endoscopic success. The need for propERCP is likely to increase given patient preference and the high proportion of complex procedures being undertaken. All endoscopy units should look to incorporate propofol-assisted endoscopy into aspects of their services.