bluuebunny/crossref_metadata_2025 huggingface dataset:
A Model for Predicting the Lift-Off Height of Premixed Jets in Vitiated Cross Flow
Authors: Kolb Michael , Ahrens Denise , Hirsch Christoph , Sattelmayer Thomas
Published: December 2015

Lean premixed single-stage combustion is state of the art for low pollution combustion in heavy-duty gas turbines with gaseous fuels. The application of premixed jets in multistage combustion to lower nitric oxide emissions and enhance turn-down ratio is a novel promising approach. At the Lehrstuhl für Thermodynamik, Technische Universität München, a large-scale atmospheric combustion test rig has been set up for studying staged combustion. The understanding of lift-off (LO) behavior is crucial for determining the amount of mixing before ignition and for avoiding flames anchoring at the combustor walls. This experiment studies jet LO depending on jet equivalence ratio (0.58–0.82), jet preheat temperature (288–673 K), cross flow temperature (1634–1821 K), and jet momentum ratio (6–210). The differences to existing LO studies are the high cross flow temperature and applying a premixed jet. The LO height of the jet flame is determined by OH* chemiluminescence images, and subsequently, the data is used to analyze the influence of each parameter and to develop a model that predicts the LO height for similar staged combustion systems. A main outcome of this work is that the LO height in a high temperature cross flow cannot be described by one dimensionless number like Damköhler- or Karlovitz-number. Furthermore, the ignition delay time scale τign also misses part of the LO height mechanism. The presented model uses turbulent time scales, the ignition delay, and a chemical time scale based on the laminar flame speed. An analysis of the model reveals flame stabilization mechanisms and explains the importance of different time scale.
High-Speed Characterization of a Prototype Leaf Seal on an Advanced Seal Test Facility
Authors: Pekris Michael J. , Nasti Adele , Jahn Ingo H. J. , Franceschini Gervas
Published: December 2015

Advanced contacting seals, such as leaf seals or brush seals, can offer reduced leakage during engine operation when compared to conventional labyrinth seals. The flexible elements of these seals provide better compliance with the rotor during flight maneuvers. The functionality and performance retention attributes of an engine-scale prototype leaf seal have been investigated on a seal test facility at Rolls-Royce that achieves engine-representative pressures and speeds and allows dynamic control of the seal position relative to the rotor, both concentric and eccentric. In this paper, the experimental setup and the test method are described in detail, including the quantification of the measurement uncertainty developed to ASME standard PTC 19.1. Experimental data are presented that show the variations in leakage and torque over typical variations of the test parameters. Insight is gained into the interactions between the operating pressure and speed and the concentric and eccentric movements imposed on the seal.
Research agencies revel in final 2016 budget
Authors: Mervis Jeffrey
Published: December 2015

NIH gets $2 billion hike, NASA and DOE science grow, NSF avoids restrictive language.
Sperm RNA fragments modify offspring metabolism
Authors: Leslie Mitch
Published: December 2015

Molecules transfer mouse paternal traits to progeny.
Funding for key data resources in jeopardy
Authors: Kaiser Jocelyn
Published: December 2015

NIH genome institute wants to scale back support of human and model organism databases.
Epigenetic (re)programming of caste-specific behavior in the ant
Camponotus floridanus
Authors: Simola Daniel F. , Graham Riley J. , Brady Cristina M. , Enzmann Brittany L. , Desplan Claude , Ray Anandasankar , Zwiebel Laurence J. , Bonasio Roberto , Reinberg Danny , Liebig Jürgen , Berger Shelley L.
Published: December 2015

Epigenetic control of caste-specific foraging

In carpenter ants, separate behavioral classes, known as castes, are determined by the epigenetic regulation of genes. Simola
et al.
treated ants of different castes with drugs that affected histone acetylation. Reducing histone acetylation stimulated scouting and foraging behavior. The foraging and scouting behaviors of young ants were permanently changed by directly injecting their brains with histone acetylation inhibitors.

Science
, this issue p.
10.1126/science.aac6633
Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior
Authors: Ferenczi Emily A. , Zalocusky Kelly A. , Liston Conor , Grosenick Logan , Warden Melissa R. , Amatya Debha , Katovich Kiefer , Mehta Hershel , Patenaude Brian , Ramakrishnan Charu , Kalanithi Paul , Etkin Amit , Knutson Brian , Glover Gary H. , Deisseroth Karl
Published: December 2015

A way to modulate reward-seeking

Which brain regions are causally involved in reward-related behavior? Ferenczi
et al.
combined focal, cell type-specific, optogenetic manipulations with brain imaging, behavioral testing, and in vivo electrophysiology (see the Perspective by Robbins). Stimulation of midbrain dopamine neurons increased activity in a brain region called the striatum and was correlated with reward-seeking across individual animals. However, elevated excitability of an area called the medial prefrontal cortex reduced both striatal responses to the stimulation of dopamine neurons and the behavioral drive to seek the stimulation of dopamine neurons. Finally, modulating the excitability of medial prefrontal cortex pyramidal neurons drove changes in neural circuit synchrony, as well as corresponding anhedonic behavior. These observations resemble imaging and clinical phenotypes observed in human depression, addiction, and schizophrenia.

Science
, this issue p.
10.1126/science.aac9698
; see also p.
10.1126/science.aad9698
Sieving hydrogen isotopes through two-dimensional crystals
Authors: Lozada-Hidalgo M. , Hu S. , Marshall O. , Mishchenko A. , Grigorenko A. N. , Dryfe R. A. W. , Radha B. , Grigorieva I. V. , Geim A. K.
Published: December 2015

Separating H
+
from D
+

In many respects, hydrogen and deuterium show similar properties because they share the same number of protons and electrons and only differ by one neutron. However, when you strip away the electron, a proton ends up having less than half the radius of a deuterion. Lozada-Hidalgo
et al.
used two-dimensional membranes of graphene or hexagonal boron nitride to separate these two charged isotopes, with a separation factor of about 10.

Science
, this issue p.
68
Myth busters
Newton's Apple and Other Myths About Science
Ronald L. Numbers and Kostas Kampourakis, Eds.
Harvard University Press, 2015. 303 pp.
Authors: Endersby Jim
Published: December 2015

Think you know your scientific history? Think again.
Statistical ortho-to-para ratio of water desorbed from ice at 10 kelvin
Authors: Hama Tetsuya , Kouchi Akira , Watanabe Naoki
Published: December 2015

Water isomers hide their origin

H
2
O exists in two spin isomers, ortho and para, in a ratio of 3:1 at room temperature. Some astronomical observations have found water with a ratio of less than 3, thought to be due to water being photodesorbed from ice that had been formed at very low temperatures (≾30 K). Hama
et al.
tested this idea in the laboratory, by forming water ice at low temperature and then photodesorbing it to measure the ortho:para ratio. They found a ratio of 3, even at 10 K. Thus, another explanation for the low ratios in some astronomical objects must be found.

Science
, this issue p.
65
Structure of the Sec61 channel opened by a signal sequence
Authors: Voorhees Rebecca M. , Hegde Ramanujan S.
Published: December 2015

Seeing the signal sequence in action

Protein translocation across the endoplasmic reticulum (ER) involves the interaction of a signal sequence with the protein translocation channel. Although much work has looked at the details of protein translocation, questions remain. Voorhees and Hegde present a single-particle cryoelectron microscopy study of the mammalian ER translocation apparatus at the point in which the signal sequence is engaging the translocation pore.

Science
, this issue p.
88
The power of crowds
Authors: Michelucci Pietro , Dickinson Janis L.
Published: December 2015

Combining humans and machines can help tackle increasingly hard problems
Microbes in a knight's armor
Authors: Müller Volker
Published: December 2015

Bacteria studded with nanoparticles produce acetate from carbon dioxide and sunlight

[Also see Report by

Sakimoto
et al.

]
When two reactions become one
Authors: Fyfe James W. B. , Watson Allan J. B.
Published: December 2015

Merging two fundamental reactions of organoboron compounds provides a new platform for catalysis

[Also see Report by

Zhang
et al.

]
Clinafloxacin for Treatment of Burkholderia cenocepacia Infection in a Cystic Fibrosis Patient
Authors: Balwan Akshu , Nicolau David P. , Wungwattana Minkey , Zuckerman Jonathan B. , Waters Valerie
Published: December 2015

Respiratory infection with
Burkholderia cenocepacia
is associated with accelerated decline in lung function and increased mortality in cystic fibrosis (CF) patients (A. M. Jones, M. E. Dodd, J. R. W. Govan, V. Barcus, C. J. Doherty, J. Morris, and A. K. Webb, Thorax 59:948–951, 2004,
http://dx.doi.org/10.1136/thx.2003.017210
).
B. cenocepacia
often possesses innate resistance to multiple antimicrobial classes, making eradication uncommon in established infection (P. B. Davis, Am J Respir Crit Care Med 173:475–482, 2006,
http://dx.doi.org/10.1164/rccm.200505-840OE
). We report the use of clinafloxacin in a CF patient with advanced
B. cenocepacia
infection, present pharmacokinetic (PK) data, and discuss the potential therapeutic role of clinafloxacin in patients with this condition.
Oral Immunization with Recombinant Vaccinia Virus Prime and Intramuscular Protein Boost Provides Protection against Intrarectal Simian-Human Immunodeficiency Virus Challenge in Macaques
Authors: Thippeshappa Rajesh , Tian Baoping , Cleveland Brad , Guo Wenjin , Polacino Patricia , Hu Shiu-Lok
Published: December 2015

Human immunodeficiency virus type 1 (HIV-1) acquisition occurs predominantly through mucosal transmission. We hypothesized that greater mucosal immune responses and protective efficacy against mucosal HIV-1 infection may be achieved by prime-boost immunization at mucosal sites. We used a macaque model to determine the safety, immunogenicity, and protective efficacy of orally delivered, replication-competent but attenuated recombinant vaccinia viruses expressing full-length HIV-1 SF162 envelope (Env) or simian immunodeficiency virus (SIV) Gag-Pol proteins. We examined the dose and route that are suitable for oral immunization with recombinant vaccinia viruses. We showed that sublingual inoculation of two vaccinia virus-naive pigtailed macaques with 5 × 10
8
PFU of recombinant vaccinia viruses was safe. However, sublingual inoculation with a higher dose or tonsillar inoculation resulted in secondary oral lesions, indicating the need to optimize the dose and route for oral immunization with replication-competent vaccinia virus vectors. Oral priming alone elicited antibody responses to vaccinia virus and to the SF162 Env protein. Intramuscular immunization with the SF162 gp120 protein at either 20 or 21 weeks postpriming resulted in a significant boost in antibody responses in both systemic and mucosal compartments. Furthermore, we showed that immune responses induced by recombinant vaccinia virus priming and intramuscular protein boosting provided protection against intrarectal challenge with the simian-human immunodeficiency virus SHIV-SF162-P4.
The “3 in 1” Study: Pooling Self-Taken Pharyngeal, Urethral, and Rectal Samples into a Single Sample for Analysis for Detection of Neisseria gonorrhoeae and Chlamydia trachomatis in Men Who Have Sex with Men
Authors: Sultan B. , White J. A. , Fish R. , Carrick G. , Brima N. , Copas A. , Robinson A. , Gilson R. , Mercey D. , Benn P.
Published: December 2015

Triple-site testing (using pharyngeal, rectal, and urethral/first-void urine samples) for
Neisseria gonorrhoeae
and
Chlamydia trachomatis
using nucleic acid amplification tests detects greater numbers of infections among men who have sex with men (MSM). However, triple-site testing represents a cost pressure for services. MSM over 18 years of age were eligible if they requested testing for sexually transmitted infections (STIs), reported recent sexual contact with either
C. trachomatis
or
N. gonorrhoeae
, or had symptoms of an STI. Each patient underwent standard-of-care (SOC) triple-site testing, and swabs were taken to form a pooled sample (PS) (pharyngeal, rectal, and urine specimens). The PS was created using two methods during different periods at one clinic, but we analyzed the data in combination because the sensitivity of the two methods did not differ significantly for
C. trachomatis
(
P
= 0.774) or
N. gonorrhoeae
(
P
= 0.163). The sensitivity of PS testing (92%) was slightly lower than that of SOC testing (96%) for detecting
C. trachomatis
(
P
= 0.167). For
N. gonorrhoeae
, the sensitivity of PS testing (90%) was significantly lower than that of SOC testing (99%) (
P
< 0.001). When pharynx-only infections were excluded, the sensitivity of PS testing to detect
N. gonorrhoeae
infections increased to 94%. Our findings show that pooling of self-taken samples could be an effective and cost-saving method, with high negative predictive values. (Interim results of this study were presented at the BASHH 2013 summer meeting.)
Flow Cytometry To Assess Cerebrospinal Fluid Fungal Burden in Cryptococcal Meningitis
Authors: Scriven James E. , Graham Lisa M. , Schutz Charlotte , Scriba Thomas J. , Wilkinson Robert J. , Boulware David R. , Meintjes Graeme , Lalloo David G. , Urban Britta C.
Published: December 2015

Fungal burden in the cerebrospinal fluid is an important determinant of mortality in cryptococcal meningitis, but its use in aiding clinical decision making is hampered by the time involved to perform quantitative cultures. Here, we demonstrate the potential of flow cytometry as a novel and rapid technique to address this issue.
Multilaboratory Evaluation of
In Vitro
Antifungal Susceptibility Testing of Dermatophytes for ME1111
Authors: Ghannoum M. , Chaturvedi V. , Diekema D. , Ostrosky-Zeichner L. , Rennie R. , Walsh T. , Wengenack N. , Fothergill A. , Wiederhold N.
Published: December 2015

ME1111 is a novel small molecule antifungal agent under development for the topical treatment of onychomycosis. Standardization of the susceptibility testing method for this candidate antifungal is needed. Toward this end, 8 independent laboratories determined the interlaboratory reproducibility of ME1111 susceptibility testing. In addition, we subsequently identified 2 strains as quality control (QC) isolates for the method. In the reproducibility study, 5 blinded clinical strains each of
Trichophyton rubrum
,
Trichophyton mentagrophytes
, and
Epidermophyton floccosum
were tested, while the QC study tested 6 blinded
T. rubrum
or
T. mentagrophytes
ATCC strains. Testing was performed in frozen microtiter panels according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 methodology. In the reproducibility study, 9 of 15 clinical strains showed interlaboratory agreement of >90% at the 80% inhibition endpoint, with a range of agreement of 76.2% to 100%. In the QC study, 4 of the 6 ATCC strains showed interlaboratory agreement of >90%. ME1111 demonstrated excellent interlaboratory agreement when tested against dermatophytes. Based on this data, the CLSI Subcommittee on Antifungal Susceptibility Tests approved the susceptibility testing of ME1111 against dermatophytes according to M38-A2 methodology, which stipulates RPMI 1640 as the test medium, an inoculum size of 1 to 3 × 10
3
CFU/ml, and an incubation time and temperature of 96 h at 35°C. The MIC endpoint should be 80% inhibition compared with the growth control.
T. rubrum
ATCC MYA-4438 and
T. mentagrophytes
ATCC 28185 were selected as QC isolates, with an acceptable range of 0.12 to 1 μg/ml for the two strains.
Epstein-Barr Virus Nuclear Antigen 3 (EBNA3) Proteins Regulate EBNA2 Binding to Distinct RBPJ Genomic Sites
Authors: Wang Anqi , Welch Rene , Zhao Bo , Ta Tram , Keleş Sündüz , Johannsen Eric
Published: December 2015

Latent infection of B lymphocytes by Epstein-Barr virus (EBV)
in vitro
results in their immortalization into lymphoblastoid cell lines (LCLs); this latency program is controlled by the EBNA2 viral transcriptional activator, which targets promoters via RBPJ, a DNA binding protein in the Notch signaling pathway. Three other EBNA3 proteins (EBNA3A, EBNA3B, and EBNA3C) interact with RBPJ to regulate cell gene expression. The mechanism by which EBNAs regulate different genes via RBPJ remains unclear. Our chromatin immunoprecipitation with deep sequencing (ChIP-seq) analysis of the EBNA3 proteins analyzed in concert with prior EBNA2 and RBPJ data demonstrated that EBNA3A, EBNA3B, and EBNA3C bind to distinct, partially overlapping genomic locations. Although RBPJ interaction is critical for EBNA3A and EBNA3C growth effects, only 30 to 40% of EBNA3-bound sites colocalize with RBPJ. Using LCLs conditional for EBNA3A or EBNA3C activity, we demonstrate that EBNA2 binding at sites near EBNA3A- or EBNA3C-regulated genes is specifically regulated by the respective EBNA3. To investigate EBNA3 binding specificity, we identified sequences and transcription factors enriched at EBNA3A-, EBNA3B-, and EBNA3C-bound sites. This confirmed the prior observation that IRF4 is enriched at EBNA3A- and EBNA3C-bound sites and revealed IRF4 enrichment at EBNA3B-bound sites. Using IRF4-negative BJAB cells, we demonstrate that IRF4 is essential for EBNA3C, but not EBNA3A or EBNA3B, binding to specific sites. These results support a model in which EBNA2 and EBNA3s compete for distinct subsets of RBPJ sites to regulate cell genes and where EBNA3 subset specificity is determined by interactions with other cell transcription factors.

IMPORTANCE
Epstein-Barr virus (EBV) latent gene products cause human cancers and transform B lymphocytes into immortalized lymphoblastoid cell lines
in vitro
. EBV nuclear antigens (EBNAs) and membrane proteins constitutively activate pathways important for lymphocyte growth and survival. An important unresolved question is how four different EBNAs (EBNA2, -3A, -3B, and -3C) exert unique effects via a single transcription factor, RBPJ. Here, we report that each EBNA binds to distinct but partially overlapping sets of genomic sites. EBNA3A and EBNA3C specifically regulate EBNA2's access to different RBPJ sites, providing a mechanism by which each EBNA can regulate distinct cell genes. We show that IRF4, an essential regulator of B cell differentiation, is critical for EBNA3C binding specificity; EBNA3A and EBNA3B specificities are likely due to interactions with other cell transcription factors. EBNA3 titration of EBNA2 transcriptional function at distinct sites likely limits cell defenses that would be triggered by unchecked EBNA2 prooncogenic activity.
Identification of Stabilizing Mutations in an H5 Hemagglutinin Influenza Virus Protein
Authors: Hanson Anthony , Imai Masaki , Hatta Masato , McBride Ryan , Imai Hirotaka , Taft Andrew , Zhong Gongxun , Watanabe Tokiko , Suzuki Yasuo , Neumann Gabriele , Paulson James C. , Kawaoka Yoshihiro
Published: December 2015

Highly pathogenic avian influenza viruses of the H5N1 subtype continue to circulate in poultry in Asia, Africa, and the Middle East. Recently, outbreaks of novel reassortant H5 viruses have also occurred in North America. Although the number of human infections with highly pathogenic H5N1 influenza viruses continues to rise, these viruses remain unable to efficiently transmit between humans. However, we and others have identified H5 viruses capable of respiratory droplet transmission in ferrets. Two experimentally introduced mutations in the viral hemagglutinin (HA) receptor-binding domain conferred binding to human-type receptors but reduced HA stability. Compensatory mutations in HA (acquired during virus replication in ferrets) were essential to restore HA stability. These stabilizing mutations in HA also affected the pH at which HA undergoes an irreversible switch to its fusogenic form in host endosomes, a crucial step for virus infectivity. To identify additional stabilizing mutations in an H5 HA, we subjected a virus library possessing random mutations in the ectodomain of an H5 HA (altered to bind human-type receptors) to three rounds of treatment at 50°C. We isolated several mutants that maintained their human-type receptor-binding preference but acquired an appreciable increase in heat stability and underwent membrane fusion at a lower pH; collectively, these properties may aid H5 virus respiratory droplet transmission in mammals.

IMPORTANCE
We have identified mutations in HA that increase its heat stability and affect the pH that triggers an irreversible conformational change (a prerequisite for virus infectivity). These mutations were identified in the genetic background of an H5 HA protein that was mutated to bind to human cells. The ability to bind to human-type receptors, together with physical stability and an altered pH threshold for HA conformational change, may facilitate avian influenza virus transmission via respiratory droplets in mammals.
Crystal Structure of the Measles Virus Nucleoprotein Core in Complex with an N-Terminal Region of Phosphoprotein
Authors: Guryanov Sergey G. , Liljeroos Lassi , Kasaragod Prasad , Kajander Tommi , Butcher Sarah J.
Published: December 2015

The enveloped negative-stranded RNA virus measles virus (MeV) is an important human pathogen. The nucleoprotein (N
0
) assembles with the viral RNA into helical ribonucleocapsids (NC) which are, in turn, coated by a helical layer of the matrix protein. The viral polymerase complex uses the NC as its template. The N
0
assembly onto the NC and the activity of the polymerase are regulated by the viral phosphoprotein (P). In this study, we pulled down an N
0
1-408
fragment lacking most of its C-terminal tail domain by several affinity-tagged, N-terminal P fragments to map the N
0
-binding region of P to the first 48 amino acids. We showed biochemically and using P mutants the importance of the hydrophobic interactions for the binding. We fused an N
0
binding peptide, P
1-48
, to the C terminus of an N
0
21-408
fragment lacking both the N-terminal peptide and the C-terminal tail of N protein to reconstitute and crystallize the N
0
-P complex. We solved the X-ray structure of the resulting N
0
-P chimeric protein at a resolution of 2.7 Å. The structure reveals the molecular details of the conserved N
0
-P interface and explains how P chaperones N
0
, preventing both self-assembly of N
0
and its binding to RNA. Finally, we propose a model for a preinitiation complex for RNA polymerization.

IMPORTANCE
Measles virus is an important, highly contagious human pathogen. The nucleoprotein N binds only to viral genomic RNA and forms the helical ribonucleocapsid that serves as a template for viral replication. We address how N is regulated by another protein, the phosphoprotein (P), to prevent newly synthesized N from binding to cellular RNA. We describe the atomic model of an N-P complex and compare it to helical ribonucleocapsid. We thus provide insight into how P chaperones N and helps to start viral RNA synthesis. Our results provide a new insight into mechanisms of paramyxovirus replication. New data on the mechanisms of phosphoprotein chaperone action allows better understanding of virus genome replication and nucleocapsid assembly. We describe a conserved structural interface for the N-P interaction which could be a target for drug development to treat not only measles but also potentially other paramyxovirus diseases.
Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency
Authors: Zhu Shu , Watanabe Makiko , Kirkpatrick Ericka , Murray Akilah B. , Sok Ryneth , Karst Stephanie M.
Published: December 2015

Human noroviruses are a leading cause of gastroenteritis across the globe, but the pathogenic mechanisms responsible for disease are not well established. The availability of a murine norovirus model system provides the opportunity to elucidate viral and host determinants of virulence in a natural host. For example, previous studies have revealed that the protruding domain of the murine norovirus capsid protein VP1, specifically residue 296 of VP1, regulates virulent infection. We identified a panel of nonsynonymous mutations in the open reading frame 2 (ORF2) gene encoding VP1 that arose in persistently infected mice and tested whether these mutations conferred phenotypic changes to viral replication and virulence. Consistent with previous studies, we demonstrate that a glutamic acid at position 296 results in attenuation. For the first time, we also demonstrate that a lysine at this position is sufficient to confer virulence on an otherwise attenuated murine norovirus strain. Moreover, our studies reveal a direct correlation between the efficiency of viral replication in B cells and virulence. These data are especially striking because mutations causing reduced B cell replication and attenuation had minimal effects on the ability of the virus to replicate in macrophages. Thus, norovirus infection of B cells may directly contribute to disease outcome.

IMPORTANCE
Human noroviruses are a major global cause of disease, yet we know very little about their pathogenic mechanisms. The availability of a murine norovirus model system facilitates investigation of noroviruses in a natural host organism and the identification of viral and host determinants of pathogenesis. We have identified a panel of mutations arising in the viral capsid protein VP1 during persistent infection of mice. Our data reveal that the protruding domain of VP1 regulates the ability of the virus to replicate in B cells, and this directly correlates with virulence. Importantly, mutations impairing B cell infection had minimal effects on macrophage infection, revealing a potentially critical role for B cell infection in norovirus pathogenesis.
New Mechanism of Hepatic Fibrogenesis: Hepatitis C Virus Infection Induces Transforming Growth Factor β1 Production through Glucose-Regulated Protein 94
Authors: Jee Min Hyeok , Hong Ka Young , Park Ji Hoon , Lee Jae Seung , Kim Hee Sun , Lee Song Hee , Jang Sung Key
Published: December 2015

Hepatitis C virus (HCV) is one of the leading causes of chronic liver inflammatory disease (hepatitis), which often leads to more severe diseases, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis, in particular, is a major pathogenic consequence of HCV infection, and transforming growth factor β1 (TGF-β1) plays a key role in its pathogenesis. Several HCV proteins have been suggested to either augment or suppress the expression of TGF-β1 by HCV-infected cells. Here, we report that TGF-β1 levels are elevated in HCV-infected hepatocytes culturedin vitroand in liver tissue of HCV patients. Notably, the level of TGF-β1 in media fromin vitro-cultured HCV-infected hepatocytes was high enough to activate primary hepatic stellate cells isolated from rats. This indicates that TGF-β1 secreted by HCV-infected hepatocytes is likely to play a key role in the liver fibrosis observed in HCV patients. Moreover, we showed that HCV E2 protein triggers the production of TGF-β1 by HCV-infected cells through overproduction of glucose-regulated protein 94 (GRP94).

IMPORTANCEHepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-β1. Here, we provide the first examination of TGF-β1 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-β1 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-β1 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-β1 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-β1 secretion via GRP94 mediated NF-κB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.
Analysis of Assembly and Budding of Lujo Virus
Authors: Urata Shuzo , Weyer Jacqueline , Storm Nadia , Miyazaki Yukiko , van Vuren Petrus Jansen , Paweska Janusz Tadeusz , Yasuda Jiro
Published: December 2015

The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.
Coeliac screening in a Scottish cohort of children with type 1 diabetes mellitus: is DQ typing the way forward?
Authors: Mitchell R T , Sun A , Mayo A , Forgan M , Comrie A , Gillett P M
Published: December 2015

Background

Children with type 1 diabetes mellitus (T1DM) are at increased risk of coeliac disease (CD). Recent guidelines indicate coeliac screening should include HLA typing for CD predisposing (DQ2/DQ8) alleles and those negative for these alleles require no further coeliac screening.

Methods

Children (n=176) with T1DM attending clinics across two Scottish regions were screened for HLA DQ2/DQ8 as part of routine screening. Data collected included the frequency of DQ2/DQ8 genotypes and the additional cost of HLA screening.

Results

Overall, DQ2/DQ8 alleles were identified in 94% of patients. The additional cost of HLA typing was £3699.52 (£21.02 per patient). All patients with known CD (11/176) were positive for DQ2/DQ8 and all were diagnosed with CD within 5 years of T1DM diagnosis.

Conclusions

The vast majority of children with T1DM have CD-predisposing HLA genotypes limiting the number of patients that can be excluded from further screening. We conclude that HLA genotyping is not currently indicated for CD screening in this population.
Exercise prescription for patients with type 2 diabetes—a synthesis of international recommendations: narrative review
Authors: Mendes Romeu , Sousa Nelson , Almeida António , Subtil Paulo , Guedes-Marques Fernando , Reis Victor Machado , Themudo-Barata José Luís
Published: December 2015

Background

Physical activity is a cornerstone of type 2 diabetes treatment and control.

Aim

We analysed and synthesised the guidelines and recommendations issued by scientific organisations, regarding exercise prescription for patients with type 2 diabetes.

Method

A systematic bibliographic search in Pubmed, Web of Science and Scopus databases was conducted. Clinical guidelines from major international scientific organisations in the field of diabetology, endocrinology, cardiology, public health and sports medicine were also considered. 11 publications were selected.

Results

Published guidelines recommend a weekly accumulation of a minimum of 150 min of aerobic exercise at moderate-to-vigorous intensity spread over a minimum of 3 days per week. Resistance exercise for muscle strengthening is also recommended at least 2 days a week. Flexibility exercises may complement other types of exercise. Combining aerobic and resistance exercise within the same exercise session is recommended by most guidelines.

Conclusions

Exercise prescription for individuals with type 2 diabetes should include specific information on the type, mode, duration, intensity and weekly frequency. The exercise strategies must be adapted for each individual, based on comorbidities, contraindications and realistic personal goals.
Reporting missing participant data in randomised trials: systematic survey of the methodological literature and a proposed guide
Authors: Akl Elie A , Shawwa Khaled , Kahale Lara A , Agoritsas Thomas , Brignardello-Petersen Romina , Busse Jason W , Carrasco–Labra Alonso , Ebrahim Shanil , Johnston Bradley C , Neumann Ignacio , Sola Ivan , Sun Xin , Vandvik Per , Zhang Yuqing , Alonso-Coello Pablo , Guyatt Gordon H
Published: December 2015

Objectives

We conducted a systematic survey of the methodological literature to identify recommended approaches for how and what randomised clinical trial (RCT) authors should report on missing participant data and, on the basis of these approaches, to propose guidance for RCT authors.

Methods

We defined missing participant data (MPD) as missing outcome data for trial participants. We considered both categorical and continuous outcome data. We searched MEDLINE and the Cochrane Methodology Register for articles in which authors proposed approaches to reporting MPD from RCTs. We selected eligible articles independently and in duplicate and extracted data in duplicate. Using an iterative process of discussion and revisions, we used the findings to develop guidance.

Results

Of 10 501 unique citations identified, 13 articles reporting on 10 approaches proved eligible. The identified approaches recommend reporting the following aspects (from most to least frequently recommended): number of participants with MPD (n=10), reasons for MPD (n=7), methods used to handle MPD in the analysis (n=4), flow of participants (n=3), pattern of missingness (eg, whether at random) (n=3), differences in rates of MPD between trial arms (n=2), differences between participants with and without MPD (n=2), results of any sensitivity analyses (n=2), implication of MPD on interpreting the results (n=2) and methods used to prevent missing data (n=1). We propose a guide with nine items related to reporting the number, reasons, patterns, analytical methods and interpretation of MPD.

Conclusions

Most identified approaches invite trial authors to report the extent of MPD and the underlying reasons. Fewer approaches focus on reporting missingness patterns, methods for handling MPD and implications of MPD on results. Our proposed guidance could help RCT authors to better report, and readers to better identify participants with missing data.
Monitoring adverse events in Norwegian hospitals from 2010 to 2013
Authors: Deilkås Ellen Tveter , Bukholm Geir , Lindstrøm Jonas Christoffer , Haugen Marion
Published: December 2015

Objectives

To describe how adverse event (AE) rates were monitored and estimated nationally across all Norwegian hospitals from 2010 to 2013, and how they developed during the monitoring period. Monitoring was based on medical record review with Global Trigger Tool (GTT).

Setting

All publicly and privately owned hospitals were mandated to review randomly selected medical records to monitor AE rates. The initiative was part of the Norwegian patient safety campaign, launched by the Norwegian Ministry of Health and Care Services. It started in January 2011 and lasted until December 2013. 2010 was the baseline for the review. One of the main aims of the campaign was to reduce patient harm.

Method

To standardise the medical record reviews in all hospitals, GTT was chosen as a standard method. GTT teams from all hospitals reviewed 40 851 medical records randomly selected from 2 249 957 discharges from 2010 to 2013. Data were plotted in time series for local measurement and national AE rates were estimated, plotted and monitored.

Results

AE rates were estimated and published nationally from 2010 to 2013. Estimated AE rates in severity categories E-I decreased significantly from 16.1% in 2011 to 13.0% in 2013 (−3.1% (95% CI −5.2% to −1.1%)).

Conclusions

Monitoring estimated AE rates emerges as a potential element in national systems for patient safety. Estimated AE rates in the category of least severity decreased significantly during the first 2 years of the monitoring.
Does a research article's country of origin affect perception of its quality and relevance? A national trial of US public health researchers
Authors: Harris M , Macinko J , Jimenez G , Mahfoud M , Anderson C
Published: December 2015

Objectives

The source of research may influence one's interpretation of it in either negative or positive ways, however, there are no robust experiments to determine how source impacts on one's judgment of the research article. We determine the impact of source on respondents’ assessment of the quality and relevance of selected research abstracts.

Design

Web-based survey design using four healthcare research abstracts previously published and included in Cochrane Reviews.

Setting

All Council on the Education of Public Health-accredited Schools and Programmes of Public Health in the USA.

Participants

899 core faculty members (full, associate and assistant professors)

Intervention

Each of the four abstracts appeared with a high-income source half of the time, and low-income source half of the time. Participants each reviewed the same four abstracts, but were randomly allocated to receive two abstracts with high-income source, and two abstracts with low-income source, allowing for within-abstract comparison of quality and relevance

Primary outcome measures

Within-abstract comparison of participants’ rating scores on two measures—strength of the evidence, and likelihood of referral to a peer (1–10 rating scale). OR was calculated using a generalised ordered logit model adjusting for sociodemographic covariates.

Results

Participants who received high income country source abstracts were equal in all known characteristics to the participants who received the abstracts with low income country sources. For one of the four abstracts (a randomised, controlled trial of a pharmaceutical intervention), likelihood of referral to a peer was greater if the source was a high income country (OR 1.28, 1.02 to 1.62, p<0.05).

Conclusions

All things being equal, in one of the four abstracts, the respondents were influenced by a high-income source in their rating of research abstracts. More research may be needed to explore how the origin of a research article may lead to stereotype activation and application in research evaluation.
A cluster-randomised controlled trial integrating a community-based water, sanitation and hygiene programme, with mass distribution of albendazole to reduce intestinal parasites in Timor-Leste: the WASH for WORMS research protocol
Authors: Nery Susana Vaz , McCarthy James S , Traub Rebecca , Andrews Ross M , Black Jim , Gray Darren , Weking Edmund , Atkinson Jo-An , Campbell Suzy , Francis Naomi , Vallely Andrew , Williams Gail , Clements Archie
Published: December 2015

Introduction

There is limited evidence demonstrating the benefits of community-based water, sanitation and hygiene (WASH) programmes on infections with soil-transmitted helminths (STH) and intestinal protozoa. Our study aims to contribute to that evidence base by investigating the effectiveness of combining two complementary approaches for control of STH: periodic mass administration of albendazole, and delivery of a community-based WASH programme.

Methods and analysis

WASH for WORMS is a cluster-randomised controlled trial to test the hypothesis that a community-based WASH intervention integrated with periodic mass distribution of albendazole will be more effective in reducing infections with STH and protozoa than mass deworming alone. All 18 participating rural communities in Timor-Leste receive mass chemotherapy every 6 months. Half the communities also receive the community-based WASH programme. Primary outcomes are the cumulative incidence of infection with STH. Secondary outcomes include the prevalence of protozoa; intensity of infection with STH; as well as morbidity indicators (anaemia, stunting and wasting). Each of the trial outcomes will be compared between control and intervention communities. End points will be measured 2 years after the first albendazole distribution; and midpoints are measured at 6 months intervals (12 months for haemoglobin and anthropometric indexes). Mixed-methods research will also be conducted in order to identify barriers and enablers associated with the acceptability and uptake of the WASH programme.

Ethics and dissemination

Ethics approval was obtained from the human ethics committees at the University of Queensland, Australian National University, Timorese Ministry of Health, and University of Melbourne. The results of the trial will be published in peer-reviewed journals presented at national and international conferences, and disseminated to relevant stakeholders in health and WASH programmes. This study is funded by a Partnership for Better Health—Project grant from the National Health and Research Council (NHMRC), Australia.

Trial registration number

ACTRN12614000680662; Pre-results
Compliance with the proper use of an individual radiation dosimeter among children and the effects of improper use on the measured dose: a retrospective study 18–20 months following Japan's 2011 Fukushima nuclear incident
Authors: Nomura Shuhei , Tsubokura Masaharu , Hayano Ryugo , Yoneoka Daisuke , Ozaki Akihiko , Shimada Yuki , Furutani Tomoyuki , Kanazawa Yukio , Oikawa Tomoyoshi
Published: December 2015

Objectives

To identify profiles of children who did not properly use individual radiation dosimeters following Japan's 2011 Fukushima nuclear incident, and to assess how much error is generated by improper dosimeter use.

Participants

The participants in this study comprised 1637 school children who participated in the external radiation exposure screening programme administrated by Minamisoma City (located 20–30 km from the Fukushima nuclear plant) between 18 and 20 months after the Fukushima incident.

Methods

We assessed the factors associated with improper use (non-use) of the dosimeters at specific time periods during the day (school commuting hours, at school, at home, outdoors and at bedtime) using logistic regression analyses. Ratios of the measured dose to regression estimates of the ‘expected’ dose (referred to as an error due to non-use) were also examined.

Results

Only 119 children (7.3%) used the dosimeters properly in all time periods. This low rate was attributed primarily to non-use when children were in the home and outdoors, rather than at school. School level, air dose rate at home, gender, membership in outdoor sports clubs and time spent outdoors on weekends, were significantly associated with improper use, after adjustment for covariates. Data from children who did not wear the dosimeters to school and outdoors had statistically significant (but clinically insignificant) errors (ratio: 1.13, p<0.01; and 0.97, p<0.05, respectively), whereas improper use of the dosimeters at school, at home and at bedtime did not generate significant errors.

Conclusions

Well-targeted rigorous instructions on the use of the dosimeter are required, with particular focus on time periods other than school hours. However, given the small dose error due to the improper use of the dosimeters, even if the dosimeters are improperly used, solid evaluation of the radiation exposure may be possible with some accuracy.
Balance ability in 7- and 10-year-old children: associations with prenatal lead and cadmium exposure and with blood lead levels in childhood in a prospective birth cohort study
Authors: Taylor Caroline M , Humphriss Rachel , Hall Amanda , Golding Jean , Emond Alan M
Published: December 2015

Objectives

Most studies reporting evidence of adverse effects of lead and cadmium on the ability to balance have been conducted in high-exposure groups or have included adults. The effects of prenatal exposure have not been well studied, nor have the effects in children been directly studied. The aim of the study was to identify the associations of lead (in utero and in childhood) and cadmium (in utero) exposure with the ability to balance in children aged 7 and 10 years.

Design

Prospective birth cohort study.

Participants

Maternal blood lead (n=4285) and cadmium (n=4286) levels were measured by inductively coupled plasma mass spectrometry in women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) during pregnancy. Child lead levels were measured in a subsample of 582 of ALSPAC children at age 30 months.

Main outcome measures

Children completed a heel-to-toe walking test at 7 years. At 10 years, the children underwent clinical tests of static and dynamic balance. Statistical analysis using SPSS V.19 included logistic regression modelling, comparing categories of ≥5 vs <5 µg/dL for lead, and ≥1 vs <1 µg/L for cadmium.

Results

Balance at age 7 years was not associated with elevated in utero lead or cadmium exposure (adjusted OR for balance dysfunction: Pb 1.01 (95% CI 0.95 to 1.01), n=1732; Cd 0.95 (0.77 to 1.20), n=1734), or with elevated child blood lead level at age 30 months (adjusted OR 0.98 (0.92 to 1.05), n=354). Similarly, neither measures of static nor dynamic balance at age 10 years were associated with in utero lead or cadmium exposure, or child lead level.

Conclusions

These findings do not provide any evidence of an association of prenatal exposure to lead or cadmium, or lead levels in childhood, on balance ability in children. Confirmation in other cohorts is needed.
Clinician-scientist MB/PhD training in the UK: a nationwide survey of medical school policy
Authors: Barnett-Vanes Ashton , Ho Guiyi , Cox Timothy M
Published: December 2015

Objective

This study surveyed all UK medical schools regarding their Bachelor of Medicine (MB), Doctor of Philosophy (PhD) (MB/PhD) training policy in order to map the current training landscape and to provide evidence for further research and policy development.

Setting

Deans of all UK medical schools registered with the Medical Schools Council were invited to participate in this survey electronically.

Primary

The number of medical schools that operate institutional MB/PhD programmes or permit self-directed student PhD intercalation.

Secondary

Medical school recruitment procedures and attitudes to policy guidance.

Findings

27 of 33 (81%) registered UK medical schools responded. Four (14%) offer an institutional MB/PhD programme. However, of those without institutional programmes, 17 (73%) permit study interruption and PhD intercalation: two do not (one of whom had discontinued their programme in 2013), three were unsure and one failed to answer the question. Regarding student eligibility, respondents cited high academic achievement in medical studies and a bachelor's or master's degree. Of the Medical schools without institutional MB/PhD programmes, 5 (21%) have intentions to establish a programme, 8 (34%) do not and 3 were unsure, seven did not answer. 19 medical schools (70%) considered national guidelines are needed for future MB/PhD programme development.

Conclusions

We report the first national survey of MB/PhD training in the UK. Four medical schools have operational institutional MB/PhD programmes, with a further five intending to establish one. Most medical schools permit study interruption and PhD intercalation. The total number MB/PhD students yet to graduate from medical school could exceed 150, with 30 graduating per year. A majority of medical school respondents to this survey believe national guidelines are required for MB/PhD programme development and implementation. Further research should focus on the MB/PhD student experience. Discussion regarding local and national MB/PhD policies between medical schools and academic stakeholders are needed.