bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of Performance of Wave Power Conversion Due to the Projecting Walls for Oscillating Water Column Type Wave Energy Converter
Authors: Ikoma Tomoki , Masuda Koichi , Omori Hikaru , Osawa Hiroyuki , Maeda Hisaaki
Published: January 2016

This paper describes a method to improve the performance of primary conversion of wave power takeoff. The wave energy converter (WEC) used here was of oscillating water column (OWC) type. This method for improvement has been already proposed in past research and its usefulness has been confirmed. It involves projecting walls (PWs) being attached to the front of the inlet–outlet of the OWC. The prediction method of hydrodynamic behaviors for the OWC type WEC with PWs installed is explained in this paper. The boundary element method with the Green's function is applied, and influence of air pressure and free surface within every air-chamber was directly taken into consideration in the prediction method based on linear potential theory. Validity of the prediction method was proved by comparing the results with the results of model experiments. Series calculations are performed with the prediction method. Behaviors of air pressure, water elevation, and the efficiency of primary conversion of wave power were investigated. From the calculations, length of the PWs was shown to affect the efficiency of primary conversion. It was possible to equip the PWs so as to enable improvements in oblique waves to beam sea conditions as well as in the head sea conditions. This paper examined not only the PWs but also the application and effects of the end walls (EWs) with the slit. The EWs were very useful to improve the efficiency.
Structural analysis of the outermost hair surface using TOF-SIMS with gas cluster ion beam sputtering
Authors: lshikawa Kazutaka , Okamoto Masayuki , Aoyagi Satoka
Published: January 2016

A hair cuticle, which consists of flat overlapping scales that surround the hair fiber, protects inner tissues against external stimuli. The outermost surface of the cuticle is covered with a thin membrane containing proteins and lipids called the epicuticle. In a previous study, the authors conducted a depth profile analysis of a hair cuticle's amino acid composition to characterize its multilayer structure. Time-of-flight secondary ion mass spectrometry with a bismuth primary ion source was used in combination with the C60 sputtering technique for the analysis. It was confirmed that the lipids and cysteine-rich layer exist on the outermost cuticle surface, which is considered to be the epicuticle, though the detailed structure of the epicuticle has not been clarified. In this study, depth profile analysis of the cuticle surface was conducted using the argon gas cluster ion beam (Ar-GCIB) sputtering technique, in order to characterize the structure of the epicuticle. The shallow depth profile of the cuticle surface was investigated using an Ar-GCIB impact energy of 5 keV. Compared to the other amino acid peaks rich in the epicuticle, the decay of 18-methyleicosanic acid (18-MEA) thiolate peak was the fastest. This result suggests that the outermost surface of the hair is rich in 18-MEA. In conclusion, our results indicate that the outermost surfaces of cuticles have a multilayer (lipid and protein layers), which is consistent with the previously proposed structure.
Initial clinical evaluation of PET‐based ion beam therapy monitoring under consideration of organ motion
Authors: Kurz Christopher , Bauer Julia , Unholtz Daniel , Richter Daniel , Herfarth Klaus , Debus Jürgen , Parodi Katia
Published: January 2016

Purpose:

Intrafractional organ motion imposes considerable challenges to scanned ion beam therapy and demands for a thorough verification of the applied treatment. At the Heidelberg Ion‐Beam Therapy Center (HIT), the scanned ion beam delivery is verified by means of postirradiation positron‐emission‐tomography (PET) imaging. This work presents a first clinical evaluation of PET‐based treatment monitoring in ion beam therapy under consideration of target motion.

Methods:

Three patients with mobile liver lesions underwent scanned carbon ion irradiation at HIT and postirradiation PET/CT (x‐ray‐computed‐tomography) imaging with a commercial scanner. Respiratory motion was recorded during irradiation and subsequent image acquisition. This enabled a time‐resolved (4D) calculation of the expected irradiation‐induced activity pattern and, for one patient where an additional 4D CT was acquired at the PET/CT scanner after treatment, a motion‐compensated PET image reconstruction. For the other patients, PET data were reconstructed statically. To verify the treatment, calculated prediction and reconstructed measurement were compared with a focus on the ion beam range.

Results:

Results in the current three patients suggest that for motion amplitudes in the order of 2 mm there is no benefit from incorporating respiratory motion information into PET‐based treatment monitoring. For a target motion in the order of 10 mm, motion‐related effects become more severe and a time‐resolved modeling of the expected activity distribution can lead to an improved data interpretation if a sufficient number of true coincidences is detected. Benefits from motion‐compensated PET image reconstruction could not be shown conclusively at the current stage.

Conclusions:

The feasibility of clinical PET‐based treatment verification under consideration of organ motion has been shown for the first time. Improvements in noise‐robust 4D PET image reconstruction are deemed necessary to enhance the clinical potential.
Short-Term Resistance Training Attenuates Cardiac Autonomic Dysfunction in Obese Adolescents
Authors: Farinatti Paulo , Neto Silvio Rodrigues Marques , Dias Ingrid , Cunha Felipe A. , Bouskela Eliete , Kraemer-Aguiar Luiz G.
Published: January 2016

Purpose:

Cardiac autonomic dysfunction (CADysf) in children is often associated to obesity and may be attenuated by physical activity. In this study, we investigated the effects of resistance training (RT) upon CADysf assessed by heart rate variability (HRV) in obese adolescents.

Method:

Volunteers were assigned into groups according to standard deviation scores for body mass index (z-BMI) and percentile for age and sex: obese (OB; z-BMI from 2 to 3 and ≥ 95th percentile, n = 24) and normal weight controls (CG; z-BMI from -2–1 and < 85th percentile, n = 20). OB performed isolated RT during 12 weeks [3 sets of 6–10reps with 70–85% 10RM]. Waist circumference, systolic/diastolic blood pressures (SBP/DBP), lipids, and HRV were assessed at baseline. Only OB underwent postintervention assessments.

Results:

At baseline, SBP (122.4 ± 9.1 vs. 109.7 ± 11.5 mmHg, p < .001) and DBP (76.1 ± 7.1 vs. 65.3 ± 5.9 mmHg, p < .001) were higher, while parasympathetic HRV indexes were lower (p < .05) in OB compared with CG. After RT, waist circumference (3%, p < .001) and SBP (10%, p < .001) reduced in OB. Parasympathetic indexes of HRV increased in OB (SDNN: 25%, p = .03; rMSSD: 48%, p = .0006; pNN50: 67%, p = .001; total power: 54%, p = .01; HF: 101%, p = .001) and baseline differences between groups for sympathetic and parasympathetic activities were no longer observed after RT.

Conclusion:

RT attenuated CAdyfs and BP in obese adolescents, by increasing parasympathetic activity and decreasing sympatho-vagal balance.
Aerobic Fitness and Trainability in Healthy Youth: Gaps in Our Knowledge
Authors: Armstrong Neil , McNarry Melitta
Published: January 2016

Peak oxygen uptake (V̇O2) is widely recognized as the criterion measure of young people’s aerobic fitness. Peak V̇O2 in youth has been assessed and documented for over 75 years but the interpretation of peak V̇O2 and its trainability are still shrouded in controversy. Causal mechanisms and their modulation by chronological age, biological maturation and sex remain to be resolved. Furthermore, exercise of the intensity and duration required to determine peak V̇O2 is rarely experienced by most children and adolescents. In sport and in everyday life young people are characterized by intermittent bouts of exercise and rapid changes in exercise intensity. In this context it is the transient kinetics of pulmonary V̇O2 (pV̇O2), not peak V̇O2, which best describe aerobic fitness. There are few rigorously determined and appropriately analyzed data from young people’s pV̇O2 kinetics responses to step changes in exercise intensity. Understanding of the trainability of pV̇O2 kinetics is principally founded on comparative studies of trained and untrained youth and much remains to be elucidated. This paper reviews peak V̇O2, pV̇O2 kinetics, and their trainability in youth. It summarizes “what we know,” identifies significant gaps in our knowledge, raises relevant questions, and indicates avenues for future research.
Most microbe-specific naïve CD4
+
T cells produce memory cells during infection
Authors: Tubo Noah J. , Fife Brian T. , Pagan Antonio J. , Kotov Dmitri I. , Goldberg Michael F. , Jenkins Marc K.
Published: January 2016

All T cells can remember

One of the hallmarks of adaptive immunity is that T and B lymphocytes “remember” previous infections, protecting the host from subsequent infections. When T cells respond to a pathogen, they proliferate, and a fraction of their progeny goes on to form long-lived memory cells. It is not clear whether all of the T cell clones that respond to the initial infection have the potential to form memory T cells. Tubo
et al.
used a single-cell adoptive transfer model in mice to answer this question. Nearly all T cell clones produced memory cells, which suggests that breadth is probably an important component of immunological memory.

Science
, this issue p.
511
Two genes substitute for the mouse Y chromosome for spermatogenesis and reproduction
Authors: Yamauchi Yasuhiro , Riel Jonathan M. , Ruthig Victor A. , Ortega Eglė A. , Mitchell Michael J. , Ward Monika A.
Published: January 2016

Replacing the Y chromosome

The mammalian Y chromosome encodes a specialized set of genes that are essential for male viability and fertility. In particular, the sex-determining region Y (SRY) protein is necessary to initiate male sex determination. However, Yamauchi
et al.
show that the functions of the entire Y chromosome can be replaced with only two genes. In mice, two transgenes,
Sox9
and
Eif2s3x
, compensated for the absence of all Y chromosome genes to allow successful sperm formation.

Science
, this issue p.
514
Periodic slow slip triggers megathrust zone earthquakes in northeastern Japan
Authors: Uchida Naoki , Iinuma Takeshi , Nadeau Robert M. , Bürgmann Roland , Hino Ryota
Published: January 2016

A silent and periodic earthquake trigger

Large earthquakes that hit places such as Japan seem to be preceded by subtle and silent deformation. Uchida
et al.
show that these “slow-slip events” are quasi-periodic in the megathrust zone in Japan. Slow-slip events occurred every 1 to 6 years and frequently were correlated with large earthquakes, including the great 2011 Tohoku-oki earthquake. The quasi-periodic behavior stretches back to at least 1930 and provides an important constraint for seismic hazard assessment in the region.

Science
, this issue p.
488
Airway acidification initiates host defense abnormalities in cystic fibrosis mice
Authors: Shah Viral S. , Meyerholz David K. , Tang Xiao Xiao , Reznikov Leah , Abou Alaiwa Mahmoud , Ernst Sarah E. , Karp Philip H. , Wohlford-Lenane Christine L. , Heilmann Kristopher P. , Leidinger Mariah R. , Allen Patrick D. , Zabner Joseph , McCray Paul B. , Ostedgaard Lynda S. , Stoltz David A. , Randak Christoph O. , Welsh Michael J.
Published: January 2016

Airway infections put to an acid test

Most people with cystic fibrosis suffer from chronic respiratory infections. The mechanistic link between this symptom and the genetic cause of the disease (mutations that compromise the function of the cystic fibrosis transmembrane conductance regulator, CFTR) is not fully understood. Studying animal models, Shah
et al.
find that in the absence of functional CFTR, the surface liquid in the airways becomes acidic, which impairs host defenses against infection. This acidification occurs through the action of a proton pump called ATP12A. Molecules inhibiting ATP12A could potentially be developed into useful drugs.

Science
, this issue p.
503
Activation of Cu(111) surface by decomposition into nanoclusters driven by CO adsorption
Authors: Eren Baran , Zherebetskyy Danylo , Patera Laerte L. , Wu Cheng Hao , Bluhm Hendrik , Africh Cristina , Wang Lin-Wang , Somorjai Gabor A. , Salmeron Miquel
Published: January 2016

Nanoclusters just by adding CO

The most closely packed surfaces of transition metals are usually stable under vacuum, but during catalytic reactions, energetic changes that result from adsorbing molecules could change the surface structure. Eren
et al.
present an extreme example for carbon monoxide (CO) adsorption on the (111) surface of copper at very low partial pressures. The surface decomposed into small nanoclusters (most containing 3 or 19 atoms). The surface was more reactive than the original and, for example, could dissociate adsorbed water at room temperature.

Science
, this issue p.
475
Prescription drugs obscure microbiome analyses
Authors: Devkota Suzanne
Published: January 2016

Patient populations should be stratified for medications when looking for gut microbial signatures of disease
Development and Validation of an Improved PCR Method Using the 23S-5S Intergenic Spacer for Detection of Rickettsiae in Dermacentor variabilis Ticks and Tissue Samples from Humans and Laboratory Animals
Authors: Kakumanu Madhavi L. , Ponnusamy Loganathan , Sutton Haley T. , Meshnick Steven R. , Nicholson William L. , Apperson Charles S.
Published: January 2016

A novel nested PCR assay was developed to detect
Rickettsia
spp. in ticks and tissue samples from humans and laboratory animals. Primers were designed for the nested run to amplify a variable region of the 23S-5S intergenic spacer (IGS) of
Rickettsia
spp. The newly designed primers were evaluated using genomic DNA from 11
Rickettsia
species belonging to the spotted fever, typhus, and ancestral groups and, in parallel, compared to other
Rickettsia
-specific PCR targets (
ompA
,
gltA
, and the 17-kDa protein gene). The new 23S-5S IGS nested PCR assay amplified all 11
Rickettsia
spp., but the assays employing other PCR targets did not. The novel nested assay was sensitive enough to detect one copy of a cloned 23S-5S IGS fragment from “
Candidatus
Rickettsia amblyommii.” Subsequently, the detection efficiency of the 23S-5S IGS nested assay was compared to those of the other three assays using genomic DNA extracted from 40 adult
Dermacentor variabilis
ticks. The nested 23S-5S IGS assay detected
Rickettsia
DNA in 45% of the ticks, while the amplification rates of the other three assays ranged between 5 and 20%. The novel PCR assay was validated using clinical samples from humans and laboratory animals that were known to be infected with pathogenic species of
Rickettsia
. The nested 23S-5S IGS PCR assay was coupled with reverse line blot hybridization with species-specific probes for high-throughput detection and simultaneous identification of the species of
Rickettsia
in the ticks. “
Candidatus
Rickettsia amblyommii,”
R. montanensis
,
R. felis
, and
R. bellii
were frequently identified species, along with some potentially novel
Rickettsia
strains that were closely related to
R. bellii
and
R. conorii
.
Detecting Staphylococcus aureus Virulence and Resistance Genes: a Comparison of Whole-Genome Sequencing and DNA Microarray Technology
Authors: Strauß Lena , Ruffing Ulla , Abdulla Salim , Alabi Abraham , Akulenko Ruslan , Garrine Marcelino , Germann Anja , Grobusch Martin Peter , Helms Volkhard , Herrmann Mathias , Kazimoto Theckla , Kern Winfried , Mandomando Inácio , Peters Georg , Schaumburg Frieder , von Müller Lutz , Mellmann Alexander
Published: January 2016

Staphylococcus aureus
is a major bacterial pathogen causing a variety of diseases ranging from wound infections to severe bacteremia or intoxications. Besides host factors, the course and severity of disease is also widely dependent on the genotype of the bacterium. Whole-genome sequencing (WGS), followed by bioinformatic sequence analysis, is currently the most extensive genotyping method available. To identify clinically relevant staphylococcal virulence and resistance genes in WGS data, we developed an
in silico
typing scheme for the software SeqSphere
+
(Ridom GmbH, Münster, Germany). The implemented target genes (
n
= 182) correspond to those queried by the Identibac
S. aureus
Genotyping DNA microarray (Alere Technologies, Jena, Germany). The
in silico
scheme was evaluated by comparing the typing results of microarray and of WGS for 154 human
S. aureus
isolates. A total of 96.8% (
n
= 27,119) of all typing results were equally identified with microarray and WGS (40.6% present and 56.2% absent). Discrepancies (3.2% in total) were caused by WGS errors (1.7%), microarray hybridization failures (1.3%), wrong prediction of ambiguous microarray results (0.1%), or unknown causes (0.1%). Superior to the microarray, WGS enabled the distinction of allelic variants, which may be essential for the prediction of bacterial virulence and resistance phenotypes. Multilocus sequence typing clonal complexes and staphylococcal cassette chromosome
mec
element types inferred from microarray hybridization patterns were equally determined by WGS. In conclusion, WGS may substitute array-based methods due to its universal methodology, open and expandable nature, and rapid parallel analysis capacity for different characteristics in once-generated sequences.
Diagnostic Performance of Xpert MTB/RIF in Tuberculous Pleural Effusion: Systematic Review and Meta-analysis
Authors: Sehgal Inderpaul Singh , Dhooria Sahajal , Aggarwal Ashutosh Nath , Behera Digambar , Agarwal Ritesh
Published: January 2016

A systematic review investigating the role of Xpert MTB/RIF in the diagnosis of tuberculous pleural effusion (TPE) was conducted. The pooled sensitivities and specificities of Xpert MTB/RIF were 51.4% and 98.6%, respectively, with culture used as a reference standard and 22.7% and 99.8%, respectively, with a composite reference standard (CRS) used as the benchmark. Xpert MTB/RIF has low sensitivity but excellent specificity in the diagnosis of TPE.
Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded
In Vitro
and Are Recognized by LANA-Specific CD4
+
T Cells
Authors: Nicol Samantha M. , Sabbah Shereen , Brulois Kevin F. , Jung Jae U. , Bell Andrew I. , Hislop Andrew D.
Published: January 2016

Kaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4
+
T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4
+
T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8
+
T cells, we suggest that CD4
+
T cells are potentially important effectors for the
in vivo
control of KSHV-infected B lymphocytes.

IMPORTANCE
KSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that recapitulates features seen in PEL and MCD by gene expression and cell phenotype analysis, allowing the study of T cell recognition of these cells. Challenge of KSHV-infected B cells with CD4
+
T cells specific for LANA, a protein expressed in all KSHV-infected cells and malignancies
in vivo
, showed that these effectors could efficiently recognize such targets. Given that the virus expresses immune evasion genes or uses proteins with intrinsic properties, such as LANA, that minimize epitope recognition by CD8
+
T cells, CD4
+
T cell immunity to KSHV may be important for maintaining the virus-host balance.
Generation and Characterization of Monoclonal Antibodies against a Cyclic Variant of Hepatitis C Virus E2 Epitope 412-422
Authors: Sandomenico Annamaria , Leonardi Antonio , Berisio Rita , Sanguigno Luca , Focà Giuseppina , Focà Annalia , Ruggiero Alessia , Doti Nunzianna , Muscariello Livio , Barone Daniela , Farina Claudio , Owsianka Ania , Vitagliano Luigi , Patel Arvind H. , Ruvo Menotti
Published: January 2016

The hepatitis C virus (HCV) E2 envelope glycoprotein is crucial for virus entry into hepatocytes. A conserved region of E2 encompassing amino acids 412 to 423 (epitope I) and containing Trp420, a residue critical for virus entry, is recognized by several broadly neutralizing antibodies. Peptides embodying this epitope I sequence adopt a β-hairpin conformation when bound to neutralizing monoclonal antibodies (MAbs) AP33 and HCV1. We therefore generated new mouse MAbs that were able to bind to a cyclic peptide containing E2 residues 412 to 422 (C-epitope I) but not to the linear counterpart. These MAbs bound to purified E2 with affinities of about 50 nM, but they were unable to neutralize virus infection. Structural analysis of the complex between C-epitope I and one of our MAbs (C2) showed that the Trp420 side chain is largely buried in the combining site and that the Asn417 side chain, which is glycosylated in E2 and solvent exposed in other complexes, is slightly buried upon C2 binding. Also, the orientation of the cyclic peptide in the antibody-combining site is rotated by 180° compared to the orientations of the other complexes. All these structural features, however, do not explain the lack of neutralization activity. This is instead ascribed to the high degree of selectivity of the new MAbs for the cyclic epitope and to their inability to interact with the epitope in more flexible and extended conformations, which recent data suggest play a role in the mechanisms of neutralization escape.

IMPORTANCEHepatitis C virus (HCV) remains a major health care burden, affecting almost 3% of the global population. The conserved epitope comprising residues 412 to 423 of the viral E2 glycoprotein is a valid vaccine candidate because antibodies recognizing this region exhibit potent neutralizing activity. This epitope adopts a β-hairpin conformation when bound to neutralizing MAbs. We explored the potential of cyclic peptides mimicking this structure to elicit anti-HCV antibodies. MAbs that specifically recognize a cyclic variant of the epitope bind to soluble E2 with a lower affinity than other blocking antibodies and do not neutralize virus. The structure of the complex between one such MAb and the cyclic epitope, together with new structural data showing the linear peptide bound to neutralizing MAbs in extended conformations, suggests that the epitope displays a conformational flexibility that contributes to neutralization escape. Such features can be of major importance for the design of epitope-based anti-HCV vaccines.
Human Cytomegalovirus pTRS1 and pIRS1 Antagonize Protein Kinase R To Facilitate Virus Replication
Authors: Ziehr Benjamin , Vincent Heather A. , Moorman Nathaniel J.
Published: January 2016

Human cytomegalovirus (HCMV) counteracts host defenses that otherwise act to limit viral protein synthesis. One such defense is the antiviral kinase protein kinase R (PKR), which inactivates the eukaryotic initiation factor 2 (eIF2) translation initiation factor upon binding to viral double-stranded RNAs. Previously, the viral TRS1 and IRS1 proteins were found to antagonize the antiviral kinase PKR outside the context of HCMV infection, and the expression of either pTRS1 or pIRS1 was shown to be necessary for HCMV replication. In this study, we found that expression of either pTRS1 or pIRS1 is necessary to prevent PKR activation during HCMV infection and that antagonism of PKR is critical for efficient viral replication. Consistent with a previous study, we observed decreased overall levels of protein synthesis, reduced viral protein expression, and diminished virus replication in the absence of both pTRS1 and pIRS1. In addition, both PKR and eIF2α were phosphorylated during infection when pTRS1 and pIRS1 were absent. We also found that expression of pTRS1 was both necessary and sufficient to prevent stress granule formation in response to eIF2α phosphorylation. Depletion of PKR prevented eIF2α phosphorylation, rescued HCMV replication and protein synthesis, and reversed the accumulation of stress granules in infected cells. Infection with an HCMV mutant lacking the pTRS1 PKR binding domain resulted in PKR activation, suggesting that pTRS1 inhibits PKR through a direct interaction. Together our results show that antagonism of PKR by HCMV pTRS1 and pIRS1 is critical for viral protein expression and efficient HCMV replication.

IMPORTANCE
To successfully replicate, viruses must counteract host defenses that limit viral protein synthesis. We have identified inhibition of the antiviral kinase PKR by the viral proteins TRS1 and IRS1 and shown that this is a critical step in HCMV replication. Our results suggest that inhibiting pTRS1 and pIRS1 function or restoring PKR activity during infection may be a successful strategy to limit HCMV disease.
A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly Neutralizing Monoclonal Antibodies
Authors: Wasilewski Lisa N. , El-Diwany Ramy , Munshaw Supriya , Snider Anna E. , Brady Jillian K. , Osburn William O. , Ray Stuart C. , Bailey Justin R.
Published: January 2016

Hepatitis C virus (HCV) infection is a global health problem, with millions of chronically infected individuals at risk for cirrhosis and hepatocellular carcinoma. HCV vaccine development is vital in the effort toward disease control and eradication, an undertaking aided by an increased understanding of the mechanisms of resistance to broadly neutralizing antibodies (bNAbs). In this study, we identified HCV codons that vary deep in a phylogenetic tree of HCV sequences and showed that a polymorphism at one of these positions renders Bole1a, a computationally derived, ancestral genotype 1a HCV strain, resistant to neutralization by both polyclonal-HCV-infected plasma and multiple broadly neutralizing monoclonal antibodies with unique binding epitopes. This bNAb resistance mutation reduces replicative fitness, which may explain the persistence of both neutralization-sensitive and neutralization-resistant variants in circulating viral strains. This work identifies an important determinant of bNAb resistance in an ancestral, representative HCV genome, which may inform HCV vaccine development.

IMPORTANCE
Worldwide, more than 170 million people are infected with hepatitis C virus (HCV), the leading cause of hepatocellular carcinoma and liver transplantation in the United States. Despite recent significant advances in HCV treatment, a vaccine is needed. Control of the HCV pandemic with drug treatment alone is likely to fail due to limited access to treatment, reinfections in high-risk individuals, and the potential for resistance to direct-acting antivirals (DAAs). Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV variants and therefore serve as a useful guide for vaccine development, but our understanding of resistance to bNAbs is incomplete. In this report, we identify a viral polymorphism conferring resistance to neutralization by both polyclonal plasma and broadly neutralizing monoclonal antibodies, which may inform HCV vaccine development.
Multiple sclerosis in a postgraduate student of anaesthesia: illness in doctors and fitness to practice
Authors: Reyes Antonio Jose , Ramcharan Kanterpersad , Sharma Sharda
Published: January 2016

A 29-year-old previously healthy woman, a doctor, was diagnosed with remitting relapsing multiple sclerosis after fulfilling McDonald's criteria for the diagnosis of definite multiple sclerosis. Despite 22 months of immunomodulatory treatment, the feasibility of continuing to train in a stressful specialty of medicine became an ethical and practical dilemma. Fitness for practice and career advancement among doctors with illnesses or having cognitive and physical decline from disease and/or ageing is a global problem. The need for addressing this issue in a compassionate and comprehensive manner is discussed. Cognitive and physical fitness are required in doctors and other healthcare workers since medical errors/adverse events are commonplace in medical practice. The public welfare is equally important in this global problem.
Assessing herd immunity against rubella in Japan: a retrospective seroepidemiological analysis of age-dependent transmission dynamics
Authors: Kinoshita Ryo , Nishiura Hiroshi
Published: January 2016

Objective

We aimed to epidemiologically assess rubella herd immunity as a function of time, age and gender in Japan, with reference to the recent 2012–2014 rubella epidemic.

Design

This study is a retrospective seroepidemiological analysis.

Main outcome measures

The susceptible fraction of the population was examined as a function of age and time. The age at infection was assessed using reported case data.

Results

Whereas 30 years ago rubella cases were seen only among children, the median (25–75th centiles) age of cases in 2014 was elevated to 32.0 (17.0–42.0) years among males and 27.0 (7.0–37.0) years among females. Susceptible pockets among male birth cohorts 1989–1993 and 1974–1978 were identified, with seropositive proportions of 70.0% and 68.0%, respectively. The majority of female age groups had greater seropositive proportions than the herd immunity threshold, with a minor susceptible pocket for those born from 1989 to 1993 (78.3% seropositive). The age-standardised seronegative proportion decreased to 18.3% (95% CI 16.8% to 19.8%) among males and 15.6% (95% CI 10.0% to 21.2%) among females in 2013, and the immune fraction was not sufficiently below the herd immunity threshold. While the number of live births born to susceptible mothers in 1983 was estimated at 171 876 across Japan, in 2013 it was reduced to 23 698.

Conclusions

An elevated age at rubella virus infection and the presence of susceptible pockets among adults were observed in Japan. Although, overall, the absolute number of rubella cases has steadily declined in Japan, the elevated age of rubella cases, along with increased numbers of susceptible adults, contributed to the observation of as many as 45 congenital rubella syndrome (CRS) cases, which calls for supplementary vaccination among susceptible adults. Assessing herd immunity is considered essential for routinely monitoring the risk of future rubella epidemics and CRS cases.
A study protocol for a randomised controlled trial evaluating clinical effects of platelet transfusion products: the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) trial
Authors: Ypma Paula F , van der Meer Pieter F , Heddle Nancy M , van Hilten Joost A , Stijnen Theo , Middelburg Rutger A , Hervig Tor , van der Bom Johanna G , Brand Anneke , Kerkhoffs Jean-Louis H
Published: January 2016

Introduction

Patients with chemotherapy-induced thrombocytopaenia frequently experience minor and sometimes severe bleeding complications. Unrestrictive availability of safe and effective blood products is presumed by treating physicians as well as patients. Pathogen reduction technology potentially offers the opportunity to enhance safety by reducing bacterial and viral contamination of platelet products along with a potential reduction of alloimmunisation in patients receiving multiple platelet transfusions.

Methods and analysis

To test efficacy, a randomised, single-blinded, multicentre controlled trial was designed to evaluate clinical non-inferiority of pathogen-reduced platelet concentrates treated by the Mirasol system, compared with standard plasma-stored platelet concentrates using the percentage of patients with WHO grade ≥2 bleeding complications as the primary endpoint. The upper limit of the 95% CI of the non-inferiority margin was chosen to be a ≤12.5% increase in this percentage. Bleeding symptoms are actively monitored on a daily basis. The adjudication of the bleeding grade is performed by 3 adjudicators, blinded to the platelet product randomisation as well as by an automated computer algorithm. Interim analyses evaluating bleeding complications as well as serious adverse events are performed after each batch of 60 patients. The study started in 2010 and patients will be enrolled up to a maximum of 618 patients, depending on the results of consecutive interim analyses. A flexible stopping rule was designed allowing stopping for non-inferiority or futility. Besides analysing effects of pathogen reduction on clinical efficacy, the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) is designed to answer several other pending questions and translational issues related to bleeding and alloimmunisation, formulated as secondary and tertiary endpoints.

Ethics and dissemination

Ethics approval was obtained in all 3 participating countries. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Trial registration number

NTR2106; Pre-results.
Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention
Authors: Bayman N , Ardron D , Ashcroft L , Baldwin D R , Booton R , Darlison L , Edwards J G , Lang-Lazdunski L , Lester J F , Peake M , Rintoul R C , Snee M , Taylor P , Lunt C , Faivre-Finn C
Published: January 2016

Introduction

Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure—a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development.

Methods and analysis

In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year.

Ethics and dissemination

PIT was approved by NRES Committee North West—Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018.

Trial registration number

ISRCTN04240319;NCT01604005; Pre-results.
Evidence of increasing public participation in advance care planning: a comparison of polls in Alberta between 2007 and 2013
Authors: Simon J E , Ghosh S , Heyland D , Cooke T , Davison S , Holroyd-Leduc J , Wasylenko E , Howlett J , Fassbender K
Published: January 2016

Background

Advance care planning (ACP) encompasses both verbal and written communications expressing preferences for future health and personal care and helps prepare people for healthcare decision-making in times of medical crisis. Healthcare systems are increasingly promoting ACP as a way to inform medical decision-making, but it is not clear how public engagement in ACP activities is changing over time.

Methods

Raw data from 3 independently conducted public polls on ACP engagement, in the same Canadian province, were analysed to assess whether participation in ACP activities changed over 6 years.

Results

Statistically significant increases were observed between 2007 and 2013 in: recognising the definition of ACP (54.8% to 80.3%, OR 3.37 (95% CI 2.68 to 4.24)), discussions about healthcare preferences with family (48.4% to 59.8%, OR 1.41 (95% CI 1.17 to 1.69)) and with healthcare providers (9.1% to 17.4%, OR 1.98 (95% CI 1.51 to 2.59)), written ACP plans (21% to 34.6%, OR 1.77 (95% CI 1.45 to 2.17)) and legal documentation (23.4% to 42.7%, OR 2.13 (95% CI 1.75 to 2.59)). These remained significant after adjusting for age, education and self-rated health status.

Conclusions

ACP engagement increased over time, although the overall frequency remains low in certain elements such as discussing ACP with healthcare providers. We discuss factors that may be responsible for the increase and provide suggestions for healthcare systems or other public bodies seeking to stimulate engagement in ACP.
Thalamic mediation of hypoxic respiratory depression in lambs
Authors: Koos Brian J. , Rajaee Arezoo , Ibe Basil , Guerra Catalina , Kruger Lawrence
Published: January 2016

Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53–80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development.
Vibrotactile stimulation of fast-adapting cutaneous afferents from the foot modulates proprioception at the ankle joint
Authors: Mildren Robyn L. , Bent Leah R.
Published: January 2016

It has previously been shown that cutaneous sensory input from across a broad region of skin can influence proprioception at joints of the hand. The present experiment tested whether cutaneous input from different skin regions across the foot can influence proprioception at the ankle joint. The ability to passively match ankle joint position (17° and 7° plantar flexion and 7° dorsiflexion) was measured while cutaneous vibration was applied to the sole (heel, distal metatarsals) or dorsum of the target foot. Vibration was applied at two different frequencies to preferentially activate Meissner's corpuscles (45 Hz, 80 μm) or Pacinian corpuscles (255 Hz, 10 μm) at amplitudes ∼3 dB above mean perceptual thresholds. Results indicated that cutaneous input from all skin regions across the foot could influence joint-matching error and variability, although the strongest effects were observed with heel vibration. Furthermore, the influence of cutaneous input from each region was modulated by joint angle; in general, vibration had a limited effect on matching in dorsiflexion compared with matching in plantar flexion. Unlike previous results in the upper limb, we found no evidence that Pacinian input exerted a stronger influence on proprioception compared with Meissner input. Findings from this study suggest that fast-adapting cutaneous input from the foot modulates proprioception at the ankle joint in a passive joint-matching task. These results indicate that there is interplay between tactile and proprioceptive signals originating from the foot and ankle.
Adaptive reliance on the most stable sensory predictions enhances perceptual feature extraction of moving stimuli
Authors: Kumar Neeraj , Mutha Pratik K.
Published: January 2016

The prediction of the sensory outcomes of action is thought to be useful for distinguishing self- vs. externally generated sensations, correcting movements when sensory feedback is delayed, and learning predictive models for motor behavior. Here, we show that aspects of another fundamental function—perception—are enhanced when they entail the contribution of predicted sensory outcomes and that this enhancement relies on the adaptive use of the most stable predictions available. We combined a motor-learning paradigm that imposes new sensory predictions with a dynamic visual search task to first show that perceptual feature extraction of a moving stimulus is poorer when it is based on sensory feedback that is misaligned with those predictions. This was possible because our novel experimental design allowed us to override the “natural” sensory predictions present when any action is performed and separately examine the influence of these two sources on perceptual feature extraction. We then show that if the new predictions induced via motor learning are unreliable, rather than just relying on sensory information for perceptual judgments, as is conventionally thought, then subjects adaptively transition to using other stable sensory predictions to maintain greater accuracy in their perceptual judgments. Finally, we show that when sensory predictions are not modified at all, these judgments are sharper when subjects combine their natural predictions with sensory feedback. Collectively, our results highlight the crucial contribution of sensory predictions to perception and also suggest that the brain intelligently integrates the most stable predictions available with sensory information to maintain high fidelity in perceptual decisions.
Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimer’s Diseases
Authors: Wang Jing , Jackson Michael F. , Xie Yu-Feng
Published: January 2016

Synaptic plasticity refers to the ability of neurons to strengthen or weaken synaptic efficacy in response to activity and is the basis for learning and memory. Glial cells communicate with neurons and in this way contribute in part to plasticity in the CNS and to the pathology of Alzheimer’s disease (AD), a neurodegenerative disease in which impaired synaptic plasticity is causally implicated. The transient receptor potential melastatin member 2 (TRPM2) channel is a nonselective Ca2+-permeable channel expressed in both glial cells (microglia and astrocytes) and neurons. Recent studies indicated that TRPM2 regulates synaptic plasticity as well as the activation of glial cells. TRPM2 also modulates oxidative stress and inflammation through interaction with glial cells. As both oxidative stress and inflammation have been implicated in AD pathology, this suggests a possible contribution of TRPM2 to disease processes. Through modulating the homeostasis of glutathione, TRPM2 is involved in the process of aging which is a risk factor of AD. These results potentially point TRPM2 channel to be involved in AD through glial cells. This review summarizes recent advances in studying the contribution of TRPM2 in health and in AD pathology, with a focus on contributions via glia cells.
Restoration of the Ellipsoid Zone and Visual Prognosis at 1 Year after Surgical Macular Hole Closure
Authors: Hasebe Hiruma , Matsuoka Naoki , Terashima Hiroko , Sasaki Ryo , Ueda Eriko , Fukuchi Takeo
Published: January 2016

Purpose. To evaluate the restoration of the ellipsoid zone (EZ) and its influence on visual prognosis 1 year after surgical macular hole (MH) closure.Method. Subjects were patients with stage 2, 3, or 4 idiopathic MH who underwent primary vitrectomy that resulted in successful hole closure. Nineteen eyes with both EZ disruption with foveal detachment and a continuous external limiting membrane on optical coherence tomography during the early postoperative period were included in this study.Result. EZ disruption was restored in 10 eyes (53%, Group A) and remained in 9 eyes (47%, Group B) at 1 year after surgery. In Group B, the diameter of the residual EZ disruption was54.7±33.1 μm. LogMAR visual acuity (VA) 1 year after surgery was significantly better than preoperative VA in each group (Group A:-0.007±0.102;P<0.001; Group B:0.051±0.148;P<0.001), but there was no significant difference between the 2 groups (P=0.332). There was no significant correlation between logMAR VA and EZ disruption diameter at 1 year after surgery.Conclusion. EZ was restored in 53% of eyes at 1 year after surgical closure of idiopathic MH. Mean residual EZ disruption diameter was54.7±33.1 μm. Neither resolved nor residual EZ disruption influenced postoperative VA.
The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer’s Disease
Authors: Habtemariam Solomon
Published: January 2016

Rosemary (Rosmarinus officinalis L.) is one of the most economically important species of the family Lamiaceae. Native to the Mediterranean region, the plant is now widely distributed all over the world mainly due to its culinary, medicinal, and commercial uses including in the fragrance and food industries. Among the most important group of compounds isolated from the plant are the abietane‐type phenolic diterpenes that account for most of the antioxidant and many pharmacological activities of the plant. Rosemary diterpenes have also been shown in recent years to inhibit neuronal cell death induced by a variety of agents both in vitro and in vivo. The therapeutic potential of these compounds for Alzheimer’s disease (AD) is reviewed in this communication by giving special attention to the chemistry of the compounds along with the various pharmacological targets of the disease. The multifunctional nature of the compounds from the general antioxidant‐mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (Aβ) formation, polymerisation, and pathologies is discussed.