bluuebunny/crossref_metadata_2025 huggingface dataset:
Rheo-optical response of carbon nanotube suspensions
Authors: Natale G. , Reddy N. K. , Ausias G. , Férec J. , Heuzey M. C. , Carreau P. J.
Published: February 2015

In this work, the rheo-optical response of multiwalled carbon nanotube (MWCNT) suspensions was analyzed. Dichroism was obtained using a polarization-modulation technique in parallel disks and for the first time for these particles in a Couette flow geometry. MWCNTs were dispersed in a Newtonian epoxy matrix, at different concentrations covering the dilute and semidilute regimes. Measurements of dichroism were performed as functions of shear rate and nanotube concentration. Surprisingly, the ultimate average orientation angle with respect to the flow direction was far from zero degree, even at high Peclet (Pe) numbers in very dilute suspensions. To explain this peculiar behavior, a new model for flexible rods, valid in the dilute regime, is proposed. It is based on the development of Strautins and Latz [Rheol. Acta 46, 1057–1064 (2007)] that considers flexible rods made of beads and connectors. We modified their bending potential that allows only straight rods at equilibrium with a harmonic cosine expression. This simple modification changes drastically the behavior of these flexible particles that exhibit a non-negligible orientation in the vorticity direction under steady state.
Alterations in Whole-Body Insulin Sensitivity Resulting From Repeated Eccentric Exercise of a Single Muscle Group: A Pilot Investigation
Authors: Gonzalez Javier T. , Barwood Martin J. , Goodall Stuart , Thomas Kevin , Howatson Glyn
Published: February 2015

Unaccustomed eccentric exercise using large muscle groups elicits soreness, decrements in physical function and impairs markers of whole-body insulin sensitivity; although these effects are attenuated with a repeated exposure. Eccentric exercise of a small muscle group (elbow flexors) displays similar soreness and damage profiles in response to repeated exposure. However, it is unknown whether damage to small muscle groups impacts upon whole-body insulin sensitivity. This pilot investigation aimed to characterize whole-body insulin sensitivity in response to repeated bouts of eccentric exercise of the elbow flexors. Nine healthy males completed two bouts of eccentric exercise separated by 2 weeks. Insulin resistance (updated homeostasis model of insulin resistance, HOMA2-IR) and muscle damage profiles (soreness and physical function) were assessed before, and 48 h after exercise. Matsuda insulin sensitivity indices (ISIMatsuda) were also determined in 6 participants at the same time points as HOMA2-IR. Soreness was elevated, and physical function impaired, by both bouts of exercise (both p < .05) but to a lesser extent following bout 2 (time x bout interaction, p < .05). Eccentric exercise decreased ISIMatsuda after the first but not the second bout of eccentric exercise (time x bout interaction p < .05). Eccentric exercise performed with an isolated upper limb impairs whole-body insulin sensitivity after the first, but not the second, bout.
Long-Term Correlates of Objectively Measured Physical Activity and Sedentary Time in Norwegian Men and Women
Authors: Solbraa Ane Kristiansen , Ekelund Ulf , Holme Ingar M. , Graff-Iversen Sidsel , Steene-Johannessen Jostein , Aadland Eivind , Anderssen Sigmund Alfred
Published: February 2015

Background:

Sex, age, body mass index (BMI), perceived health and health behavior are correlates known to affect physical activity and sedentary time. However, studies have often been cross-sectional, and less is known about long-term correlates. Thus, the aims were to investigate 1) the associations between a set of characteristics (demographic, biological, psychological, and behavioral) and objectively measured physical activity and sedentary time at 13-year follow-up, and 2) the association between changes in these characteristics over time and physical activity and sedentary time.

Methods:

Baseline characteristics were collected in 40-year-olds in 1996, and follow-up data on objectively measured physical activity and sedentary time were obtained in 2009 (n = 240). Data were analyzed by multiple linear regressions.

Results:

Self-reported physical activity (P < .001) and improved perceived health (P = .046) were positively associated with moderate-to-vigorous physical activity (MVPA) whereas BMI (P = .034) and increased BMI (P = .014) were negatively associated with MVPA at follow-up. Women spent less time being sedentary than men (P = .019). Education (P < .001) was positively associated and improved perceived health (P = .010) was negatively associated with sedentary time at follow-up.

Conclusions:

MVPA and sedentary time at follow-up were associated with behavioral, biological and demographic correlates. However, the nature of our analyses prevents us from inferring causality.
Social Media Scholarship in Sport Management Research: A Critical Review
Authors: Abeza Gashaw , O’Reilly Norm , Séguin Benoit , Nzindukiyimana Ornella
Published: February 2015

This work critically assesses the history and current state of social media scholarship in sport management research. Methodologically, the study is based on a comprehensive census review of the current body of literature in the area of social media. The review identifies 123 social media articles in sport management research that were mined from a cross-disciplinary examination of 29 scholarly journals from January 2008 (earliest found) to June 2014. The work identifies the topic areas, the platforms, the theories, and the research methods that have received the (most/least) attention of the social media research community, and provides suggestions for future research.
Dental Occlusion Influences the Standing Balance on an Unstable Platform
Authors: Julià-Sánchez Sonia , Álvarez-Herms Jesús , Gatterer Hannes , Burtscher Martin , Pagès Teresa , Viscor Ginés
Published: February 2015

Contradictory results are still reported on the influence of dental occlusion on the balance control. We attempted to determine whether there are differences in balance between opposed dental occlusion (Intercuspal position (ICP)/“Cotton rolls” mandibular position [CR]) for two extreme levels of stability (stable/unstable). Twenty-five subjects were monitored under both dental occlusion and level of stability conditions using an unstable platform Balance System SD. The resulting stability index suggests that body balance is significantly better when dental occlusion is set in CR (p < .001) in unstable but not in stable conditions. Occlusal traits significantly influencing postural control were Angle Class (p < .001), crowding (p = .006), midline deviation (p < .001), crossbite (p < .001), anterior open bite (p = .05), and overjet (p = .01). It could be concluded that the sensory information linked to the dental occlusion for the balance control comes strongly into effect in unstable conditions.
Movement Adjustments Have Short Latencies Because There is No Need to Detect Anything
Authors: Smeets Jeroen B.J. , Wijdenes Leonie Oostwoud , Brenner Eli
Published: February 2015

We can adjust an ongoing movement to a change in the target’s position with a latency of about 100 ms, about half of the time that is needed to start a new movement in response to the same change in target position (reaction time). In this opinion paper, we discuss factors that could explain the difference in latency between initiating and adjusting a movement in response to target displacements. We consider the latency to be the sum of the durations of various stages in information processing. Many of these stages are identical for adjusting and initiating a movement; however, for movement initiation, it is essential to detect that something has changed to respond, whereas adjustments to movements can be based on updated position information without detecting that the position has changed. This explanation for the shorter latency for movement adjustments also explains why we can respond to changes that we do not detect.
Light-induced superconductivity using a photoactive electric double layer
Authors: Suda Masayuki , Kato Reizo , Yamamoto Hiroshi M.
Published: February 2015

Light switch for superconductivity

The conducting properties of materials sensitively depend on the available carrier concentration. Physicists can vary this concentration by inducing carriers in the material; for example, by placing it next to an ionic liquid in an electric field. Suda
et al.
instead used a layer of the molecule spiropyran, which changes from a non-ionic to an ionic form when it is irradiated by ultraviolet (UV) light. The authors placed the layer on top of a thin crystal of an organic material. When they shone UV light on the spiropyran, the adjacent material became superconducting, thanks to the carriers induced at the interface.

Science
, this issue p.
743
China's lakes of pig manure spawn antibiotic resistance
Authors: Larson Christina
Published: February 2015

Researchers begin to size up a public health threat from burgeoning pork production.
Stories from the heart
The Man Who Touched His Own Heart
True Tales of Science, Surgery, and Mystery
Rob Dunn
Little, Brown, 2015. 384 pp.
Authors: Nusinovich Yevgeniya
Published: February 2015

A history of cardiac research and therapies
Tying up a transcription factor
Authors: Chen Andrew , Koehler Angela N.
Published: February 2015

A bivalent small molecule inhibits the activity of a rogue transcription factor in leukemia

[Also see Report by

Illendula
et al.

]
Immune Responses of Bison and Efficacy after Booster Vaccination with Brucella abortus Strain RB51
Authors: Olsen S. C. , McGill J. L. , Sacco R. E. , Hennager S. G.
Published: February 2015

Thirty-one bison heifers were randomly assigned to receive saline or a single vaccination with 1010CFU ofBrucella abortusstrain RB51. Some vaccinated bison were randomly selected for booster vaccination with RB51 at 11 months after the initial vaccination. Mean antibody responses to RB51 were greater (P< 0.05) in vaccinated bison after initial and booster vaccination than in nonvaccinated bison. The proliferative responses by peripheral blood mononuclear cells (PBMC) from the vaccinated bison were greater (P< 0.05) than those in the nonvaccinated bison at 16 and 24 weeks after the initial vaccination but not after the booster vaccination. The relative gene expression of gamma interferon (IFN-γ) was increased (P< 0.05) in the RB51-vaccinated bison at 8, 16, and 24 weeks after the initial vaccination and at 8 weeks after the booster vaccination. The vaccinated bison had greater (P< 0.05)in vitroproduction of IFN-γ at all sampling times, greater interleukin-1β (IL-1β) production in various samplings after the initial and booster vaccinations, and greater IL-6 production at one sampling time after the booster vaccination. Between 170 and 180 days of gestation, the bison were intraconjunctivally challenged with approximately 1 × 107CFU ofB. abortusstrain 2308. The incidences of abortion and infection were greater (P< 0.05) in the nonvaccinated bison after experimental challenge than in the bison receiving either vaccination treatment. Booster-vaccinated, but not single-vaccinated bison, had a reduced (P< 0.05) incidence of infection in fetal tissues and maternal tissues compared to that in the controls. Compared to the nonvaccinated bison, both vaccination treatments lowered the colonization (measured as the CFU/g of tissue) ofBrucellaorganisms in all tissues, except in retropharyngeal and supramammary lymph nodes. Our study suggests that RB51 booster vaccination is an effective vaccination strategy for enhancing herd immunity against brucellosis in bison.
Genomic Insights of Pectobacterium carotovorum Strain M022 Quorum-Sensing Activity through Whole-Genome Sequencing
Authors: Chan Kok-Gan , Tan Wen-Si
Published: February 2015

Pectobacterium carotovorum
is known to cause serious damage to various major crops worldwide. Here, we report the draft genome of
Pectobacterium carotovorum
strain M022, a freshwater isolate from a Malaysian waterfall, which has been reported as a plant pathogen and is able to communicate with
N
-acylhomoserine lactone-mediated quorum sensing.
Genome Sequence of the AIDS-Associated Pathogen Penicillium marneffei (ATCC18224) and Its Near Taxonomic Relative Talaromyces stipitatus (ATCC10500)
Authors: Nierman William C. , Fedorova-Abrams Natalie D. , Andrianopoulos Alex
Published: February 2015

Penicillium marneffei can cause a fatal systemic mycosis in patients infected with the HIV. Infections are endemic in the tropical regions of southeast Asia. Here, we report the genome sequences of the type strains of P. marneffei and its avirulent near relative, Talaromyces stipitatus.
A17, the First Sequenced Strain of Lactococcus lactis subsp. cremoris with Potential Immunomodulatory Functions
Authors: Yang Chih-Hsien , Wu Chien-Chen , Cheng Wei-Shen , Chung Ming-Chuan , Tsai Ying-Chieh , Chang Chuan-Hsiung
Published: February 2015

Lactococcus lactis
subsp. cremoris A17, isolated from Taiwan fermented cabbage, is the first sequenced strain of
L. lactis
subsp. cremoris with immunomodulatory activity and antiallergic functions. The resulting A17 draft genome contains 2,679,936 bp and indicates that A17 is a potential exopolysaccharide-producing strain without any known virulence gene.
Draft Genome of Janthinobacterium sp. RA13 Isolated from Lake Washington Sediment
Authors: McTaggart Tami L. , Shapiro Nicole , Woyke Tanja , Chistoserdova Ludmila
Published: February 2015

Sequencing the genome of Janthinobacterium sp. RA13 from Lake Washington sediment is announced. From the genome content, a versatile life-style is predicted, but not
bona fide
methylotrophy. With the availability of its genomic sequence, Janthinobacterium sp. RA13 presents a prospective model for studying microbial communities in lake sediments.
Variola Virus-Specific Diagnostic Assays: Characterization, Sensitivity, and Specificity
Authors: Kondas Ashley V. , Olson Victoria A. , Li Yu , Abel Jason , Laker Miriam , Rose Laura , Wilkins Kimberly , Turner Jonathan , Kline Richard , Damon Inger K.
Published: February 2015

A public health response relies upon rapid and reliable confirmation of disease by diagnostic assays. Here, we detail the design and validation of two variola virus-specific real-time PCR assays, since previous assays cross-reacted with newly identified cowpox viruses. The assay specificity must continually be reassessed as other closely related viruses are identified.
An Anti-H5N1 Influenza Virus FcDART Antibody Is a Highly Efficacious Therapeutic Agent and Prophylactic against H5N1 Influenza Virus Infection
Authors: Zanin Mark , Keck Zhen-Yong , Rainey G. Jonah , Lam Chia-Ying Kao , Boon Adrianus C. M. , Rubrum Adam , Darnell Daniel , Wong Sook-San , Griffin Yolanda , Xia Jinming , Webster Robert G. , Webby Richard , Johnson Syd , Foung Steven
Published: February 2015

Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. While vaccines are available, other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. To produce a therapeutic agent that is highly efficacious at low doses and is broadly specific against antigenically drifted H5N1 influenza viruses, we developed two neutralizing monoclonal antibodies and combined them into a single bispecific Fc fusion protein (the Fc dual-affinity retargeting [FcDART] molecule). In mice, a single therapeutic or prophylactic dose of either monoclonal antibody at 2.5 mg/kg of body weight provided 100% protection against challenge with A/Vietnam/1203/04 (H5N1) or the antigenically drifted strain A/Whooper swan/Mongolia/244/05 (H5N1). In ferrets, a single 1-mg/kg prophylactic dose provided 100% protection against A/Vietnam/1203/04 challenge. FcDART was also effective, as a single 2.5-mg/kg therapeutic or prophylactic dose in mice provided 100% protection against A/Vietnam/1203/04 challenge. Antibodies bound to conformational epitopes in antigenic sites on the globular head of the hemagglutinin protein, on the basis of analysis of mutants with antibody escape mutations. While it was possible to generate escape mutants
in vitro
, they were neutralized by the antibodies
in vivo
, as mice infected with escape mutants were 100% protected after only a single therapeutic dose of the antibody used to generate the escape mutant
in vitro
. In summary, we have combined the antigen specificities of two highly efficacious anti-H5N1 influenza virus antibodies into a bispecific FcDART molecule, which represents a strategy to produce broadly neutralizing antibodies that are effective against antigenically diverse influenza viruses.

IMPORTANCE
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and are a pandemic threat. A vaccine is available, but other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. The variability of the virus means that such an approach must be broad spectrum. To achieve this, we developed two antibodies that neutralize H5N1 influenza viruses. In mice, these antibodies provided complete protection against a spectrum of H5N1 influenza viruses at a single low dose. We then combined the two antibodies into a single molecule, FcDART, which combined the broad-spectrum activity and protective efficacy of both antibodies. This treatment provides a novel and effective therapeutic agent or prophylactic with activity against highly pathogenic H5N1 avian influenza viruses.
Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication
Authors: Shanmugam Saravanabalaji , Saravanabalaji Dhanaranjani , Yi MinKyung
Published: February 2015

Previously, we demonstrated that the efficiency of hepatitis C virus (HCV) E2-p7 processing regulates p7-dependent NS2 localization to putative virus assembly sites near lipid droplets (LD). In this study, we have employed subcellular fractionations and membrane flotation assays to demonstrate that NS2 associates with detergent-resistant membranes (DRM) in a p7-dependent manner. However, p7 likely plays an indirect role in this process, since only the background level of p7 was detectable in the DRM fractions. Our data also suggest that the p7-NS2 precursor is not involved in NS2 recruitment to the DRM, despite its apparent targeting to this location. Deletion of NS2 specifically inhibited E2 localization to the DRM, indicating that NS2 regulates this process. Treatment of cells with methyl-β-cyclodextrin (MβCD) significantly reduced the DRM association of Core, NS2, and E2 and reduced infectious HCV production. Since disruption of the DRM localization of NS2 and E2, either due to p7 and NS2 defects, respectively, or by MβCD treatment, inhibited infectious HCV production, these proteins' associations with the DRM likely play an important role during HCV assembly. Interestingly, we detected the HCV replication-dependent accumulation of ApoE in the DRM fractions. Taking into consideration the facts that ApoE was shown to be a major determinant for infectious HCV particle production at the postenvelopment step and that the HCV Core protein strongly associates with the DRM, recruitment of E2 and ApoE to the DRM may allow the efficient coordination of Core particle envelopment and postenvelopment events at the DRM to generate infectious HCV production.

IMPORTANCE
The biochemical nature of HCV assembly sites is currently unknown. In this study, we investigated the correlation between NS2 and E2 localization to the detergent-resistant membranes (DRM) and HCV particle assembly. We determined that although NS2's DRM localization is dependent on p7, p7 was not targeted to these membranes. We then showed that NS2 regulates E2 localization to the DRM, consistent with its role in recruiting E2 to the virus assembly sites. We also showed that short-term treatment with the cholesterol-extracting agent methyl-β-cyclodextrin (MβCD) not only disrupted the DRM localization of Core, NS2, and E2 but also specifically inhibited intracellular virus assembly without affecting HCV RNA replication. Thus, our data support the role of the DRM as a platform for particle assembly process.
Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169
+
Macrophage Function during Viral Infection
Authors: Xu Haifeng C. , Huang Jun , Khairnar Vishal , Duhan Vikas , Pandyra Aleksandra A. , Grusdat Melanie , Shinde Prashant , McIlwain David R. , Maney Sathish Kumar , Gommerman Jennifer , Löhning Max , Ohashi Pamela S. , Mak Tak W. , Pieper Kathrin , Sic Heiko , Speletas Matthaios , Eibel Hermann , Ware Carl F. , Tumanov Alexei V. , Kruglov Andrey A. , Nedospasov Sergei A. , Häussinger Dieter , Recher Mike , Lang Karl S. , Lang Philipp A.
Published: February 2015

The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169
+
macrophage compartment. Consequently,
Baffr
−

/

−
mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in
Baffr
−

/

−
animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169
+
cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.

IMPORTANCE
Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169
+
macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.
Regulation and Function of Phosphorylation on VP8, the Major Tegument Protein of Bovine Herpesvirus 1
Authors: Zhang Kuan , Afroz Sharmin , Brownlie Robert , Snider Marlene , van Drunen Littel-van den Hurk Sylvia
Published: February 2015

The major tegument protein of bovine herpesvirus 1 (BoHV-1), VP8, is essential for virus replication in cattle. VP8 is phosphorylated
in vitro
by casein kinase 2 (CK2) and BoHV-1 unique short protein 3 (U
S
3). In this study, VP8 was found to be phosphorylated in both transfected and infected cells but was detected as a nonphosphorylated form in mature virions. This suggests that phosphorylation of VP8 is strictly controlled during different stages of the viral life cycle. The regulation and function of VP8 phosphorylation by U
S
3 and CK2 were further analyzed. An
in vitro
kinase assay, site-directed mutagenesis, and liquid chromatography-mass spectrometry were used to identify the active sites for U
S
3 and CK2. The two kinases phosphorylate VP8 at different sites, resulting in distinct phosphopeptide patterns. S
16
is a primary phosphoreceptor for U
S
3, and it subsequently triggers phosphorylation at S
32
. CK2 has multiple active sites, among which T
107
appears to be the preferred residue. Additionally, CK2 consensus motifs in the N terminus of VP8 are essential for phosphorylation. Based on these results, a nonphosphorylated VP8 mutant was constructed and used for further studies. In transfected cells phosphorylation was not required for nuclear localization of VP8. Phosphorylated VP8 appeared to recruit promyelocytic leukemia (PML) protein and to remodel the distribution of PML in the nucleus; however, PML protein did not show an association with nonphosphorylated VP8. This suggests that VP8 plays a role in resisting PML-related host antiviral defenses by redistributing PML protein and that this function depends on the phosphorylation of VP8.

IMPORTANCE
The progression of VP8 phosphorylation over time and its function in BoHV-1 replication have not been characterized. This study demonstrates that activation of S
16
initiates further phosphorylation at S
32
by U
S
3. Additionally, VP8 is phosphorylated by CK2 at several residues, with T
107
having the highest level of phosphorylation. Evidence for a difference in the phosphorylation status of VP8 in host cells and mature virus is presented for the first time. Phosphorylation was found to be a critical modification, which enables VP8 to attract and to redistribute PML protein in the nucleus. This might promote viral replication through interference with a PML-mediated antiviral defense. This study provides new insights into the regulation of VP8 phosphorylation and suggests a novel, phosphorylation-dependent function for VP8 in the life cycle of BoHV-1, which is important in view of the fact that VP8 is essential for virus replication
in vivo
.
Dimerization of Matrix Protein Is Required for Budding of Respiratory Syncytial Virus
Authors: Förster Andreas , Maertens Goedele N. , Farrell Paul J. , Bajorek Monika
Published: February 2015

Respiratory syncytial virus (RSV) infects epithelial cells of the respiratory tract and is a major cause of bronchiolitis and pneumonia in children and the elderly. The virus assembles and buds through the plasma membrane, forming elongated membrane filaments, but details of how this happens remain obscure. Oligomerization of the matrix protein (M) is a key step in the process of assembly and infectious virus production. In addition, it was suggested to affect the conformation of the fusion protein, the major current target for RSV antivirals, in the mature virus. The structure and assembly of M are thus key parameters in the RSV antiviral development strategy. The structure of RSV M was previously published as a monomer. Other paramyxovirus M proteins have been shown to dimerize, and biochemical data suggest that RSV M also dimerizes. Here, using size exclusion chromatography-multiangle laser light scattering, we show that the protein is dimeric in solution. We also crystallized M in two crystal forms and show that it assembles into equivalent dimers in both lattices. Dimerization interface mutations destabilize the M dimer
in vitro
. To assess the biological relevance of dimerization, we used confocal imaging to show that dimerization interface mutants of M fail to assemble into viral filaments on the plasma membrane. Additionally, budding and release of virus-like particles are prevented in M mutants that fail to form filaments. Importantly, we show that M is biologically active as a dimer and that the switch from M dimers to higher-order oligomers triggers viral filament assembly and virus production.

IMPORTANCE
Human respiratory syncytial virus (RSV) is the most frequent cause of infantile bronchiolitis and pneumonia. The enormous burden of RSV makes it a major unmet target for a vaccine and antiviral drug therapy. Oligomerization of the matrix protein is a key step in the process of assembly and production of infectious virus, but the molecular mechanism of RSV assembly is still poorly understood. Here we show that the RSV matrix protein forms dimers in solution and in crystals; the dimer is essential for formation of higher-order oligomers. Destabilizing the dimer interface resulted in the loss of RSV filament formation and a lack of budding of virus-like particles. Importantly, our findings can potentially lead to new structure-based RSV inhibitors targeting the assembly process.
Monoclonal Antibodies against Extracellular Domains of Claudin-1 Block Hepatitis C Virus Infection in a Mouse Model
Authors: Fukasawa Masayoshi , Nagase Shotaro , Shirasago Yoshitaka , Iida Manami , Yamashita Mayo , Endo Kohki , Yagi Kiyohito , Suzuki Tetsuro , Wakita Takaji , Hanada Kentaro , Kuniyasu Hiroki , Kondoh Masuo
Published: February 2015

Hepatitis C virus (HCV) entry into host cells is a complex process requiring multiple host factors, including claudin-1 (CLDN1). Safe and effective therapeutic entry inhibitors need to be developed. We isolated a human hepatic Huh7.5.1-derived cell mutant that is nonpermissive to HCV, and comparative microarray analysis showed that the mutant was CLDN1 defective. Four hybridomas were obtained, which produced monoclonal antibodies (MAbs) that interacted with the parental Huh7.5.1 cell but not with the CLDN1-defective mutant. All MAbs produced by these hybridomas specifically bound to human CLDN1 with a very high affinity and prevented HCV infection of Huh7.5.1 cells in a dose-dependent manner, without apparent cytotoxicity. Two selected MAbs also inhibited HCV infection of human liver-chimeric mice without significant adverse effects. CLDN1 may be a potential target to prevent HCV infection
in vivo
. Anti-CLDN1 MAbs may hence be promising candidates as novel anti-HCV agents.

IMPORTANCE
Safe and effective therapeutic entry inhibitors against hepatitis C virus (HCV) are very useful for combination therapies with other anti-HCV drugs, such as direct-acting antivirals. In this study, we first showed an effective strategy for developing functional monoclonal antibodies (MAbs) against extracellular domains of a multimembrane-spanning target protein, claudin-1 (CLDN1), by using parental cells expressing the intact target membrane protein and target-defective cells. The established MAbs against CLDN1, which had a very high affinity for intact CLDN1, efficiently inhibited
in vitro
and
in vivo
HCV infections. These anti-CLDN1 MAbs are promising leads for novel entry inhibitors against HCV.
HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes
Authors: Cardone Marco , Ikeda Kyojiro N. , Varano Barbara , Gessani Sandra , Conti Lucia
Published: February 2015

The interplay between dendritic cells (DC) and γδ T lymphocytes represents a network of paracrine and cell contact interactions important for an integrated immune response to pathogens. HIV-1 infection dramatically affects the number and functions of both cell populations, and DC/γδ T cell cross talk may represent a target of virus-induced immune escape. We investigated whether HIV-exposed DC could deliver aberrant signals to interacting γδ T cells. Here we report that the interaction of human γδ T lymphocytes with HIV-1-exposed autologous monocyte-derived DC, but not direct exposure to the virus, impairs lymphocyte expansion and gamma interferon (IFN-γ) production in response to phosphoantigens. This effect is independent of virus strain and occurred in 55% of the donors analyzed. The donor-dependent variation observed relies on the responsiveness of DC to HIV-1 and is strictly related to the capacity of the virus to suppress the maturation-induced expression of interleukin 12 (IL-12). In fact, γδ T cell response to phosphoantigens is almost completely recovered when this cytokine is exogenously added to the DC/lymphocyte cocultures. Interestingly, we show that γδ T lymphocytes are recruited by HIV-1-exposed DC through a CCR5-mediated mechanism and exert a CCL4-mediated control on virus dissemination within DC and susceptible CD4+T lymphocytes. These results demonstrate an association between HIV-induced DC dysfunction and alterations of γδ T cell responses. The aberrant cross talk between these two cell populations may contribute to the pathogenesis of HIV infection by further reducing the strength of antiviral immune response.

IMPORTANCEThis study provides new evidence on the mechanisms exploited by HIV-1 to evade the host immune response. We report that HIV-1 impairs the cross talk between DC and γδ T lymphocytes, by reducing the capacity of DC to promote functional γδ T cell activation. Interestingly, the virus does notper seinterfere with γδ T cell activation, thus highlighting the key role of early DC–HIV-1 interaction in this phenomenon. Furthermore, the results obtained unravel the novel role of γδ T cells in controlling HIV-1 dissemination within the DC population as well as virus transfer to susceptible CD4+T lymphocytes. The interactions of DC with innate lymphocytes represent a major control mechanism for an integrated immune response to infection. Understanding how HIV-1 harnesses these pathways may provide important insights on the pathogenesis of disease and offer new opportunities for therapeutic interventions.
Complete resolution of the symptoms of refractory Osgood-Schlatter disease following percutaneous fixation of the tibial tuberosity
Authors: Narayan Nitisha , Mitchell Piers D , Latimer Mark David
Published: February 2015

Osgood-Schlatter disease is a common cause of anterior knee pain in adolescents. In a good proportion of cases the pain is relieved through stopping sport alone, or by doing so in conjunction with undertaking physiotherapy. However, resolution of symptoms may take several years. A proportion of teenagers are prevented from participating in sport for a prolonged period as a result of the condition, and some have persisting knee pain into adulthood. We report the use of a new surgical treatment for this disease. We describe the case of a 12-year-old boy who was unable to play rugby for a year due to this pain. Following percutaneous fixation of the tibial tuberosity his symptoms entirely resolved and he returned to competitive sport 6 weeks after surgery. A year later the screw was removed. As soon as he resumed sport his symptoms immediately returned and he requested that the screw be replaced. Following replacement his symptoms once more resolved.
Altered mental status: what is the diagnosis?
Authors: Gupta Arjun , Shelton William , Singh Rajeev , Pandey Ambarish
Published: February 2015

We report a patient presenting with a 2-day history of altered mental status and lethargy. She had recently started taking prednisone for suspected ‘autoimmune arthritis’. Clinical deterioration in hospital characterised by increasing confusion, alternating hyperarousal and somnolence, auditory hallucinations and eventual unresponsiveness led to an intensive care unit transfer. Initial laboratory and radiological testing did not reveal a cause for her symptoms. The only abnormality detected was antithyroid peroxidase antibody levels elevated to >900 IU/mL with patient demonstrating marked clinical improvement within 24 h of receiving high-dose steroids and plasmapheresis. Hashimoto's encephalitis is an underdiagnosed reversible neuropsychiatric disorder with unknown pathogenesis. Recent studies indicate that autoimmune encephalopathy and specifically Hashimoto's encephalitis is under-reported. Our case demonstrates the importance of maintaining a wide differential for altered mental status, especially after negative initial diagnostic work-up of more common aetiologies. Although steroids are an effective treatment for Hashimoto's encephalitis, the addition of early plasmapheresis may be indicated in patients with severe presentation and those who develop disease while taking steroids.
Hip osteoarthritis: patients with complex comorbidities can make exceptional improvements following intensive exercise and education
Authors: Wainwright Thomas William , Immins Tikki , Middleton Robert Gordon
Published: February 2015

A 71-year-old man presenting with hip osteoarthritis, with a complex range of comorbidities was referred by his general practitioner to CHAIN (Cycling against Hip PAIN), a 6 week programme developed to aid self-management of hip osteoarthritis through exercise, education and advice, as defined by the National Institute for Health and Care Excellence (NICE) guidelines. Significant improvements were seen in Oxford hip score, the Hip disability and Osteoarthritis Outcome Score (HOOS) – function score, sit-to-stand test, timed up and go test, pain scores and hip flexion. There was also a weight loss of 2.1 kg. The man reported ‘an amazing difference’ in his affected hip and leg, and improved fitness. Many clinicians would have questioned the man's suitability for the programme due to his coexisting medical conditions. This case study shows that patients may be much more able than we think to achieve significant improvement with exercise.
Diagnostic accuracy of ultrasonography, MRI and MR arthrography in the characterisation of rotator cuff disorders: a systematic review and meta-analysis
Authors: Roy Jean-Sébastien , Braën Caroline , Leblond Jean , Desmeules François , Dionne Clermont E , MacDermid Joy C , Bureau Nathalie J , Frémont Pierre
Published: February 2015

Background

Different diagnostic imaging modalities, such as ultrasonography (US), MRI, MR arthrography (MRA) are commonly used for the characterisation of rotator cuff (RC) disorders. Since the most recent systematic reviews on medical imaging, multiple diagnostic studies have been published, most using more advanced technological characteristics. The first objective was to perform a meta-analysis on the diagnostic accuracy of medical imaging for characterisation of RC disorders. Since US is used at the point of care in environments such as sports medicine, a secondary analysis assessed accuracy by radiologists and non-radiologists.

Methods

A systematic search in three databases was conducted. Two raters performed data extraction and evaluation of risk of bias independently, and agreement was achieved by consensus. Hierarchical summary receiver-operating characteristic package was used to calculate pooled estimates of included diagnostic studies.

Results

Diagnostic accuracy of US, MRI and MRA in the characterisation of full-thickness RC tears was high with overall estimates of sensitivity and specificity over 0.90. As for partial RC tears and tendinopathy, overall estimates of specificity were also high (>0.90), while sensitivity was lower (0.67–0.83). Diagnostic accuracy of US was similar whether a trained radiologist, sonographer or orthopaedist performed it.

Conclusions

Our results show the diagnostic accuracy of US, MRI and MRA in the characterisation of full-thickness RC tears. Since full thickness tear constitutes a key consideration for surgical repair, this is an important characteristic when selecting an imaging modality for RC disorder. When considering accuracy, cost, and safety, US is the best option.
Incidence and fatality of serious suicide attempts in a predominantly rural population in Shandong, China: a public health surveillance study
Authors: Sun Jiandong , Guo Xiaolei , Zhang Jiyu , Wang Mei , Jia Cunxian , Xu Aiqiang
Published: February 2015

Objectives

To estimate the incidence of serious suicide attempts (SSAs, defined as suicide attempts resulting in either death or hospitalisation) and to examine factors associated with fatality among these attempters.

Design

A surveillance study of incidence and mortality. Linked data from two public health surveillance systems were analysed.

Setting

Three selected counties in Shandong, China.

Participants

All residents in the three selected counties.

Outcome measures

Incidence rate (per 100 000 person-years) and case fatality rate (%).

Methods

Records of suicide deaths and hospitalisations that occurred among residents in selected counties during 2009–2011 (5 623 323 person-years) were extracted from electronic databases of the Disease Surveillance Points (DSP) system and the Injury Surveillance System (ISS) and were linked by name, sex, residence and time of suicide attempt. A multiple logistic regression model was developed to examine the factors associated with a higher or lower fatality rate.

Results

The incidence of SSAs was estimated to be 46 (95% CI 44 to 48) per 100 000 person-years, which was 1.5 times higher in rural versus urban areas, slightly higher among females, and increased with age. Among all SSAs, 51% were hospitalised and survived, 9% were hospitalised but later died and 40% died with no hospitalisation. Most suicide deaths (81%) were not hospitalised and most hospitalised SSAs (85%) survived. The fatality rate was 49% overall, but was significantly higher among attempters living in rural areas, who were male, older, with lower education or with a farming occupation. With regard to the method of suicide, fatality was lowest for non-pesticide poisons (7%) and highest for hanging (97%).

Conclusions

The incidence of serious suicide attempts is substantially higher in rural areas than in urban areas of China. The risk of death is influenced by the attempter's sex, age, education level, occupation, method used and season of year.
A tool to improve communication in the neonatal unit
Authors: van de Vijver Margot , Evans Mari
Published: February 2015

Frequent and sensitive communication from neonatal staff is important to alleviate parental stress and to ensure that parents understand their baby's condition and progress. It also consequently empowers and involves parents in their baby's care. A lack of regular and informative communication from neonatal staff is a common reason for parental complaint. We sought to assess whether the implementation of a baby diary used as a communication tool would improve parent-staff communication and optimise the parental experience of neonatal care.

In this study, parents and carers of babies on our neonatal unit were invited to complete a questionnaire to assess their level of satisfaction with communication by neonatal staff before and after the implementation of the diaries. The diary was designed to act as an aid to improve communication to parents about their baby and thereby complementing face-to face communication and encouraging parental involvement.

The study design was a retrospective parental satisfaction questionnaire based on the Department of Health [1] and the National Institute for Health and Care Excellence (NICE) [2] quality standards for specialist neonatal care on communication and parental involvement (n=44, response rate 57%). Following implementation of the diary, the questionnaire was repeated on two occasions: one month post implementation (n=17, response rate 23%) and 15 months post implementation (n=44, response rate 65%).

More parents in the post-intervention cohort felt they were receiving regular communication from staff, that their questions and concerns were being addressed, and felt involved in their baby's care than in the pre-intervention cohort. In addition, 100% of parents said they liked reading the diary and 94% felt it added to their understanding of how their baby was doing.

Our project demonstrates an improvement in parents' satisfaction with communication from neonatal staff following the implementation of individual baby diaries. The diary is a simple, practical, and cost-effective tool to enhance communication between parents and staff in a neonatal unit.
Out of hours intravenous fluid therapy: a prompt to guide prescribing
Authors: Fehmi Janev , Carpenter Alexander , Townsend Matthew , Sheppeard Rhian , Gannon Elizabeth , Hewitson Lynsey , Auerbach Natalie , Thomas Katherine
Published: February 2015

Recent NICE guidance has highlighted the importance of appropriate and safe intravenous fluid use. We aimed to improve the quality of out of hours fluid prescription in a Bristol hospital by ensuring that indications and cautions for fluid therapy were clearly documented at the time of initiation.

Time-pressured on-call doctors need quick access to information regarding patients’ care. A documented “fluid plan” allows doctors to undertake a more informed assessment of the patient's fluid balance, leading to safer prescriptions.

Our ideal was for 100% of out of hours intravenous fluid prescriptions to be appropriate. Our process measures included the proportion of patients on intravenous fluids who had a documented fluid plan in the medical notes or on the prescription chart on Friday, prior to the weekend on call period. This was defined as mention of indications and/or cautions to fluid therapy.

The introduction of a sticker to prompt fluid plan documentation did marginally improve use of fluid plans. It was notable that 96% of these were followed where plans were documented (n=23). Initiation of IV fluid with an accompanying plan is likely to make subsequent fluid prescriptions safer.

Rapid turnover of staff and stationary proved significant barriers to consistent implementation of the sticker. Despite these challenges we demonstrated a “proof of concept”, suggesting system modification to include fluid plans is safe and effective.
The endoscopy safety checklist: A longitudinal study of factors affecting compliance in a tertiary referral centre within the United Kingdom
Authors: Matharoo Manmeet , Sevdalis Nick , Thillai Muhunthan , Bouri Sonia , Marjot Thomas , Haycock Adam , Thomas-Gibson Siwan
Published: February 2015

Gastrointestinal endoscopy is a widely used diagnostic and therapeutic procedure both within the United Kingdom and worldwide. With an increasingly older population the potential for complications is increased. The Wolfson Unit for Endoscopy at St. Mark’s Hospital in London is a tertiary referral centre, which conducts over 14,000 endoscopic procedures annually. However, despite this high throughput, our baseline observations were that the procedure for safety checks was highly variable.

Over a seven-day period we conducted a questionnaire-based survey to all staff members involved with endoscopy within our unit. We found that there was little consensus between team members, both in terms of essential safety checks and designating responsibility for the checks. A panel of experts was convened in order to devise a safety checklist and a strategy for increasing compliance with the checklist among all staff members. Using a combination of electronic and physical reminders and incentives, we found that there was a significant increase in completed checklist (53% to 66%, p = 0.021) and decrease in the number of checklists left blank post intervention (10% to 2%, p=0.03). We believe that post implementation validation of safety checklists is an important method to ensure their proper use.