bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR2‐dependent amelioration of allergic airway inflammation by parasitic nematode type II MIF in mice
Authors: Cho M. K. , Park M. K. , Kang S. A. , Park S. K. , Lyu J. H. , Kim D.‐H. , Park H.‐K. , Yu H. S. 
Published: January 2015

SummaryIn our previous studies, the recombinant type II macrophage migration inhibitory factor homologue (rAs‐MIF) secreted from Anisakis simplex suppressed experimental inflammation mouse model through IL‐10 production and CD4+CD25+Foxp3+ T‐cell recruitment. Also, TLR2 gene expression was significantly increased following rAs‐MIF treatment. To know the relation between TLR2 and amelioration mechanisms of rAs‐MIF, we induced allergic airway inflammation by ovalbumin and alum with or without rAs‐MIF under TLR2 blocking systems [anti‐TLR2‐specific antibody (α‐mTLR2 Ab) treatment and using TLR2 knockout mice]. As a result, the amelioration effects of rAs‐MIF in allergic airway inflammation model (diminished inflammation and Th2 response in the lung, increased IL‐10 secretion, CD4+CD25+Foxp3+ T‐cell recruitment) were diminished under two of the TLR2 blocking model. The expression of TLR2 on the surface of lung epithelial cell was significantly elevated by rAs‐MIF treatment or Pam3CSK (TLR2‐specific agonist) treatment, but they might have some competition effect on the elevation of TLR2 expression. In addition, the elevation of IL‐10 gene expression by rAs‐MIF treatment was significantly inhibited by α‐mTLR2 Ab or Pam3CSK pretreatment. In conclusion, anti‐inflammatory effects of the rAs‐MIF on OVA‐induced allergic airway inflammation might be closely related to TLR2.
The Scientific Revolution—The Kidney and Nephrology in and about the Seventeenth Century (Part 1)
Authors: Eknoyan Garabed 
Published: January 2015

AbstractIn the history of the evolution of the medical sciences, it is in the 17th century that the conscious, deliberate, and systematic study of the workings of the human body began. It was a product of the radical changing attitudes of this insurgent century when mathematical reasoning and mechanistic philosophy replaced the teleological outlook of earlier times. It was then that meticulous observation, reproducible quantification, experimental validation, and mathematical exactitude in the quest for truths launched the Scientific Revolution. The effect on medicine was a transformative change from a descriptive to an explanatory body of knowledge during the course of which rigorous anatomical dissections were used for the mechanical explanation of organ function, when morbid changes observed at postmortem began to be related to clinical features of disease, and when the secretive analytical methods of alchemy began to be refined for the study of chemical changes in living matter. Essentially what began with meticulous observations of anatomical features begat physiology and laid the foundations of pathology and chemistry. As a result, studies of organ structure, function, and changes in disease in general, and of the kidney in particular, were clarified and progressed at a rate never achieved theretofore.
Gender‐typing of leadership: Evaluations of real and ideal managers
Authors: Cuadrado Isabel , García‐Ael Cristina , Molero Fernando 
Published: January 2015

This research focuses on female underrepresentation in managerial positions. Specifically, two studies examine gender‐typing for managerial roles in Spain using ratings for real and ideal managers. In addition, we analyse the existence of same‐gender bias on evaluations of the behavior of actual leaders. In the first study, 195 Spanish workers evaluate the extent to which gender‐stereotypical traits are important for becoming a successful middle manager in three conditions (female managers, male managers, and managers in general). In the second study, we explore the degree to which the behavior of real Spanish managers is gender‐typed and the existence of same‐gender bias on leadership styles – transformational, transactional and avoidant/passive – and on leadership outcomes – effectiveness, extra effort and satisfaction – from the perspective of subordinates (N = 605). Overall, the results demonstrate that masculine characteristics were rated as more important than feminine characteristics for managerial positions, and they were more often assigned to male managers than to female managers. Unexpectedly, this manager‐male association is stronger among female participants than among male participants. Our findings also demonstrate that women subordinates evaluate their same‐sex supervisors more favorably in transformational leadership, effectiveness, and extra effort. The negative consequences derived from gender‐typing managerial positions are highlighted according to the role congruity theory of prejudice toward female leaders. The positive effects of in‐group female bias on behavior ratings are also noted. The mixed implications of these results for women's advancement to leadership positions are discussed.
The role of antimicrobials in the treatment of sepsis and critical illness‐related bacterial infections: Examination of the evidence
Authors: Keir Iain , Dickinson Amy E. 
Published: January 2015

AbstractObjectiveTo appraise the evidence behind the Surviving Sepsis Campaign Guidelines on antimicrobial therapy in sepsis and evaluate relevant literature in small animal veterinary critical care.Data SourceElectronic searches using MEDLINE and EMBASE databases.Human Data SynthesisCurrent recommendations are to administer appropriate antimicrobials within 1 hour of a diagnosis of severe sepsis or septic shock. Evidence is supportive of this recommendation in septic shock but the evidence is less compelling in milder forms of critical illness‐related infections. It is unclear when the administration of appropriate antimicrobials is most beneficial and when it should be considered essential. Evidence supports shorter courses of antimicrobial therapy for many infections seen in the critical care unit with the biomarkers procalcitonin and C‐reactive protein helpful in guiding the duration of therapy.Veterinary Data SynthesisCurrent evidence is lacking to support the use of early and aggressive use of antimicrobials in all patients with critical illness‐related bacterial infections. Two studies failed to demonstrate improved survival in patients with pulmonary or abdominal infections administered appropriate vs inappropriate empirical antimicrobials. One study failed to show an improved survival when dogs with abdominal infections were administered antimicrobials within 1 hour vs 6 hours of diagnosis of infection. Information regarding ideal duration of antimicrobial therapy and use of biomarkers to guide therapy is currently lacking.ConclusionClinicians should aim to administer early and appropriate antimicrobials; however, the impact this will have on patient outcome remains uncertain. The ability to administer early and appropriate antimicrobials may be considered a measure of the quality of medical practice rather than a prognostic indicator.
Self-Report Versus Direct Measurement for Assessment of Fluid Intake During a 70.3-Mile Triathlon
Authors: Wilson Patrick B. , Rhodes Gregory S. , Ingraham Stacy J. 
Published: January 2015

Purpose:Self-report (SR) has been the primary method used to assess fluid intake during endurance events, but unfortunately, little is known about the validity of SR. The purpose of this study was to compare SR fluid intake with direct measurement (DM) during a 70.3-mile triathlon.Methods:Fifty-three (42 men, 11 women) individuals competing in a 70.3-mile triathlon participated in the study. On the 13.1-mile-run section of the triathlon, 11 research stations provided fluid in bottles filled with 163 mL of water or carbohydrate-electrolyte beverage (CEB). Participants submitted bottles 25 m past aid stations to be reweighed postrace. Participants also answered questions regarding fluid intake postrace. Bland-Altman plots and 95% limits of agreement were used to assess precision of the measures, while least-squares regression assessed linear agreement.Results:SR intakes during the run ranged from 0–1793, 0–1837, and 0–2628 mL for water, CEB, and total fluid, with corresponding DM intakes of 0–1599, 0–1642, and 0–2250 mL. DM and SR showed strong linear agreement for water, CEB, and total fluid (R2 = .71, .80, and .80). Mean differences between the measures on the Bland-Altman plots were small (13–41 mL), but relatively large differences (±500 mL) between the measures were apparent for some participants.Conclusions:SR is the predominant methodology used in field studies assessing hydration, despite little to no data confirming its validity. The results herein suggest that fluid-intake-assessment methodology should be chosen on a case-by-case basis and that caution should be used when interpreting data based on SR.
Comparison of Transcutaneous Electrical Nerve Stimulation and Cryotherapy for Increasing Quadriceps Activation in Patients With Knee Pathologies
Authors: Gabler Conrad M. , Lepley Adam S. , Uhl Tim L. , Mattacola Carl G. 
Published: January 2015

Clinical Scenario:Proper neuromuscular activation of the quadriceps muscle is essential for maintaining quadriceps (quad) strength and lower-extremity function. Quad activation (QA) failure is a common characteristic observed in patients with knee pathologies, defined as an inability to voluntarily activate the entire alpha-motor-neuron pool innervating the quad. One of the more popular techniques used to assess QA is the superimposed burst (SIB) technique, a force-based technique that uses a supramaximal, percutaneous electrical stimulation to activate all of the motor units in the quad during a maximal, voluntary isometric contraction. Central activation ratio (CAR) is the formula used to calculate QA level (CAR = voluntary force/SIB force) with the SIB technique. People who can voluntarily activate 95% or more (CAR = 0.95–1.0) of their motor units are defined as being fully activated. Therapeutic exercises aimed at improving quad strength in patients with knee pathologies are limited in their effectiveness due to a failure to fully activate the muscle. Within the past decade, several disinhibitory interventions have been introduced to treat QA failure in patients with knee pathologies. Transcutaneous electrical nerve stimulation (TENS) and cryotherapy are sensory-targeted modalities traditionally used to treat pain, but they have been shown to be 2 of the most successful treatments for increasing QA levels in patients with QA failure. Both modalities are hypothesized to positively affect voluntary QA by disinhibiting the motor-neuron pool of the quad. In essence, these modalities provide excitatory afferent stimuli to the spinal cord, which thereby overrides the inhibitory afferent signaling that arises from the involved joint. However, it remains unknown whether 1 is more effective than the other for restoring QA levels in patients with knee pathologies. By knowing the capabilities of each disinhibitory modality, clinicians can tailor treatments based on the rehabilitation goals of their patients.Focused Clinical Question:Is TENS or cryotherapy the more effective disinhibitory modality for treating QA failure (quantified via CAR) in patients with knee pathologies?
Development of a Mouse-Adapted Live Attenuated Influenza Virus That PermitsIn VivoAnalysis of Enhancements to the Safety of Live Attenuated Influenza Virus Vaccine
Authors: Cox Andrew , Baker Steven F. , Nogales Aitor , Martínez-Sobrido Luis , Dewhurst Stephen 
Published: January 2015

ABSTRACTThe live attenuated influenza virus vaccine (LAIV) is preferentially recommended for use in persons 2 through 49 years of age but has not been approved for children under 2 or asthmatics due to safety concerns. Therefore, increasing safety is desirable. Here we describe a murine LAIV with reduced pathogenicity that retains lethality at high doses and further demonstrate that we can enhance safetyin vivothrough mutations within NS1. This model may permit preliminary safety analysis of improved LAIVs.
Serine Phosphorylation of the Hepatitis C Virus NS5A Protein Controls the Establishment of Replication Complexes
Authors: Ross-Thriepland Douglas , Mankouri Jamel , Harris Mark 
Published: January 2015

ABSTRACT
The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is highly phosphorylated and involved in both virus genome replication and virion assembly. We and others have identified serine 225 in NS5A to be a phosphorylation site, but the function of this posttranslational modification in the virus life cycle remains obscure. Here we describe the phenotype of mutants with mutations at serine 225; this residue was mutated to either alanine (S225A; phosphoablatant) or aspartic acid (S225D; phosphomimetic) in the context of both the JFH-1 cell culture infectious virus and a corresponding subgenomic replicon. The S225A mutant exhibited a 10-fold reduction in genome replication, whereas the S225D mutant replicated like the wild type. By confocal microscopy, we show that, in the case of the S225A mutant, the replication phenotype correlated with an altered subcellular distribution of NS5A. This phenotype was shared by viruses with other mutations in the low-complexity sequence I (LCS I), namely, S229D, S232A, and S235D, but not by viruses with mutations that caused a comparable replication defect that mapped to domain II of NS5A (P315A, L321A). Together with other components of the genome replication complex (NS3, double-stranded RNA, and cellular lipids, including phosphatidylinositol 4-phosphate), the mutation in NS5A was restricted to a perinuclear region. This phenotype was not due to cell confluence or another environmental factor and could be partially transcomplemented by wild-type NS5A. We propose that serine phosphorylation within LCS I may regulate the assembly of an active genome replication complex.

IMPORTANCE
The mechanisms by which hepatitis C virus replicates its RNA genome remain poorly characterized. We show here that phosphorylation of the viral nonstructural protein NS5A at serine residues is important for the efficient assembly of a complex that is able to replicate the viral genome. This research implicates cellular protein kinases in the control of virus replication and highlights the need to further understand the interplay between the virus and the host cell in order to develop potential avenues for future antiviral therapy.
Heterosubtypic Antibodies to Influenza A Virus Have Limited Activity against Cell-Bound Virus but Are Not Impaired by Strain-Specific Serum Antibodies
Authors: Wyrzucki Arkadiusz , Bianchi Matteo , Kohler Ines , Steck Marco , Hangartner Lars 
Published: January 2015

ABSTRACT
The majority of influenza virus-specific antibodies elicited by vaccination or natural infection are effective only against the eliciting or closely related viruses. Rare stem-specific heterosubtypic monoclonal antibodies (hMAbs) can neutralize multiple strains and subtypes by preventing hemagglutinin (HA)-mediated fusion of the viral membrane with the endosomal membrane. The epitopes recognized by these hMAbs are therefore considered promising targets for the development of pan-influenza virus vaccines. Here, we report the isolation of a novel human HA stem-reactive monoclonal antibody, hMAb 1.12, with exceptionally broad neutralizing activity encompassing viruses from 15 distinct HA subtypes. Using MAb 1.12 and two other monoclonal antibodies, we demonstrate that neutralization by hMAbs is virtually irreversible but becomes severely impaired following virus attachment to cells. In contrast, no interference by human anti-influenza virus serum antibodies was found, indicating that apically binding antibodies do not impair access to the membrane-proximal heterosubtypic epitopes. Our findings therefore encourage development of new vaccine concepts aiming at the induction of stem-specific heterosubtypic antibodies, as we provide support for their effectiveness in individuals previously exposed to influenza virus.

IMPORTANCE
The influenza A virus hemagglutinin (HA) can easily accommodate changes in its antigenic structures to escape preexisting immunity. This variability restricts the breadth and long-term efficacy of influenza vaccines. Only a few heterosubtypic antibodies (hMAbs), i.e., antibodies that can neutralize more than one subtype of influenza A virus, have been identified. The molecular interactions between these heterosubtypic antibodies and hemagglutinin are well characterized, yet little is known about the functional properties of these antibodies. Using a new, extraordinarily broad hMAb, we show that virus neutralization by hMAbs is virtually irreversible and that efficient neutralization is possible only if stem-specific hMAbs bind to HA before the virus attaches to the cell surface. No interference between strain-specific human serum immunoglobulin and hMAbs was found, indicating that preexisting humoral immunity to influenza virus does not limit the efficacy of stem-reactive heterosubtypic antibodies. This knowledge supports the development of a pan-influenza virus vaccine.
Efficient Virus Assembly, but Not Infectivity, Determines the Magnitude of Hepatitis C Virus-Induced Interferon Alpha Responses of Plasmacytoid Dendritic Cells
Authors: Grabski Elena , Wappler Ilka , Pfaender Stephanie , Steinmann Eike , Haid Sibylle , Dzionek Andrzej , Pietschmann Thomas , Kalinke Ulrich 
Published: January 2015

ABSTRACT
Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV.

IMPORTANCE
Although pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses.
Heat Shock Protein 70 Regulates Degradation of the Mumps Virus Phosphoprotein via the Ubiquitin-Proteasome Pathway
Authors: Katoh Hiroshi , Kubota Toru , Kita Shunsuke , Nakatsu Yuichiro , Aoki Natsuko , Mori Yoshio , Maenaka Katsumi , Takeda Makoto , Kidokoro Minoru 
Published: January 2015

ABSTRACT
Mumps virus (MuV) infection induces formation of cytoplasmic inclusion bodies (IBs). Growing evidence indicates that IBs are the sites where RNA viruses synthesize their viral RNA. However, in the case of MuV infection, little is known about the viral and cellular compositions and biological functions of the IBs. In this study, pulldown purification and N-terminal amino acid sequencing revealed that stress-inducible heat shock protein 70 (Hsp72) was a binding partner of MuV phosphoprotein (P protein), which was an essential component of the IB formation. Immunofluorescence and immunoblotting analyses revealed that Hsp72 was colocalized with the P protein in the IBs, and its expression was increased during MuV infection. Knockdown of Hsp72 using small interfering RNAs (siRNAs) had little, if any, effect on viral propagation in cultured cells. Knockdown of Hsp72 caused accumulation of ubiquitinated P protein and delayed P protein degradation. These results show that Hsp72 is recruited to IBs and regulates the degradation of MuV P protein through the ubiquitin-proteasome pathway.

IMPORTANCE
Formation of cytoplasmic inclusion bodies (IBs) is a common characteristic feature in mononegavirus infections. IBs are considered to be the sites of viral RNA replication and transcription. However, there have been few studies focused on host factors recruited to the IBs and their biological functions. Here, we identified stress-inducible heat shock protein 70 (Hsp72) as the first cellular partner of mumps virus (MuV) phosphoprotein (P protein), which is an essential component of the IBs and is involved in viral RNA replication/transcription. We found that the Hsp72 mobilized to the IBs promoted degradation of the MuV P protein through the ubiquitin-proteasome pathway. Our data provide new insight into the role played by IBs in mononegavirus infection.