bluuebunny/crossref_metadata_2025_split huggingface dataset:
Faster cross‐bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation
Authors: Witjas‐Paalberends E. Rosalie , Ferrara Claudia , Scellini Beatrice , Piroddi Nicoletta , Montag Judith , Tesi Chiara , Stienen Ger J. M. , Michels Michelle , Ho Carolyn Y. , Kraft Theresia , Poggesi Corrado , van der Velden Jolanda 
Published: June 2014

Key points
The R403Q mutation, located in the S1 domain of the β‐myosin heavy chain, is associated with a severe phenotype of hypertrophic cardiomyopathy (HCM).
Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of sarcomeric tension generation; however, direct evidence is absent.
We studied the relationship between cross‐bridge kinetics and energetics in single cardiac myofibrils and multicellular cardiac muscle strips in human HCM tissue with and without the R403Q mutation.
In human HCM with the R403Q mutation, cross‐bridge relaxation was faster and correlated well with a rise in energetic cost of tension generation.
Our data suggest that an increase in tension cost is one of the causes underlying cardiomyopathy development in patients with the R403Q mutation.
AbstractThe first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β‐myosin heavy chain (β‐MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross‐bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation‐negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross‐bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s−1, respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l–1 s−1 kN−1 m−2, respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross‐bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation.
Comparative Analysis of the Capacity of Elite Suppressor CD4
+
and CD8
+
T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages
Authors: Walker-Sperling Victoria E. K. , Buckheit Robert W. , Blankson Joel N. 
Published: June 2014

ABSTRACT

Elite controllers or suppressors (ESs) are HIV-1-infected individuals who are able to maintain viral loads below the limit of detection of clinical assays without antiretroviral therapy. The mechanisms of virologic control are not fully understood, but ESs have been shown to have a more effective CD8
+
T cell response to infected CD4
+
T cells than chronic progressors (CPs). While macrophages are another cell type productively infected by HIV-1, few studies have examined the ability of primary effector T cells to suppress HIV-1 replication in these target cells. Here, we compared the ability of unstimulated primary CD4
+
and CD8
+
effector T cells to suppress viral replication in monocyte-derived macrophages (MDMs) in ESs and CPs. While CD4
+
effector T cells were capable of inhibiting viral replication in MDMs, the magnitude of this response was not significantly different between ESs and CPs. In contrast, the CD8
+
T cells from ESs were significantly more effective than those from CPs at inhibiting viral replication in MDMs. The CD4
+
T cell response was partially mediated by soluble factors, while the CD8
+
T cell response required cell-to-cell interaction. Our results suggest that the individual contributions of various effector cells should be considered in rational vaccine design and in ongoing eradication efforts.

IMPORTANCE
Elite suppressors are individuals capable of maintaining low-level viremia in HIV-1 infection without antiretroviral drugs. Their T cell responses have been implicated in eliminating infected CD4
+
T cells, and as such, elite suppressors may represent a model of a functional cure of HIV-1 infection. Here, we sought to determine whether the suppressive T cell responses against infected CD4
+
T cells also apply to infected macrophages by comparing the responses of elite suppressors and HIV-1-positive individuals on highly active antiretroviral therapy (HAART). Our results show that the CD8
+
cells but not CD4
+
T cells from elite suppressors have a response against infected macrophages superior to the response of CD8
+
cells from patients on HAART. Our results suggest that the induction of a CD8
+
T cell response effective against infected macrophages is an outcome to consider in rational vaccine design.
Interaction Patterns betweenPotato Virus Yand eIF4E-Mediated Recessive Resistance in the Solanaceae
Authors: Moury Benoît , Janzac Bérenger , Ruellan Youna , Simon Vincent , Ben Khalifa Mekki , Fakhfakh Hatem , Fabre Frédéric , Palloix Alain 
Published: June 2014

ABSTRACTThe structural pattern of infectivity matrices, which contains infection data resulting from inoculations of a set of hosts by a set of parasites, is a key parameter for our understanding of biological interactions and their evolution. This pattern determines the evolution of parasite pathogenicity and host resistance, the spatiotemporal distribution of host and parasite genotypes, and the efficiency of disease control strategies. Two major patterns have been proposed for plant-virus genotype infectivity matrices. In the gene-for-gene model, infectivity matrices show a nested pattern, where the host ranges of specialist virus genotypes are subsets of the host ranges of less specialized viruses. In contrast, in the matching-allele (MA) model, each virus genotype is specialized to infect one (or a small set of) host genotype(s). The corresponding infectivity matrix shows a modular pattern where infection is frequent for plants and viruses belonging to the same module but rare for those belonging to different modules. We analyzed the structure of infectivity matrices betweenPotato virus Y(PVY) and plant genotypes in the familySolanaceaecarrying different eukaryotic initiation factor 4E (eIF4E)-coding alleles conferring recessive resistance. Whereas this system corresponds mechanistically to an MA model, the expected modular pattern was rejected based on our experimental data. This was mostly because PVY mutations involved in adaptation to a particular plant genotype displayed frequent pleiotropic effects, conferring simultaneously an adaptation to additional plant genotypes with different eIF4E alleles. Such effects should be taken into account for the design of strategies of sustainable control of PVY through plant varietal mixtures or rotations.IMPORTANCEThe interaction pattern between host and virus genotypes has important consequences on their respective evolution and on issues regarding the application of disease control strategies. We found that the structure of the interaction betweenPotato virus Y(PVY) variants and host plants in the familySolanaceaedeparts significantly from the current model of interaction considered for these organisms because of frequent pleiotropic effects of virus mutations. These mutational effects allow the virus to expand rapidly its range of host plant genotypes, make it very difficult to predict the effects of mutations in PVY infectivity factors, and raise concerns about strategies of sustainable management of plant genetic resistance to viruses.
Isolation and Characterization of a Novel Alphaherpesvirus in Fruit Bats
Authors: Sasaki Michihito , Setiyono Agus , Handharyani Ekowati , Kobayashi Shintaro , Rahmadani Ibenu , Taha Siswatiana , Adiani Sri , Subangkit Mawar , Nakamura Ichiro , Sawa Hirofumi , Kimura Takashi 
Published: June 2014

ABSTRACT

Bats are known to harbor emerging RNA viruses. Recent studies have used high-throughput sequencing technology to identify various virus species, including DNA viruses that are harbored by bats; however, little is known about the nature of these potentially novel viruses. Here, we report the characterization of a novel herpesvirus isolated from an Indonesian pteropodid bat. The virus, tentatively named fruit bat alphaherpesvirus 1 (FBAHV1), has a double-stranded DNA genome of 149,459 bp. The phylogenetic analyses suggested that FBAHV1 is phylogenetically grouped with simplexviruses within the subfamily
Alphaherpesvirinae
. Inoculation of FBAHV1 into laboratory mice caused a lethal infection. Virus infection was observed in lung, liver, and brain tissue. Serological and PCR screening revealed that fruit bats infected with FBAHV1 or its related virus are widely distributed in Indonesia. The identification of FBAHV1 makes a considerable contribution to our understanding of simplexviruses associated with bats.

IMPORTANCE
Bats are known to harbor emerging viruses, such as lyssaviruses, henipaviruses, severe acute respiratory syndrome-like coronaviruses, and filoviruses. Although alphaherpesviruses are disseminated in humans and other animals, there is little information about their distribution in bats. Here, we isolated a previously unknown alphaherpesvirus from an Indonesian fruit bat. Genome sequence analysis suggested that the virus is a member of the genus
Simplexvirus
within the subfamily
Alphaherpesvirinae
, which also includes common human viruses, such as herpes simplex virus 1 and herpes simplex virus 2. FBAHV1 is the first bat-derived alphaherpesvirus whose complete genome has been sequenced.
The West Nile Virus-Like Flavivirus Koutango Is Highly Virulent in Mice due to Delayed Viral Clearance and the Induction of a Poor Neutralizing Antibody Response
Authors: Prow Natalie A. , Setoh Yin X. , Biron Rebecca M. , Sester David P. , Kim Kwang Sik , Hobson-Peters Jody , Hall Roy A. , Bielefeldt-Ohmann Helle 
Published: June 2014

ABSTRACT

The mosquito-borne West Nile virus (WNV) is responsible for outbreaks of viral encephalitis in humans, horses, and birds, with particularly virulent strains causing recent outbreaks of disease in eastern Europe, the Middle East, North America, and Australia. Previous studies have phylogenetically separated WNV strains into two main genetic lineages (I and II) containing virulent strains associated with neurological disease. Several WNV-like strains clustering outside these lineages have been identified and form an additional five proposed lineages. However, little is known about whether these strains have the potential to induce disease. In a comparative analysis with the highly virulent lineage I American strain (WNV
NY99
), the low-pathogenicity lineage II strain (B956), a benign Australian strain, Kunjin (WNV
KUN
), the African WNV-like Koutango virus (WNV
KOU
), and a WNV-like isolate from Sarawak, Malaysia (WNV
Sarawak
), were assessed for neuroinvasive properties in a murine model and for their replication kinetics
in vitro
. While WNV
NY99
replicated to the highest levels
in vitro
,
in vivo
mouse challenge revealed that WNV
KOU
was more virulent, with a shorter time to onset of neurological disease and higher morbidity. Histological analysis of WNV
KOU
- and WNV
NY99
-infected brain and spinal cords demonstrated more prominent meningoencephalitis and the presence of viral antigen in WNV
KOU
-infected mice. Enhanced virulence of WNV
KOU
also was associated with poor viral clearance in the periphery (sera and spleen), a skewed innate immune response, and poor neutralizing antibody development. These data demonstrate, for the first time, potent neuroinvasive and neurovirulent properties of a WNV-like virus outside lineages I and II.

IMPORTANCE
In this study, we characterized the
in vitro
and
in vivo
properties of previously uncharacterized West Nile virus strains and West Nile-like viruses. We identified a West Nile-like virus, Koutango virus (WNV
KOU
), that was more virulent than a known virulent lineage I virus, WNV
NY99
. The enhanced virulence of WNV
KOU
was associated with poor viral clearance and the induction of a poor neutralizing antibody response. These findings provide new insights into the pathogenesis of West Nile virus.
Interactions between the Influenza A Virus RNA Polymerase Components and Retinoic Acid-Inducible Gene I
Authors: Li Weizhong , Chen Hongjun , Sutton Troy , Obadan Adebimpe , Perez Daniel R. 
Published: June 2014

ABSTRACT
The influenza A virus genome possesses eight negative-strand RNA segments in the form of viral ribonucleoprotein particles (vRNPs) in association with the three viral RNA polymerase subunits (PB2, PB1, and PA) and the nucleoprotein (NP). Through interactions with multiple host factors, the RNP subunits play vital roles in replication, host adaptation, interspecies transmission, and pathogenicity. In order to gain insight into the potential roles of RNP subunits in the modulation of the host's innate immune response, the interactions of each RNP subunit with retinoic acid-inducible gene I protein (RIG-I) from mammalian and avian species were investigated. Studies using coimmunoprecipitation (co-IP), bimolecular fluorescence complementation (BiFc), and colocalization using confocal microscopy provided direct evidence for the RNA-independent binding of PB2, PB1, and PA with RIG-I from various hosts (human, swine, mouse, and duck). In contrast, the binding of NP with RIG-I was found to be RNA dependent. Expression of the viral NS1 protein, which interacts with RIG-I, did not interfere with the association of RNA polymerase subunits with RIG-I. The association of each individual virus polymerase component with RIG-I failed to significantly affect the interferon (IFN) induction elicited by RIG-I and 5′ triphosphate (5′ppp) RNA in reporter assays, quantitative reverse transcription-PCR (RT-PCR), and IRF3 phosphorylation tests. Taken together, these findings indicate that viral RNA polymerase components PB2, PB1, and PA directly target RIG-I, but the exact biological significance of these interactions in the replication and pathogenicity of influenza A virus needs to be further clarified.

IMPORTANCE
RIG-I is an important RNA sensor to elicit the innate immune response in mammals and some bird species (such as duck) upon influenza A virus infection. Although the 5′-triphosphate double-stranded RNA (dsRNA) panhandle structure at the end of viral genome RNA is responsible for the binding and subsequent activation of RIG-I, this structure is supposedly wrapped by RNA polymerase complex (PB2, PB1, and PA), which may interfere with the induction of RIG-I signaling pathway. In the present study, PB2, PB1, and PA were found to individually interact with RIG-Is from multiple mammalian and avian species in an RNA-independent manner, without significantly affecting the generation of IFN. The data suggest that although RIG-I binding by RNA polymerase complex is conserved in different species, it does not appear to play crucial role in the modulation of IFN
in vitro
.
Parents’ perspectives on the value of assistance dogs for children with autism spectrum disorder: a cross-sectional study
Authors: Burgoyne Louise , Dowling Lisa , Fitzgerald Anthony , Connolly Micaela , P Browne John , Perry Ivan J 
Published: June 2014

ObjectiveWhile there is an emerging literature on the usefulness of assistance dogs for children with autism spectrum disorder (ASD), there is a dearth of quantitative data on the value of assistance dog interventions for the family unit and family functioning. Using previously validated scales and scales developed specifically for this study, we measured parents’/guardians’ perceptions of how having an assistance dog affects: (1) child safety from environmental dangers, (2) public reception of ASD and (3) levels of caregiver strain and sense of competence. We also obtained open-ended response data from parents/guardians on benefits and constraints of having an assistance dog.SettingThis study was based in the primary care setting, within the context of a specific accredited assistance dog centre in Ireland.ParticipantsA total of 134 parents/guardians with an assistance dog, and 87 parents of children on the waiting list were surveyed.Primary and secondary outcome measuresThe primary outcome measures were scores on environmental hazards and public reception scales. The secondary outcome measures were scores on caregiver strain and competence scales.ResultsParents/guardians of children who have ASD and an assistance dog rate their child as significantly safer from environmental dangers (p<0.001), perceive that the public act more respectfully and responsibly towards their child (p<0.001) and feel more competent about managing their child (p=0.023) compared with parents on the waiting list. There was a concentration of positive feeling towards assistance dog interventions with particular focus on safety and comfort for children, and a sense of freedom from family restrictions associated with ASD. The amount of dedication and commitment required to care for a dog were viewed as the primary constraints.ConclusionsOur findings indicate that parents perceive that assistance dog interventions can be a valuable intervention for families with children who have ASD.
How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience
Authors: Finocchiaro Gherardo , Haddad Francois , Pavlovic Aleksandra , Magavern Emma , Sinagra Gianfranco , Knowles Joshua W , Myers Jonathan , Ashley Euan A 
Published: June 2014

ObjectivesIt is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.SettingTertiary referral centre from Stanford, California, USA.Partecipants383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Primary and secondary outcome measuresEchocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).ResultsReverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E′<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E′ was similarly elevated (E/E′: 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m2was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m2(OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E′>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E′<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.ConclusionsIn HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.
Managing risk in cancer presentation, detection and referral: a qualitative study of primary care staff views
Authors: Cook Neil , Thomson Gillian , Dey Paola 
Published: June 2014

ObjectivesIn the UK, there have been a number of national initiatives to promote earlier detection and prompt referral of patients presenting to primary care with signs and symptoms of cancer. The aim of the study was to explore the experiences of a range of primary care staff in promoting earlier presentation, detection and referral of patients with symptoms suggestive of cancer.SettingSix primary care practices in northwest England. Participants: 39 primary care staff from a variety of disciplines took part in five group and four individual interviews.ResultsThe global theme to emerge from the interviews was ‘managing risk’, which had three underpinning organising themes: ‘complexity’, relating to uncertainty of cancer diagnoses, service fragmentation and plethora of guidelines; ‘continuity’, relating to relationships between practice staff and their patients and between primary and secondary care; ‘conflict’ relating to policy drivers and staff role boundaries. A key concern of staff was that policymakers and those implementing cancer initiatives did not fully understand how risk was managed within primary care.ConclusionsPrimary care staff expressed a range of views and opinions on the benefits of cancer initiatives. National initiatives did not appear to wholly resolve issues in managing risk for all practitioners. Staff were concerned about the number of guidelines and priorities they were expected to implement. These issues need to be considered by policymakers when developing and implementing new initiatives.
Dietary changes and associations with metabolic improvements in adults with type 2 diabetes during a patient-centred dietary intervention: an exploratory analysis
Authors: England C Y , Thompson J L , Jago R , Cooper A R , Andrews R C 
Published: June 2014

ObjectivesDescribe dietary intake of participants enrolled in a non-prescriptive dietary intervention and dietary changes at 6 months and explore whether these changes had a role in observed improvements in glycated haemoglobin (HbA1c), weight, lipids and blood pressure.DesignSecondary analysis of data from the Early ACTivity in Diabetes randomised controlled trial.Participants262 patients with newly diagnosed type 2 diabetes randomised to the dietary intervention.Outcomes and analysisChanges in energy intake, macronutrients, fibre and alcohol and in weight, waist circumference, lipids, HbA1c and blood pressure at baseline and 6 months. Multivariate models were used to examine associations between dietary changes and metabolic variables.ResultsMen reported reducing mean energy intake from 1903±462 kcal to 1685 kcal±439 kcal (p<0.001), increasing carbohydrate intake from 42.4±6.6% to 43.8±6.6% (p=0.002) and reducing median alcohol intake from 13 (0–27) g to 5 (0–18) g (p<0.001). Women reported reducing mean energy intake from 1582±379 kcal to 1459±326 kcal (p<0.001) with no change to macronutrient distribution and alcohol. Fibre intake was maintained. In men (n=148), weak and clinically insignificant associations were found between increased carbohydrates and reduction in HbA1c (β=−0.003 (−0.006, −0.001); p=0.009), increased fibre and reduction in total cholesterol (β=−0.023 (−0.044, −0.002); p=0.033), decreased total fat and reduction in low-density lipoprotein (LDL)-cholesterol (β=0.024 (0.006, 0.001); p=0.011), and decreased alcohol and reduction in diastolic blood pressure (β=0.276 (0.055, 0.497); p=0.015). In women (n=75), associations were found between a decrease in transfats and reductions in waist circumference (β=−0.029 (0.006, 0.052); p=0.015), total cholesterol (β=0.399 (0.028, 0.770); p=0.036) and LDL cholesterol (β=0.365 (0.042, 0.668); p=0.028).ConclusionsClinically important metabolic improvements observed in a patient-centred dietary intervention were not explained by changes in macronutrients. However, a non-prescriptive approach may promote a reduction in total energy intake while maintaining fibre consumption.Trial registration numberThe Early ACTID trial numberISRCTN92162869.