Multiple paternity in superfetatious live-bearing fishes.

Superfetation, the ability to carry several overlapping broods at different developmental stages, has evolved independently multiple times within the live-bearing fish family Poeciliidae. Even though superfetation is widespread among poeciliids, its evolutionary advantages remain unclear. Theory predicts that superfetation should increase polyandry by increasing the probability that temporally overlapping broods are fertilized by different fathers. Here, we test this key prediction in two poeciliid species that each carry two temporally overlapping broods: Poeciliopsis retropinna and P. turrubarensis. We collected 25 females per species from freshwater streams in South-Eastern Costa Rica and assessed multiple paternity by genotyping all their embryos (420 embryos for P. retropinna; 788 embryos for P. turrubarensis) using existing and newly developed microsatellite markers. We observed a high frequency of unique sires in the simultaneous, temporally overlapping broods in P. retropinna (in 56% of the pregnant females) and P. turrubarensis (79%). We found that the mean number of sires within females was higher than the number of sires within the separate broods (2.92 sires within mothers vs. 2.36 within separate broods in P. retropinna; and 3.40 vs 2.56 in P. turrubarensis). We further observed that there were significant differences in the proportion of offspring sired by each male in 42% of pregnant female P. retropinna and 65% of female P. turrubarensis; however, this significance applied to only 9% and 46% of the individual broods in P. retropinna and P. turrubarensis, respectively, suggesting that the unequal reproductive success of sires (i.e. reproductive skew) mostly originated from differences in paternal contribution between, rather than within broods. Together, these findings tentatively suggest that superfetation may promote polyandry and reproductive skew in live-bearing fishes

Laughter as a paradigm of socio-emotional signal processing in dementia

Laughter is a fundamental communicative signal in our relations with other people and is used to convey a diverse repertoire of social and emotional information. It is therefore potentially a useful probe of impaired socio-emotional signal processing in neurodegenerative diseases. Here we investigated the cognitive and affective processing of laughter in forty-seven patients representing all major syndromes of frontotemporal dementia, a disease spectrum characterised by severe socio-emotional dysfunction (twenty-two with behavioural variant frontotemporal dementia, twelve with semantic variant primary progressive aphasia, thirteen with nonfluent-agrammatic variant primary progressive aphasia), in relation to fifteen patients with typical amnestic Alzheimer’s disease and twenty healthy age-matched individuals. We assessed cognitive labelling (identification) and valence rating (affective evaluation) of samples of spontaneous (mirthful and hostile) and volitional (posed) laughter versus two auditory control conditions (a synthetic laughter-like stimulus and spoken numbers). Neuroanatomical associations of laughter processing were assessed using voxel-based morphometry of patients’ brain MR images. While all dementia syndromes were associated with impaired identification of laughter subtypes relative to healthy controls, this was significantly more severe overall in frontotemporal dementia than in Alzheimer’s disease and particularly in the behavioural and semantic variants, which also showed abnormal affective evaluation of laughter. Over the patient cohort, laughter identification accuracy was correlated with measures of daily-life socio-emotional functioning. Certain striking syndromic signatures emerged, including enhanced liking for hostile laughter in behavioural variant frontotemporal dementia, impaired processing of synthetic laughter in the nonfluent-agrammatic variant (consistent with a generic complex auditory perceptual deficit) and enhanced liking for numbers (‘numerophilia’) in the semantic variant. Across the patient cohort, overall laughter identification accuracy correlated with regional grey matter in a core network encompassing inferior frontal and cingulo-insular cortices; and more specific correlates of laughter identification accuracy were delineated in cortical regions mediating affective disambiguation (identification of hostile and posed laughter in orbitofrontal cortex) and authenticity (social intent) decoding (identification of mirthful and posed laughter in anteromedial prefrontal cortex) (all p<0.05 after correction for multiple voxel-wise comparisons over the whole brain). These findings reveal a rich diversity of cognitive and affective laughter phenotypes in canonical dementia syndromes and suggest that laughter is an informative probe of neural mechanisms underpinning socio-emotional dysfunction in neurodegenerative disease

Aerobic Exercise during Pregnancy and Presence of Fetal-Maternal Heart Rate Synchronization

It has been shown that short-term direct interaction between maternal and fetal heart rates may take place and that this interaction is affected by the rate of maternal respiration. The aim of this study was to determine the effect of maternal aerobic exercise during pregnancy on the occurrence of fetal-maternal heart rate synchronization.In 40 pregnant women at the 36th week of gestation, 21 of whom exercised regularly, we acquired 18 min. RR interval time series obtained simultaneously in the mothers and their fetuses from magnetocardiographic recordings. The time series of the two groups were examined with respect to their heart rate variability, the maternal respiratory rate and the presence of synchronization epochs as determined on the basis of synchrograms. Surrogate data were used to assess whether the occurrence of synchronization was due to chance.In the original data, we found synchronization occurred less often in pregnancies in which the mothers had exercised regularly. These subjects also displayed higher combined fetal-maternal heart rate variability and lower maternal respiratory rates. Analysis of the surrogate data showed shorter epochs of synchronization and a lack of the phase coordination found between maternal and fetal beat timing in the original data.The results suggest that fetal-maternal heart rate coupling is present but generally weak. Maternal exercise has a damping effect on its occurrence, most likely due to an increase in beat-to-beat differences, higher vagal tone and slower breathing rates

The TOPGAME-study: effectiveness of extracorporeal shockwave therapy in jumping athletes with patellar tendinopathy. Design of a randomised controlled trial

BACKGROUND: Patellar tendinopathy is a major problem for many athletes, especially those involved in jumping activities. Despite its frequency and negative impact on athletic careers, no evidence-based guidelines for management of this overuse injury exist. Since functional outcomes of conservative and surgical treatments remain suboptimal, new diagnostic and therapeutic strategies have to be developed and evaluated. Extracorporeal shockwave therapy (ESWT) appears to be a promising treatment in patients with chronic patellar tendinopathy. ESWT is most often applied after the known conservative treatments have failed. However, its effectiveness as primary therapy has not been studied in athletes who keep playing sports despite having patellar tendon pain. The aim of this study is to determine the effectiveness of ESWT in athletes with patellar tendinopathy who are still in training and competition. METHODS/DESIGN: The TOPGAME-study (Tendinopathy of Patella Groningen Amsterdam Maastricht ESWT) is a multicentre two-armed randomised controlled trial with blinded participants and outcome assessors, in which the effectiveness of patient-guided focussed ESWT treatment (compared to placebo ESWT) on pain reduction and recovery of function in athletes with patellar tendinopathy will be investigated. Participants are volleyball, handball and basketball players with symptoms of patellar tendinopathy for a minimum of 3 to a maximum duration of 12 months who are still able to train and compete. The intervention group receives three patient-guided focussed medium-energy density ESWT treatments without local anaesthesia at a weekly interval in the first half of the competition. The control group receives placebo treatment. The follow-up measurements take place 1, 12 and 22 weeks after the final ESWT or placebo treatment, when athletes are still in competition. Primary outcome measure is the VISA-P (Victorian Institute of Sport Assessment - patella) score. Data with regard to pain during function tests (jump tests and single-leg decline squat) and ultrasound characteristics are also collected. During the follow-up period participants also register pain, symptoms, sports participation, side effects of treatment and additional medical consumption in an internet-based diary. DISCUSSION: The TOPGAME-study is the first RCT to study the effectiveness of patient-guided ESWT in athletes with patellar tendinopathy who are still in training and competition. TRIAL REGISTRATION: Trial registration number NTR1408

Identification and functional characterization of a novel acetyl-CoA carboxylase mutation associated with ketoenol resistance in Bemisia tabaci

This is the final version. Available from Elsevier / Academic Press via the DOI in this record. Insecticides of the tetronic/tetramic acid family (cyclic ketoenols) are widely used to control sucking pests such as whiteflies, aphids and mites. They act as inhibitors of acetyl-CoA carboxylase (ACC), a key enzyme for lipid biosynthesis across taxa. While it is well documented that plant ACCs targeted by herbicides have developed resistance associated with mutations at the carboxyltransferase (CT) domain, resistance to ketoenols in invertebrate pests has been previously associated either with metabolic resistance or with non-validated candidate mutations in different ACC domains. A recent study revealed high levels of spiromesifen and spirotetramat resistance in Spanish field populations of the whitefly Bemisia tabaci that was not thought to be associated with metabolic resistance. We confirm the presence of high resistance levels (up to >640-fold) against ketoenol insecticides in both Spanish and Australian B. tabaci strains of the MED and MEAM1 species, respectively. RNAseq analysis revealed the presence of an ACC variant bearing a mutation that results in an amino acid substitution, A2083V, in a highly conserved region of the CT domain. F1 progeny resulting from reciprocal crosses between susceptible and resistant lines are almost fully resistant, suggesting an autosomal dominant mode of inheritance. In order to functionally investigate the contribution of this mutation and other candidate mutations previously reported in resistance phenotypes, we used CRISPR/Cas9 to generate genome modified Drosophila lines. Toxicity bioassays using multiple transgenic fly lines confirmed that A2083V causes high levels of resistance to commercial ketoenols. We therefore developed a pyrosequencing-based diagnostic assay to map the spread of the resistance alleles in field-collected samples from Spain. Our screening confirmed the presence of target-site resistance in numerous field-populations collected in Sevilla, Murcia and Almeria. This emphasizes the importance of implementing appropriate resistance management strategies to prevent or slow the spread of resistance through global whitefly populations.European Union Horizon 2020Australian cotton research and development corporatio

The functional neuroanatomy of emotion processing in frontotemporal dementias

This is a pre-copyedited, author-produced version of an article accepted for publication in Brain following peer review. The version of record: Charles R Marshall, Christopher J D Hardy, Lucy L Russell et al., The functional neuroanatomy of emotion processing in frontotemporal dementias, Brain, awz204, is available online at: https://doi.org/10.1093/brain/awz204Brain Research TrustAlzheimer’s SocietyLeonard Wolfson Experimental Neurology CentreMedical Research Council UKNIHR UCLH Biomedical Research Centr

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8(+) T cells during cytomegalovirus infection.

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and both CD4(+) and CD8(+) CMV-specific T cells are essential. These virus-specific T cells persist in exceptionally large numbers during the infection, traffic into peripheral tissues and remain functional, making CMV an attractive vaccine vector for driving CMV-like T cell responses against recombinant antigens of choice. However, the mechanisms by which these T cells persist and differentiate while remaining functional are still poorly understood, and we have no means to promote their development in immune-compromised patients at risk for CMV disease. In this review, I will briefly summarize our current knowledge of CMV-specific CD8(+) T cells and propose a mechanism that may explain their maintenance and preservation of function during chronic infection

Chaste: an open source C++ library for computational physiology and biology

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to "re-invent the wheel" with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials

The acceptability and feasibility of using the Adult Social Care Outcomes Toolkit (ASCOT) to inform practice in care homes

Background: The Adult Social Care Outcomes Toolkit (ASCOT) measures social care related quality of life (SCRQoL) and can be used to measure outcomes and demonstrate impact across different social care settings. This exploratory study built on previous work by collecting new inter-rater reliability data on the mixed-methods version of the toolkit and exploring how it might be used to inform practice in four case study homes. Method: We worked with two care home providers to agree an in-depth study collecting SCRQoL data in four case-study homes. Data was collected about residents’ age, ethnicity, cognitive impairment, ability to perform activities of daily living and SCRQoL in the four homes. Feedback sessions with staff and managers were held in the homes two weeks after baseline and follow-up data collected three months later. Interviews with managers explored their views of the feedback and recorded any changes that had been made because of it. Results: Participant recruitment was challenging, despite working in partnership with the homes. Resident response rates ranged from 23 to 54 % with 58 residents from four care homes taking part in the research. 53 % lacked capacity to consent. Inter-rater reliability for the ASCOT ratings of SCRQoL were good at time one (IRR = 0.72) and excellent at time two (IRR = 0.76). During the study, residents’ ability to perform activities of daily living declined significantly (z = -2.67, p < .01), as did their expected needs in the absence of services (z = -2.41, p < .05). Despite these rapid declines in functionings, residents’ current SCRQoL declined slightly but not significantly (Z = -1.49, p = .14). Staff responded positively to the feedback given and managers reported implementing changes in practice because of it. Conclusion: This exploratory study faced many challenges in the recruitment of residents, many of whom were cognitively impaired. Nevertheless, without a mixed-methods approach many of the residents living in the care homes would have been excluded from the research altogether or had their views represented only by a representative or proxy. The value of the mixed-methods toolkit and its potential for use by providers is discussed

Saffold Virus, a Human Theiler's-Like Cardiovirus, Is Ubiquitous and Causes Infection Early in Life

The family Picornaviridae contains well-known human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and parechovirus). In addition, this family contains a number of viruses that infect animals, including members of the genus Cardiovirus such as Encephalomyocarditis virus (EMCV) and Theiler's murine encephalomyelits virus (TMEV). The latter are important murine pathogens that cause myocarditis, type 1 diabetes and chronic inflammation in the brains, mimicking multiple sclerosis. Recently, a new picornavirus was isolated from humans, named Saffold virus (SAFV). The virus is genetically related to Theiler's virus and classified as a new species in the genus Cardiovirus, which until the discovery of SAFV did not contain human viruses. By analogy with the rodent cardioviruses, SAFV may be a relevant new human pathogen. Thus far, SAFVs have sporadically been detected by molecular techniques in respiratory and fecal specimens, but the epidemiology and clinical significance remained unclear. Here we describe the first cultivated SAFV type 3 (SAFV-3) isolate, its growth characteristics, full-length sequence, and epidemiology. Unlike the previously isolated SAFV-1 and -2 viruses, SAFV-3 showed efficient growth in several cell lines with a clear cytopathic effect. The latter allowed us to conduct a large-scale serological survey by a virus-neutralization assay. This survey showed that infection by SAFV-3 occurs early in life (>75% positive at 24 months) and that the seroprevalence reaches >90% in older children and adults. Neutralizing antibodies were found in serum samples collected in several countries in Europe, Africa, and Asia. In conclusion, this study describes the first cultivated SAFV-3 isolate, its full-length sequence, and epidemiology. SAFV-3 is a highly common and widespread human virus causing infection in early childhood. This finding has important implications for understanding the impact of these ubiquitous viruses and their possible role in acute and/or chronic disease