Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection.

BackgroundWe reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later.ResultsThe early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia.ConclusionThis is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be beneficial, particularly when assisted by antiviral immune responses

Design of a framework to promote physical activity for the elderly

Physical inactivity is estimated to be one of the leading risk factors for global mortality and it is associated with several illnesses, such as type 2 diabetes, cardiovascular diseases and various types of cancers. To tackle this issue and promote physical activity amongst the elderly, a system that computes automatically, in real-time, the score of a Boccia game was developed. The objective of this paper is to infer the best design possible for the User Interface (UI) that displays this information. To achieve this, two surveys were conducted involving 45 participants. In the first survey, the participants were asked what features they would like to see in the UI. Based on these remarks, the authors designed an UI, along with several variations. The preferences between these variations were afterwards evaluated in the second survey. Thus, the final design of the UI was validated before being shown to the elders.This article is a result of the project Deus ex Machina: NORTE – 01 – 0145 – FEDER - 000026, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Boccia court analysis for promoting elderly physical activity

Physical inactivity is one of the leading risk factors for global mortality. Older adults, in particular, are more probable to suffer the consequences of physical inactivity, since it is one of the most sedentary age groups. On the other hand, engaging physical activity can have various benefits for the prevention of several diseases and functional loss prevention, therefore, it is critical to encourage its regular practice amongst the elderly. Boccia is a simple precision ball sport that is easily adaptable for individuals with physical limitations, which makes it a perfectly good game for this circumstance. The present paper proposes a ball-detection based system for monitoring the Boccia court, compute the current game score and display it on a user interface. The future goal of such system will be to motivate the elders to participate more frequently in the Boccia game and make the overall game experience more enjoyable. The proposed system was tested with twenty video recordings of different simulated game situations. Overall, the obtained results were encouraging, having only one incorrect game score being computed by the developed algorithm.This article is a result of the project Deus ex Machina: NORTE01-0145-FEDER-000026, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Cytotoxic Mediators in Paradoxical HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) frequently complicates combined antiretroviral therapy and antituberculosis therapy in HIV-1–coinfected tuberculosis patients. The immunopathological mechanisms underlying TB-IRIS are incompletely defined, and improved understanding is required to derive new treatments and to reduce associated morbidity and mortality. We performed longitudinal and cross-sectional analyses of human PBMCs from paradoxical TB-IRIS patients and non-IRIS controls (HIV-TB–coinfected patients commencing antiretroviral therapy who did not develop TB-IRIS). Freshly isolated PBMC stimulated with heat-killed Mycobacterium tuberculosis H37Rv (hkH37Rv) were used for IFN-γ ELISPOT and RNA extraction. Stored RNA was used for microarray and RT-PCR, whereas corresponding stored culture supernatants were used for ELISA. Stored PBMC were used for perforin and granzyme B ELISPOT and flow cytometry. There were significantly increased IFN-γ responses to hkH37Rv in TB-IRIS, compared with non-IRIS PBMC (p = 0.035). Microarray analysis of hkH37Rv-stimulated PBMC indicated that perforin 1 was the most significantly upregulated gene, with granzyme B among the top five (log(2) fold difference 3.587 and 2.828, respectively), in TB-IRIS. Downstream experiments using RT-PCR, ELISA, and ELISPOT confirmed the increased expression and secretion of perforin and granzyme B. Moreover, granzyme B secretion reduced in PBMC from TB-IRIS patients during corticosteroid treatment. Invariant NKT cell (CD3(+)Vα24(+)) proportions were higher in TB-IRIS patients (p = 0.004) and were a source of perforin. Our data implicate the granule exocytosis pathway in TB-IRIS pathophysiology. Further understanding of the immunopathogenesis of this condition will facilitate development of specific diagnostic and improved therapeutic options

Aquatic community response to volcanic eruptions on the Ecuadorian Andean flank: evidence from the palaeoecological record

Aquatic ecosystems in the tropical Andes are under increasing pressure from human modification of the landscape (deforestation and dams) and climatic change (increase of extreme events and 1.5 °C on average temperatures are projected for AD 2100). However, the resilience of these ecosystems to perturbations is poorly understood. Here we use a multi-proxy palaeoecological approach to assess the response of aquatic ecosystems to a major mechanism for natural disturbance, volcanic ash deposition. Specifically, we present data from two Neotropical lakes located on the eastern Andean flank of Ecuador. Laguna Pindo (1°27.132′S–78°04.847′W) is a tectonically formed closed basin surrounded by a dense mid-elevation forest, whereas Laguna Baños (0°19.328′S–78°09.175′W) is a glacially formed lake with an inflow and outflow in high Andean Páramo grasslands. In each lake we examined the dynamics of chironomids and other aquatic and semi-aquatic organisms to explore the effect of thick (> 5 cm) volcanic deposits on the aquatic communities in these two systems with different catchment features. In both lakes past volcanic ash deposition was evident from four large tephras dated to c.850 cal year BP (Pindo), and 4600, 3600 and 1500 cal year BP (Baños). Examination of the chironomid and aquatic assemblages before and after the ash depositions revealed no shift in composition at Pindo, but a major change at Baños occurred after the last event around 1500 cal year BP. Chironomids at Baños changed from an assemblage dominated by Pseudochironomus and Polypedilum nubifer-type to Cricotopus/Paratrichocladius type-II, and such a dominance lasted for approximately 380 years. We suggest that, despite potential changes in the water chemistry, the major effect on the chironomid community resulted from the thickness of the tephra being deposited, which acted to shallow the water body beyond a depth threshold. Changes in the aquatic flora and fauna at the base of the trophic chain can promote cascade effects that may deteriorate the ecosystem, especially when already influenced by human activities, such as deforestation and dams, which is frequent in the high Andes

Visual, Motor and Attentional Influences on Proprioceptive Contributions to Perception of Hand Path Rectilinearity during Reaching

We examined how proprioceptive contributions to perception of hand path straightness are influenced by visual, motor and attentional sources of performance variability during horizontal planar reaching. Subjects held the handle of a robot that constrained goal-directed movements of the hand to the paths of controlled curvature. Subjects attempted to detect the presence of hand path curvature during both active (subject driven) and passive (robot driven) movements that either required active muscle force production or not. Subjects were less able to discriminate curved from straight paths when actively reaching for a target versus when the robot moved their hand through the same curved paths. This effect was especially evident during robot-driven movements requiring concurrent activation of lengthening but not shortening muscles. Subjects were less likely to report curvature and were more variable in reporting when movements appeared straight in a novel “visual channel” condition previously shown to block adaptive updating of motor commands in response to deviations from a straight-line hand path. Similarly, compromised performance was obtained when subjects simultaneously performed a distracting secondary task (key pressing with the contralateral hand). The effects compounded when these last two treatments were combined. It is concluded that environmental, intrinsic and attentional factors all impact the ability to detect deviations from a rectilinear hand path during goal-directed movement by decreasing proprioceptive contributions to limb state estimation. In contrast, response variability increased only in experimental conditions thought to impose additional attentional demands on the observer. Implications of these results for perception and other sensorimotor behaviors are discussed

A systematic review of physiological reactivity to stimuli in autism

Objective: The prevalence of abnormal behavioural responses to a variety of stimuli among individuals with autism has led researchers to examine whether physiological reactivity is typical in this population. The current paper reviewed studies assessing physiological reactivity to sensory, social and emotional, and stressor stimuli in individuals with autism. Methods: Systematic searches of electronic databases identified 57 studies that met our inclusion criteria. A novel measure of methodological quality suitable for use with non-randomised, non-interventional, psychophysiological studies was also developed and applied. Results: Individuals with autism were found to respond differently than typically developing controls in 78.6%, 66.7%, and 71.4% of sensory, social and emotional, and stressor stimulus classes, respectively. Conclusions: Individual differences in physiological reactivity are clearly present in autism, suggesting additional research is needed to determine the variables relating to physiological reactivity among those with ASD and to examine the possibility of physiological subtype responders in this population

On the genetic architecture of rapidly adapting and convergent life history traits in guppies

This is the final version. Available on open access from Springer Nature via the DOI in this recordData availability: All sequencing read data are available from the ENA (Study accession: PRJEB48691). All scripts and other data associated with analysis are available on GitHub (github.com/JimWhiting91/guppy_LH_QTL) and are archived on Zenodo (https://doi.org/10.5281/zenodo.5938562). The VCF, phenotypes, and linkage map are deposited with dryad (https://doi.org/10.5061/dryad.w3r2280sk).The genetic basis of traits shapes and constrains how adaptation proceeds in nature; rapid adaptation can proceed using stores of polygenic standing genetic variation or hard selective sweeps, and increasing polygenicity fuels genetic redundancy, reducing gene re-use (genetic convergence). Guppy life history traits evolve rapidly and convergently among natural high- and low-predation environments in northern Trinidad. This system has been studied extensively at the phenotypic level, but little is known about the underlying genetic architecture. Here, we use four independent F2 QTL crosses to examine the genetic basis of seven (five female, two male) guppy life history phenotypes and discuss how these genetic architectures may facilitate or constrain rapid adaptation and convergence. We use RAD-sequencing data (16,539 SNPs) from 370 male and 267 female F2 individuals. We perform linkage mapping, estimates of genome-wide and per-chromosome heritability (multi-locus associations), and QTL mapping (single-locus associations). Our results are consistent with architectures of many loci of small-effect for male age and size at maturity and female interbrood period. Male trait associations are clustered on specific chromosomes, but female interbrood period exhibits a weak genome-wide signal suggesting a potentially highly polygenic component. Offspring weight and female size at maturity are also associated with a single significant QTL each. These results suggest rapid, repeatable phenotypic evolution of guppies may be facilitated by polygenic trait architectures, but subsequent genetic redundancy may limit gene re-use across populations, in agreement with an absence of strong signatures of genetic convergence from recent analyses of wild guppies.European Research Council (ERC)Natural Environment Research Council (NERC)National Science Foundation (NSF)Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC

On the genetic architecture of rapidly adapting and convergent life history traits in guppies

This is the final version. Available on open access from Springer Nature via the DOI in this recordData availability: All sequencing read data are available from the ENA (Study accession: PRJEB48691). All scripts and other data associated with analysis are available on GitHub (github.com/JimWhiting91/guppy_LH_QTL) and are archived on Zenodo (https://doi.org/10.5281/zenodo.5938562). The VCF, phenotypes, and linkage map are deposited with dryad (https://doi.org/10.5061/dryad.w3r2280sk).The genetic basis of traits shapes and constrains how adaptation proceeds in nature; rapid adaptation can proceed using stores of polygenic standing genetic variation or hard selective sweeps, and increasing polygenicity fuels genetic redundancy, reducing gene re-use (genetic convergence). Guppy life history traits evolve rapidly and convergently among natural high- and low-predation environments in northern Trinidad. This system has been studied extensively at the phenotypic level, but little is known about the underlying genetic architecture. Here, we use four independent F2 QTL crosses to examine the genetic basis of seven (five female, two male) guppy life history phenotypes and discuss how these genetic architectures may facilitate or constrain rapid adaptation and convergence. We use RAD-sequencing data (16,539 SNPs) from 370 male and 267 female F2 individuals. We perform linkage mapping, estimates of genome-wide and per-chromosome heritability (multi-locus associations), and QTL mapping (single-locus associations). Our results are consistent with architectures of many loci of small-effect for male age and size at maturity and female interbrood period. Male trait associations are clustered on specific chromosomes, but female interbrood period exhibits a weak genome-wide signal suggesting a potentially highly polygenic component. Offspring weight and female size at maturity are also associated with a single significant QTL each. These results suggest rapid, repeatable phenotypic evolution of guppies may be facilitated by polygenic trait architectures, but subsequent genetic redundancy may limit gene re-use across populations, in agreement with an absence of strong signatures of genetic convergence from recent analyses of wild guppies.European Research Council (ERC)Natural Environment Research Council (NERC)National Science Foundation (NSF)Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC