Hearing Ability with Age in Northern European Women: A New Web-Based Approach to Genetic Studies

Age-related hearing impairment (ARHI) affects 25–40% of individuals over the age of 65. Despite the high prevalence of this complex trait, ARHI is still poorly understood. We hypothesized that variance in hearing ability with age is largely determined by genetic factors. We collected audiologic data on females of Northern European ancestry and compared different audiogram representations. A web-based speech-to-noise ratio (SNR) hearing test was compared with pure-tone thresholds to see if we could determine accurately hearing ability on people at home and the genetic contribution to each trait compared. Volunteers were recruited from the TwinsUK cohort. Hearing ability was determined using pure-tone audiometry and a web-based hearing test. Different audiogram presentations were compared for age-correlation and reflection of audiogram shape. Using structural equation modelling based on the classical twin model the heritability of ARHI, as measured by the different phenotypes, was estimated and shared variance between the web-based SNR test and pure-tone audiometry determined using bivariate modelling. Pure-tone audiometric data was collected on 1033 older females (age: 41–86). 1970 volunteers (males and females, age: 18–85) participated in the SNR. In the comparison between different ARHI phenotypes the difference between the first two principle components (PC1–PC2) best represented ARHI. The SNR test showed a sensitivity and specificity of 89% and 80%, respectively, in comparison with pure-tone audiogram data. Univariate heritability estimates ranged from 0.70 (95% CI: 0.63–0.76) for (PC1–PC2) to 0.56 (95% CI: 0.48–0.63) for PC2. The genetic correlation of PC1–PC2 and SNR was −0.67 showing that the 2 traits share variances attributed to additive genetic factors. Hearing ability showed considerable heritability in our sample. We have shown that the SNR test provides a useful surrogate marker of hearing. This will enable a much larger sample to be collected at a fraction of the cost, facilitating future genetic association studies

Rapport final du projet européen CatClay sur les processus de migration des cations dans les roches argileuses indurées

International audienceIn the framework of the feasibility studies on the radioactive waste disposal in deep argillaceous formations, it isnow well established that the transport properties of solutes in clay rocks, i.e. parameter values for Fick’s law, are mainlygoverned by the negatively charged clay mineral surface. While a good understanding of the diffusive behaviour of non-reactiveanionic and neutral species is now achieved, much effort has to be placed on improving understanding of coupledsorption/diffusion phenomena for sorbing cations. Indeed, several cations known to form highly stable surface complexes withsites on mineral surfaces migrate more deeply into clay rock than expected. Therefore, the overall objective of the EC CatClayproject is to address this issue, using a ‘bottom-up’ approach, in which simpler, analogous systems (here a compacted clay,‘pure’ illite) are experimentally studied and modelled, and then the transferability of these results to more complex materials, i.e.the clay rocks under consideration in France, Switzerland and Belgium for hosting radioactive waste disposal facilities, isverified. The cations of interest were chosen for covering a representative range of cations families: from a moderately sorbingcation, the strontium, to three strongly sorbing cations, Co(II), Zn(II) and Eu(III). For the 4 years of this project, much effort wasdevoted to developing and applying specific experimental methods needed for acquiring the high precision, reliable data neededto test the alternative hypotheses represented by different conceptual-numerical models. The enhanced diffusion of the sorbingcations of interest was confirmed both in the simpler analogous illite system for Sr2+, Co(II) and Zn(II), but also in the naturalclay rocks, except for Eu(III). First modelling approach including diffusion in the diffuse double layer (DDL) promisinglysucceeded in reproducing the experimental data under the various conditions both in illite and clay rocks, even though someassumptions made have to be verified. In parallel, actual 3D geometrical pore size distributions of compacted illite, and in lessextent, clay rock samples, were successfully determined by combining TEM and FIB-nt analyses on materials maintained in awater-like saturation state by means of an extensive impregnation step. Based on this spatial distribution of pores, first numericaldiffusion experiments were carried at the pore scale through virtual illite, enabling a better understanding of how transferpathways are organized in the porous media. Finally, the EC CatClay project allowed a better understanding of the migration ofstrongly sorbing tracers through low permeability ‘clay rock’ formations, increasing confidence in our capacity to demonstratethat the models used to predict radionuclide migration through these rocks are scientifically sound

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents

Survival of the Fittest: Positive Selection of CD4+ T Cells Expressing a Membrane-Bound Fusion Inhibitor Following HIV-1 Infection

Although a variety of genetic strategies have been developed to inhibit HIV replication, few direct comparisons of the efficacy of these inhibitors have been carried out. Moreover, most studies have not examined whether genetic inhibitors are able to induce a survival advantage that results in an expansion of genetically-modified cells following HIV infection. We evaluated the efficacy of three leading genetic strategies to inhibit HIV replication: 1) an HIV-1 tat/rev-specific small hairpin (sh) RNA; 2) an RNA antisense gene specific for the HIV-1 envelope; and 3) a viral entry inhibitor, maC46. In stably transduced cell lines selected such that >95% of cells expressed the genetic inhibitor, the RNA antisense envelope and viral entry inhibitor maC46 provided the strongest inhibition of HIV-1 replication. However, when mixed populations of transduced and untransduced cells were challenged with HIV-1, the maC46 fusion inhibitor resulted in highly efficient positive selection of transduced cells, an effect that was evident even in mixed populations containing as few as 1% maC46-expressing cells. The selective advantage of the maC46 fusion inhibitor was also observed in HIV-1-infected cultures of primary T lymphocytes as well as in HIV-1-infected humanized mice. These results demonstrate robust inhibition of HIV replication with the fusion inhibitor maC46 and the antisense Env inhibitor, and importantly, a survival advantage of cells expressing the maC46 fusion inhibitor both in vitro and in vivo. Evaluation of the ability of genetic inhibitors of HIV-1 replication to confer a survival advantage on genetically-modified cells provides unique information not provided by standard techniques that may be important in the in vivo efficacy of these genes

Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome

\ua9 The Author(s) 2024.Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN

A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS

Consumer Complaints and Company Market Value

Consumer complaints affect company market value and common sense suggests that a negative impact is expected. However, do complaints always negatively impact company market value? We hypothesize in this study that complaints may have a non-linear effect on market value. Positive (e.g. avoiding high costs to solve complaints) and negative (e.g. speedy and intense diffusion) tradeoffs may occur given the level of complaints. To test our non-linear hypothesis, a panel data was collected from cell phone service providers from 2005 to 2013. The results supported our tradeoff rationale. Low levels of complaints allow for companies to increase market value, while high levels of complaints cause increasing harm to market value. The sample, model and period considered in this study, indicates a level of 0.49 complaints per thousand consumers as the threshold for a shift in tradeoffs. The effects on market value become increasingly negative when trying to make reductions to move below this level, due to negative tradeoffs

Eye-Hand Coordination during Dynamic Visuomotor Rotations

Background for many technology-driven visuomotor tasks such as tele-surgery, human operators face situations in which the frames of reference for vision and action are misaligned and need to be compensated in order to perform the tasks with the necessary precision. The cognitive mechanisms for the selection of appropriate frames of reference are still not fully understood. This study investigated the effect of changing visual and kinesthetic frames of reference during wrist pointing, simulating activities typical for tele-operations. Methods using a robotic manipulandum, subjects had to perform center-out pointing movements to visual targets presented on a computer screen, by coordinating wrist flexion/extension with abduction/adduction. We compared movements in which the frames of reference were aligned (unperturbed condition) with movements performed under different combinations of visual/kinesthetic dynamic perturbations. The visual frame of reference was centered to the computer screen, while the kinesthetic frame was centered around the wrist joint. Both frames changed their orientation dynamically (angular velocity\u200a=\u200a36\ub0/s) with respect to the head-centered frame of reference (the eyes). Perturbations were either unimodal (visual or kinesthetic), or bimodal (visual+kinesthetic). As expected, pointing performance was best in the unperturbed condition. The spatial pointing error dramatically worsened during both unimodal and most bimodal conditions. However, in the bimodal condition, in which both disturbances were in phase, adaptation was very fast and kinematic performance indicators approached the values of the unperturbed condition. Conclusions this result suggests that subjects learned to exploit an \u201caffordance\u201d made available by the invariant phase relation between the visual and kinesthetic frames. It seems that after detecting such invariance, subjects used the kinesthetic input as an informative signal rather than a disturbance, in order to compensate the visual rotation without going through the lengthy process of building an internal adaptation model. Practical implications are discussed as regards the design of advanced, high-performance man-machine interfaces