13 research outputs found
Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families
Why Does Fog Deepen? An Analytical Perspective
The overall depth of a fog layer is one of the important factors in determining the hazard that a fog event presents. With discrete observations and often coarse numerical grids, however, fog depth cannot always be accurately determined. To address this, we derive a simple analytical relation that describes the change in depth of a fog interface with time, which depends on the tendencies and vertical gradients of moisture. We also present a lengthscale estimate for the maximum depth over which mixing can occur in order for the fog layer to be sustained, assuming a uniform mixing of the vertical profiles of temperature and moisture. Even over several hours, and when coarse observational resolution is used, the analytical description is shown to accurately diagnose the depth of a fog layer when compared against observational data and the results of large-eddy simulations. Such an analytical description not only enables the estimation of sub-grid or inter-observation fog depth, but also provides a simple framework for interpreting the evolution of a fog layer in time
Parameters for the Collapse of Turbulence in the Stratified Plane Couette Flow
We perform direct numerical simulation of the Couette flow as a model for the stable boundary layer. The flow evolution is investigated for combinations of the (bulk) Reynolds number and the imposed surface buoyancy flux. First, we establish what the similarities and differences are between applying a fixed buoyancy difference (Dirichlet) and a fixed buoyancy flux (Neumann) as boundary conditions. Moreover, two distinct parameters were recently proposed for the turbulent-to-laminar transition: the Reynolds number based on the Obukhov length and the shear capacity, a velocity-scale ratio based on the buoyancy flux maximum. We study how these parameters relate to each other and to the atmospheric boundary layer. The results show that in a weakly stratified equilibrium state, the flow statistics are virtually the same between the different types of boundary conditions. However, at stronger stratification and, more generally, in nonequilibrium conditions, the flow statistics do depend on the type of boundary condition imposed. In the case of Neumann boundary conditions, a clear sensitivity to the initial stratification strength is observed because of the existence of multiple equilibriums, while for Dirichlet boundary conditions, only one statistically steady turbulent equilibrium exists for a particular set of boundary conditions. As in previous studies, we find that when the imposed surface flux is larger than the maximum buoyancy flux, no turbulent steady state occurs. Analytical investigation and simulation data indicate that this maximum buoyancy flux converges for increasing Reynolds numbers, which suggests a possible extrapolation to the atmospheric case
High-Resolution DTS Temperature Measurements During Fog at Cabauw
DTS temperature measurements at the Cabauw site during a field experiment to observe the growth of shallow fog
External validation of an MR-based radiomic model predictive of locoregional control in oropharyngeal cancer
OBJECTIVES: To externally validate a pre-treatment MR-based radiomics model predictive of locoregional control in oropharyngeal squamous cell carcinoma (OPSCC) and to assess the impact of differences between datasets on the predictive performance. METHODS: Radiomic features, as defined in our previously published radiomics model, were extracted from the primary tumor volumes of 157 OPSCC patients in a different institute. The developed radiomics model was validated using this cohort. Additionally, parameters influencing performance, such as patient subgroups, MRI acquisition, and post-processing steps on prediction performance will be investigated. For this analysis, matched subgroups (based on human papillomavirus (HPV) status of the tumor, T-stage, and tumor subsite) and a subgroup with only patients with 4-mm slice thickness were studied. Also the influence of harmonization techniques (ComBat harmonization, quantile normalization) and the impact of feature stability across observers and centers were studied. Model performances were assessed by area under the curve (AUC), sensitivity, and specificity. RESULTS: Performance of the published model (AUC/sensitivity/specificity: 0.74/0.75/0.60) drops when applied on the validation cohort (AUC/sensitivity/specificity: 0.64/0.68/0.60). The performance of the full validation cohort improves slightly when the model is validated using a patient group with comparable HPV status of the tumor (AUC/sensitivity/specificity: 0.68/0.74/0.60), using patients acquired with a slice thickness of 4 mm (AUC/sensitivity/specificity: 0.67/0.73/0.57), or when quantile harmonization was performed (AUC/sensitivity/specificity: 0.66/0.69/0.60). CONCLUSION: The previously published model shows its generalizability and can be applied on data acquired from different vendors and protocols. Harmonization techniques and subgroup definition influence performance of predictive radiomics models. KEY POINTS: • Radiomics, a noninvasive quantitative image analysis technique, can support the radiologist by enhancing diagnostic accuracy and/or treatment decision-making. • A previously published model shows its generalizability and could be applied on data acquired from different vendors and protocols