On the calculation of the D-optimal multisine excitation power spectrum for broadband impedance spectroscopy measurements

The successful application of impedance spectroscopy in daily practice requires accurate measurements for modeling complex physiological or electrochemical phenomena in a single frequency or several frequencies at different (or simultaneous) time instants. Nowadays, two approaches are possible for frequency domain impedance spectroscopy measurements: (1) using the classical technique of frequency sweep and (2) using (non-)periodic broadband signals, i.e. multisine excitations. Both techniques share the common problem of how to design the experimental conditions, e.g. the excitation power spectrum, in order to achieve accuracy of maximum impedance model parameters from the impedance data modeling process. The original contribution of this paper is the calculation and design of the D-optimal multisine excitation power spectrum for measuring impedance systems modeled as 2R-1C equivalent electrical circuits. The extension of the results presented for more complex impedance models is also discussed. The influence of the multisine power spectrum on the accuracy of the impedance model parameters is analyzed based on the Fisher information matrix. Furthermore, the optimal measuring frequency range is given based on the properties of the covariance matrix. Finally, simulations and experimental results are provided to validate the theoretical aspects presented.Peer ReviewedPostprint (published version

Molecular impact of launch related dynamic vibrations and static hypergravity in planarians

Although many examples of simulated and real microgravity demonstrating their profound effect on biological systems are described in literature, few reports deal with hypergravity and vibration effects, the levels of which are severely increased during the launch preceding the desired microgravity period. Here, we used planarians, flatworms that can regenerate any body part in a few days. Planarians are an ideal model to study the impact of launch-related hypergravity and vibration during a regenerative process in a “whole animal” context. Therefore, planarians were subjected to 8.5 minutes of 4 g hypergravity (i.e. a human-rated launch level) in the Large Diameter Centrifuge (LDC) and/or to vibrations (20–2000 Hz, 11.3 Grms) simulating the conditions of a standard rocket launch. The transcriptional levels of genes (erg-1, runt-1, fos, jnk, and yki) related with the early stress response were quantified through qPCR. The results show that early response genes are severely deregulated after static and dynamic loads but more so after a combined exposure of dynamic (vibration) and static (hypergravity) loads, more closely simulating real launch exposure profiles. Importantly, at least four days after the exposure, the transcriptional levels of those genes are still deregulated. Our results highlight the deep impact that short exposures to hypergravity and vibration have in organisms, and thus the implications that space flight launch could have. These phenomena should be taken into account when planning for well-controlled microgravity studies

LPMLE3 : a novel 1-D approach to study water flow in streambeds using heat as a tracer

We introduce LPMLE3, a new 1-D approach to quantify vertical water flow components at streambeds using temperature data collected in different depths. LPMLE3 solves the partial differential equation for coupled water flow and heat transport in the frequency domain. Unlike other 1-D approaches it does not assume a semi-infinite halfspace with the location of the lower boundary condition approaching infinity. Instead, it uses local upper and lower boundary conditions. As such, the streambed can be divided into finite subdomains bound at the top and bottom by a temperature-time series. Information from a third temperature sensor within each subdomain is then used for parameter estimation. LPMLE3 applies a low order local polynomial to separate periodic and transient parts (including the noise contributions) of a temperature-time series and calculates the frequency response of each subdomain to a known temperature input at the streambed top. A maximum-likelihood estimator is used to estimate the vertical component of water flow, thermal diffusivity, and their uncertainties for each streambed subdomain and provides information regarding model quality. We tested the method on synthetic temperature data generated with the numerical model STRIVE and demonstrate how the vertical flow component can be quantified for field data collected in a Belgian stream. We show that by using the results in additional analyses, nonvertical flow components could be identified and by making certain assumptions they could be quantified for each subdomain. LPMLE3 performed well on both simulated and field data and can be considered a valuable addition to the existing 1-D methods

Correcting for non-periodic behaviour in perturbative experiments: application to heat pulse propagation and modulated gas-puff experiments

This paper introduces a recent innovation in dealing with non-periodic behavior often referred to as transients. These transients can be the result from unforced response due to the initial condition and other drifts which are a source of error when performing and interpreting Fourier analysis on measurement data. Fourier analysis is particularly relevant in system identification used to build feedback controllers and the analysis of various pulsed experiments such as heat pulse propagation studies. The basic idea behind the methodology is that transients are continuous complex-valued smooth functions in the Fourier domain which can be estimated from the Fourier data. Then, these smooth functions can be approximately subtracted from the data such that only periodic components are retained. The merit of the approach is shown in two experimental examples, i.e., heat pulse propagation (core transport analysis) and radiation front movement due to gas puffing. The examples show that the quality of the data is significantly improved such that it allows new interpretation of the results even for non-ideal measurements.</p

Correcting for non-periodic behaviour in perturbative experiments: application to heat pulse propagation and modulated gas-puff experiments

This paper introduces a recent innovation in dealing with non-periodic behavior often referred to as transients in perturbative experiments. These transients can be the result from the unforced response due to the initial condition and other slow trends in the measurement data and are a source of error when performing and interpreting Fourier spectra. Fourier analysis is particularly relevant in system identification used to build feedback controllers and the analysis of various pulsed experiments such as heat pulse propagation studies. The basic idea behind the methodology is that transients are continuous complex-valued smooth functions in the Fourier domain which can be estimated from the Fourier data. Then, these smooth functions can be subtracted from the data such that only periodic components are retained. The merit of the approach is shown in two experimental examples, i.e. heat pulse propagation (core transport analysis) and radiation front movement due to gas puffing in the divertor. The examples show that the quality of the data is significantly improved such that it allows for new interpretation of the results even for non-ideal measurements

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features

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

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]