The use of animal models to study cell transplantation in neuropathic hearing loss

Auditory neuropathy (AN) is a form of sensorineural deafness specifically affecting the conduction of the nerve impulse from the cochlear hair cells to the auditory centres of the brain. As such, the condition is a potential clinical target for ‘cell replacement therapy’, in which a functioning auditory nerve is regenerated by transplanting an appropriated neural progenitor. In this review, we survey the current literature and examine possible experimental models for this condition, with particular reference to their compatibility as suitable hosts for transplantation. The use of exogenous neurotoxic agents such as ouabain or β-bungarotoxin is discussed, as are ageing and noise-induced synaptopathy models. Lesioning of the nerve by mechanical damage during surgery and the neuropathy resulting from infectious diseases may be very relevant clinically, and we discuss whether there are good models for these situations. We also address genetic models for AN, examining whether the phenotypes truly model the clinical situation in their human counterpart syndromes - we use the example of the hyperbilirubinaemic Gunn rat as a particular instance in this regard

If the Fed sneezes, who catches a cold?

This paper studies the international spillovers of US monetary policy shocks on a number of macroeconomic and financial variables in 36 advanced and emerging economies. In most countries, a surprise US monetary tightening leads to depreciation against the dollar; industrial production and real GDP fall, unemployment rises. Inflation declines especially in advanced economies. At the same time, there is significant heterogeneity across countries in the response of asset prices, and portfolio and banking cross-border flows. However, no clear-cut systematic relation emerges between country responses and likely relevant country characteristics, such as their income level, dollar exchange rate flexibility, financial openness, trade openness vs. the US, dollar exposure in foreign assets and liabilities, and incidence of commodity exports. 2017 Elsevier B.V. All rights reserved

Anodal tDCS and High-Frequency tRNS Targeting the Occipitotemporal Cortex Do Not Always Enhance Face Perception

There has been increasing interest in the utility of transcranial electrical stimulation as a tool to enhance cognitive abilities. In the domain of face perception, enhancements have been reported for both transcranial direct current stimulation (tDCS) and high-frequency transcranial random noise stimulation (tRNS) targeting the occipitotemporal cortex. In a series of two experiments, we attempted to replicate these findings for face identity perception, and extend on previous studies, to determine if similar enhancements are also observed for object and facial expression perception. In Experiment 1, using a single blind, between-subjects design in healthy volunteers (N = 53), we examined whether anodal tDCS over the occipitotemporal cortex enhanced performance on tasks involving perception of face identity, facial expression, and object stimuli, when compared to sham stimulation. We failed to replicate previous findings of enhanced performance on face and object perception, nor extend findings to facial expression perception. In Experiment 2, using a single blind, between-subjects design (N = 39), we examined the effect of high-frequency tRNS over the occipitotemporal cortex using the same three tasks employed in Experiment 1. We failed to replicate previous findings of enhanced face perception following high-frequency tRNS over the occipitotemporal cortex, relative to sham stimulation (although we used different stimulation parameters to that employed in a previous study). We also found no evidence of enhanced facial expression and object perception following high-frequency tRNS. The findings align with a growing body of studies that have failed to replicate previously reported enhancements following administration of tDCS and hint for different efficacy of, on first sight, related stimulation protocols. Future studies should explore the foundation of these differential effects in greater detail

Theoretical and Empirical Estimates of V-index Variability

Spatial heterogeneity of the ventricular repolarization (SHVR) might lead to life-threatening events when pathologically increases. The V-index is a metric meant to assess SHVR from the surface ECG and is computed on a set of ECG beats. The number of beats required to ensure low variability estimates is still matter of investigation. In this study, we investigated the role of the variability of the V-index estimator as function of the number of beats, using computerized simulations. We generated 100 sets of 1000 beats with seven different values of SHVR (from 10 to 70 ms) using the ECGSIM model. Using such dataset, we tested two approaches to estimate the variability of the V-index estimator. First, we analytically derived the probability density function of the estimator under independence and normality assumptions. Second, we used the bootstrap technique and derived that 1000 bootstrap iterations ensured stable estimates. We obtained that the standard deviation (STD) of V-index increased with SHVR values and decreased with the number of beats considered, with a rate similar to that of the sample mean. The independence assumption overestimated the STD by a factor of about 2. To conclude, the variability of the V-index estimator is below 5 ms when at least 100 beats are considered. The number of beats is in line with other techniques meant to estimate SHVR

Generation of otic lineages from integration-free human-induced pluripotent stem cells reprogrammed by mRNAs

Damage to the sensory hair cells and the spiral ganglion neurons of the cochlea leads to deafness. Induced pluripotent stem cells (iPSCs) are a promising tool to regenerate the cells in the inner ear that have been affected by pathology or have been lost. To facilitate the clinical application of iPSCs, the reprogramming process should minimize the risk of introducing undesired genetic alterations while conferring the cells the capacity to differentiate into the desired cell type. Currently, reprogramming induced by synthetic mRNAs is considered to be one of the safest ways of inducing pluripotency, as the transgenes are transiently delivered into the cells without integrating into the genome. In this study, we explore the ability of integration-free human-induced pluripotent cell lines that were reprogrammed by mRNAs, to differentiate into otic progenitors and, subsequently, into hair cell and neuronal lineages. hiPSC lines were induced to differentiate by culturing them in the presence of fibroblast growth factors 3 and 10 (FGF3 and FGF10). Progenitors were identified by quantitative microscopy, based on the coexpression of otic markers PAX8, PAX2, FOXG1, and SOX2. Otic epithelial progenitors (OEPs) and otic neuroprogenitors (ONPs) were purified and allowed to differentiate further into hair cell-like cells and neurons. Lineages were characterised by immunocytochemistry and electrophysiology. Neuronal cells showed inward Na+ () currents and outward () and inward K+ () currents while hair cell-like cells had inward and outward delayed rectifier K+ currents, characteristic of developing hair cells. We conclude that human-induced pluripotent cell lines that have been reprogrammed using nonintegrating mRNAs are capable to differentiate into otic cell types

Atrial Flutter Mechanism Detection Using Directed Network Mapping

Atrial flutter (AFL) is a common atrial arrhythmia typically characterized by electrical activity propagating around specific anatomical regions. It is usually treated with catheter ablation. However, the identification of rotational activities is not straightforward, and requires an intense effort during the first phase of the electrophysiological (EP) study, i.e., the mapping phase, in which an anatomical 3D model is built and electrograms (EGMs) are recorded. In this study, we modeled the electrical propagation pattern of AFL (measured during mapping) using network theory (NT), a well-known field of research from the computer science domain. The main advantage of NT is the large number of available algorithms that can efficiently analyze the network. Using directed network mapping, we employed a cycle-finding algorithm to detect all cycles in the network, resembling the main propagation pattern of AFL. The method was tested on two subjects in sinus rhythm, six in an experimental model of in-silico simulations, and 10 subjects diagnosed with AFL who underwent a catheter ablation. The algorithm correctly detected the electrical propagation of both sinus rhythm cases and in-silico simulations. Regarding the AFL cases, arrhythmia mechanisms were either totally or partially identified in most of the cases (8 out of 10), i.e., cycles around the mitral valve, tricuspid valve and figure-of-eight reentries. The other two cases presented a poor mapping quality or a major complexity related to previous ablations, large areas of fibrotic tissue, etc. Directed network mapping represents an innovative tool that showed promising results in identifying AFL mechanisms in an automatic fashion. Further investigations are needed to assess the reliability of the method in different clinical scenarios

PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa

Proteins PRPF31, PRPF3 and PRPF8 (RP-PRPFs) are ubiquitously expressed components of the spliceosome, a macromolecular complex that processes nearly all pre-mRNAs. Although these spliceosomal proteins are conserved in eukaryotes and are essential for survival, heterozygous mutations in human RP-PRPF genes lead to retinitis pigmentosa, a hereditary disease restricted to the eye. Using cells from patients with 10 different mutations, we show that all clinically relevant RP-PRPF defects affect the stoichiometry of spliceosomal small nuclear RNAs (snRNAs), the protein composition of tri-small nuclear ribonucleoproteins and the kinetics of spliceosome assembly. These mutations cause inefficient splicing in vitro and affect constitutive splicing ex-vivo by impairing the removal of at least 9% of endogenously expressed introns. Alternative splicing choices are also affected when RP-PRPF defects are present. Furthermore, we show that the steady-state levels of snRNAs and processed pre-mRNAs are highest in the retina, indicating a particularly elevated splicing activity. Our results suggest a role for PRPFs defects in the etiology of PRPF-linked retinitis pigmentosa, which appears to be a truly systemic splicing disease. Although these mutations cause widespread and important splicing defects, they are likely tolerated by the majority of human tissues but are critical for retinal cell surviva

Restoration of auditory evoked responses by human ES-cell-derived otic progenitors

Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells1, is responsible for a substantial proportion of patients with hearing impairment2. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant3. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness