Is there an unmet medical need for improved hearing restoration?

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade

Overloaded adeno-associated virus as a novel gene therapeutic tool for otoferlin-related deafness

Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (OTOF), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (Otof-KO) mice. Here, we employed in vitro and in vivo approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length Otof coding sequence. Upon early postnatal injection into the cochlea of Otof-KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9—using a single overloaded AAV vector—is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches

A role of oligodendrocytes in information processing

Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, oligodendrocytes play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition to speeding up conduction velocity. Here, we analyze the role of myelin in auditory information processing using paradigms that are also good predictors of speech understanding in humans. We compare mice with different degrees of dysmyelination using acute multiunit recordings in the auditory cortex, in combination with behavioral readouts. We find complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. We observe partially discriminable but similar deficits in well myelinated mice in which glial cells cannot fully support axons metabolically. We suggest a model in which myelination contributes to sus- tained stimulus perception in temporally complex paradigms, with a role of metabolically active oligodendrocytes in cortical information processing

On the CCA2 Security of McEliece in the Standard Model

In this paper we study public-key encryption schemes based on error-correcting codes that are IND-CCA2 secure in the standard model. In particular, we analyze a protocol due to Dowsley, Muller-Quade and Nascimento, based on a work of Rosen and Segev. The original formulation of the protocol contained some ambiguities and incongruences, which we point out and correct; moreover, the protocol deviates substantially from the work it is based on. We then present a construction which resembles more closely the original Rosen-Segev framework, and show how this can be instantiated with the McEliece scheme

A single gene defect causing claustrophobia

Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3′untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia

QC-MDPC: A Timing Attack and a CCA2 KEM

International audienceIn 2013, Misoczki, Tillich, Sendrier and Barreto proposed a variant of the McEliece cryptosystem based on quasi-cyclic moderate-density parity-check (QC-MDPC) codes. This proposal uses an iterative bit-flipping algorithm in its decryption procedure. Such algorithms fail with a small probability. At Asiacrypt 2016, Guo, Johansson and Stankovski (GJS) exploited these failures to perform a key recovery attack. They introduced the notion of the distance spectrum of a sparse vector and showed that the knowledge of the spectrum is enough to find the vector. By observing many failing plaintexts they recovered the distance spectrum of the QC-MDPC secret key. In this work, we explore the underlying causes of this attack, ways in which it can be improved, and how it can be mitigated. We prove that correlations between the spectrum of the key and the spectrum of the error induce a bias on the distribution of the syndrome weight. Hence, the syndrome weight is the fundamental quantity from which secret information leaks. Assuming a side-channel allows the observation of the syndrome weight, we are able to perform a key-recovery attack, which has the advantage of exploiting all known plaintexts, not only those leading to a decryption failure. Based on this study, we derive a timing attack. It performs well on most decoding algorithms, even on the recent variants where the decryption failure rate is low, a case which is more challenging to the GJS attack. To our knowledge, this is the first timing attack on a QC-MDPC scheme. Finally, we show how to construct a new KEM, called ParQ that can reduce the decryption failure rate to a level negligible in the security parameter, without altering the QC-MDPC parameters. This is done through repeated encryption. We formally prove the IND-CCA2 security of ParQ, in a model that considers decoding failures. This KEM offers smaller key sizes and is suitable for purposes where the public key is used statically

Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here, we find that expression of the tetraspan-transmembrane protein CMTM5 (chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and central nervous system (CNS) myelin. Genetic disruption of the Cmtm5 gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial Cmtm5 deficiency causes an early-onset progressive axonopathy, which we also observe in global and tamoxifen-induced oligodendroglial Cmtm5 mutants. Presence of the WldS mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis

Mice do not require auditory input for the normal development of their ultrasonic vocalizations

<p>Abstract</p> <p>Background</p> <p>Transgenic mice have become an important tool to elucidate the genetic foundation of the human language faculty. While learning is an essential prerequisite for the acquisition of human speech, it is still a matter of debate whether auditory learning plays any role in the development of species-specific vocalizations in mice. To study the influence of auditory input on call development, we compared the occurrence and structure of ultrasonic vocalizations from deaf otoferlin-knockout mice, a model for human deafness DFNB9, to those of hearing wild-type and heterozygous littermates.</p> <p>Results</p> <p>We found that the occurrence and structure of ultrasonic vocalizations recorded from deaf otoferlin-knockout mice and hearing wild-type and heterozygous littermates do not differ. Isolation calls from 16 deaf and 15 hearing pups show the same ontogenetic development in terms of the usage and structure of their vocalizations as their hearing conspecifics. Similarly, adult courtship 'songs' produced by 12 deaf and 16 hearing males did not differ in the latency to call, rhythm of calling or acoustic structure.</p> <p>Conclusion</p> <p>The results indicate that auditory experience is not a prerequisite for the development of species-specific vocalizations in mice. Thus, mouse models are of only limited suitability to study the evolution of vocal learning, a crucial component in the development of human speech. Nevertheless, ultrasonic vocalizations of mice constitute a valuable readout in studies of the genetic foundations of social and communicative behavior.</p

Reproductive Isolation and Ecological Niche Partition among Larvae of the Morphologically Cryptic Sister Species Chironomus riparius and C. piger

Background One of the central issues in ecology is the question what allows sympatric occurrence of closely related species in the same general area? The non-biting midges Chironomus riparius and C. piger, interbreeding in the laboratory, have been shown to coexist frequently despite of their close relatedness, similar ecology and high morphological similarity. Methodology/Principal Findings In order to investigate factors shaping niche partitioning of these cryptic sister species, we explored the actual degree of reproductive isolation in the field. Congruent results from nuclear microsatellite and mitochondrial haplotype analyses indicated complete absence of interspecific gene-flow. Autocorrelation analysis showed a non-random spatial distribution of the two species. Though not dispersal limited at the scale of the study area, the sister species occurred less often than expected at the same site, indicating past or present competition. Correlation and multiple regression analyses suggested the repartition of the available habitat along water chemistry gradients (nitrite, conductivity, CaCO3), ultimately governed by differences in summer precipitation regime. Conclusions We show that these morphologically cryptic sister species partition their niches due to a certain degree of ecological distinctness and total reproductive isolation in the field. The coexistence of these species provides a suitable model system for the investigation of factors shaping the distribution of closely related, cryptic species