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The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected by a variety of links and also carry an electron-dense surface coat. The coat may contribute to stereocilia adhesion or protect from stereocilia fusion, but its molecular identity remains unknown. From a database of hair-cell-enriched translated proteins, we identify Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein of 4249 amino acids with a single transmembrane domain. Using serial immunogold scanning electron microscopy, we show that PKHD1L1 is expressed at the tips of stereocilia, especially in the high-frequency regions of the cochlea. PKHD1L1-deficient mice lack the surface coat at the upper but not lower regions of stereocilia, and they develop progressive hearing loss. We conclude that PKHD1L1 is a component of the surface coat and is required for normal hearing in mice. There is little known about the function or molecular identity of the electron-dense stereocilia coat, which is transiently present at the surface of stereocilia. In this study authors screened a database of hair-cell-enriched translated proteins to identify the expression of Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein, and show that it forms the coat at the tips of stereocilia and is required for normal hearing in mice

We propose a novel biologically plausible computational model of working memory (WM) implemented by a spiking neuron network (SNN) interacting with a network of astrocytes. The SNN is modeled by synaptically coupled Izhikevich neurons with a non-specific architecture connection topology. Astrocytes generating calcium signals are connected by local gap junction diffusive couplings and interact with neurons via chemicals diffused in the extracellular space. Calcium elevations occur in response to the increased concentration of the neurotransmitter released by spiking neurons when a group of them fire coherently. In turn, gliotransmitters are released by activated astrocytes modulating the strength of the synaptic connections in the corresponding neuronal group. Input information is encoded as two-dimensional patterns of short applied current pulses stimulating neurons. The output is taken from frequencies of transient discharges of corresponding neurons. We show how a set of information patterns with quite significant overlapping areas can be uploaded into the neuron-astrocyte network and stored for several seconds. Information retrieval is organized by the application of a cue pattern representing one from the memory set distorted by noise. We found that successful retrieval with the level of the correlation between the recalled pattern and ideal pattern exceeding 90% is possible for the multi-item WM task. Having analyzed the dynamical mechanism of WM formation, we discovered that astrocytes operating at a time scale of a dozen of seconds can successfully store traces of neuronal activations corresponding to information patterns. In the retrieval stage, the astrocytic network selectively modulates synaptic connections in the SNN leading to successful recall. Information and dynamical characteristics of the proposed WM model agrees with classical concepts and other WM models.

Usher syndrome type 1 F (USH1F), caused by mutations in the protocadherin-15 gene ( PCDH15 ), is characterized by congenital deafness, lack of balance, and progressive blindness. In hair cells, the receptor cells of the inner ear, PCDH15 is a component of tip links, fine filaments which pull open mechanosensory transduction channels. A simple gene addition therapy for USH1F is challenging because the PCDH15 coding sequence is too large for adeno-associated virus (AAV) vectors. We use rational, structure-based design to engineer mini-PCDH15s in which 3–5 of the 11 extracellular cadherin repeats are deleted, but which still bind a partner protein. Some mini-PCDH15s can fit in an AAV. An AAV encoding one of these, injected into the inner ears of mouse models of USH1F, produces a mini-PCDH15 which properly forms tip links, prevents the degeneration of hair cell bundles, and rescues hearing. Mini-PCDH15s may be a useful therapy for the deafness of USH1F. Mutations in PCDH15 cause deafness and blindness in Usher syndrome 1 F, but gene therapy is difficult because the PCDH15 sequence is too large for AAV vectors. Here, the authors engineered a miniPCDH15 that fits in AAV and rescues hearing in mouse Usher syndrome 1F models.

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual-adeno-associated virus (dual-AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and nonhuman primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector.

In the process of developing deposits of magnetite quartzites, hematite quartzites are simultaneously involved in mining. But the processing of hematite quartzites is associated with significant difficulties, so they accumulate in warehouses, landfills and spread uncontrollably in the environment. A detailed study of the features of the composition, structure and technological properties of hematite ores made it possible to develop a new method for complex processing in a vortex air-mineral flow. Under laboratory conditions, a number of commercial products were produced from them: iron ore concentrate, sinter ore, clinker ore, mineral paint and quartz sand, without waste accumulation. The formation of magnetic floccules is reduced in the air stream. Therefore, this technology also improves the processing of magnetite ores.

Mutations in the GJB2 gene cause DFNB1, the most common hereditary hearing loss. GJB2 is expressed by cochlear epithelial cells and fibrocytes, but not by sensory hair cells or neurons. Attempts to treat DFNB1 mouse models with gene therapy have not substantially restored function, as inappropriate expression in hair cells and neurons might compromise their electrical activity. Here, we use ATAC-seq to identify candidate gene regulatory elements (GREs) that can drive cell-type-specific expression of GJB2 . HA-tagged GJB2, delivered to a conditional knockout mouse with AAV vectors carrying GREs, is expressed by the appropriate cells, prevents degeneration, and rescues hearing by only 10–20 dB. In a Gjb2 partial knockdown model, a vector lacking HA prevents degeneration and completely restores hearing. In cynomolgus monkey cochleas, human GJB2.HA delivered with similar vectors is located in the appropriate cell types and causes little or no compromise of hearing sensitivity. Together, these findings suggest that GRE-mediated expression of GJB2 can prevent hearing loss in DFNB1 patients. Mutations in GJB2 cause DFNB1, the most common hereditary deafness. ATAC-seq identification of gene regulatory elements enables targeted GJB2 delivery to cochlear cells, preventing hearing loss in mouse models.

Cognitive abilities decline with age, constituting a major manifestation of aging. The quantitative biomarkers of this process, as well as the correspondence to different biological clocks, remain largely an open problem. In this paper we employ the following cognitive tests: 1. differentiation of shades (campimetry); 2. evaluation of the arithmetic correctness and 3. detection of reversed letters and identify the most significant age-related cognitive indices. Based on their subsets we construct a machine learning-based Cognitive Clock that predicts chronological age with a mean absolute error of 8.62 years. Remarkably, epigenetic and phenotypic ages are predicted by Cognitive Clock with an even better accuracy. We also demonstrate the presence of correlations between cognitive, phenotypic and epigenetic age accelerations that suggests a deep connection between cognitive performance and aging status of an individual.

Accumulated experimental data strongly suggest that astrocytes play an important role in the pathogenesis of neurodegeneration, including Alzheimer’s disease (AD). The effect of astrocytes on the calcium activity of neuron–astroglia networks in AD modelling was the object of the present study. We have expanded and improved our approach’s capabilities to analyze calcium activity. We have developed a novel algorithm to construct dynamic directed graphs of both astrocytic and neuronal networks. The proposed algorithm allows us not only to identify functional relationships between cells and determine the presence of network activity, but also to characterize the spread of the calcium signal from cell to cell. Our study showed that Alzheimer’s astrocytes can change the functional pattern of the calcium activity of healthy nerve cells. When healthy nerve cells were cocultivated with astrocytes treated with Aβ42, activation of calcium signaling was found. When healthy nerve cells were cocultivated with 5xFAD astrocytes, inhibition of calcium signaling was observed. In this regard, it seems relevant to further study astrocytic–neuronal interactions as an important factor in the regulation of the functional activity of brain cells during neurodegenerative processes. The approach to the analysis of streaming imaging data developed by the authors is a promising tool for studying the collective calcium dynamics of nerve cells.

Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2-treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).