Fibrosis, or excessive scarring, is characterized by the emergence of alpha-smooth muscle actin (αSMA)-expressing myofibroblasts and the excessive accumulation of fibrotic extracellular matrix (ECM). ...Currently, there is a lack of effective treatment options for fibrosis, highlighting an unmet need to identify new therapeutic targets. The acquisition of a fibrotic phenotype is associated with changes in chromatin structure, a key determinant of gene transcription activation and repression. The major repressive histone mark, H3K27me3, has been linked to dynamic changes in gene expression in fibrosis through alterations in chromatin structure. H3K27-specific homologous histone methylase (HMT) enzymes, Enhancer of zeste 1 and 2 (EZH1, EZH2), which are the alternative subunits of the Polycomb Repressive Complex 2 (PRC2) and demethylase (KDM) enzymes, Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and Lysine demethylase 6B (KDM6B), are responsible for regulating methylation status of H3K27me3. In this review, we explore how these key enzymes regulate chromatin structure to alter gene expression in fibrosis, highlighting them as attractive targets for the treatment of fibrosis.
While the lens is an avascular tissue with an immune-privileged status, studies have now revealed that there are immune responses specifically linked to the lens. The response to lens injury, such as ...following cataract surgery, has been shown to involve the activation of the resident immune cell population of the lens and the induction of immunomodulatory factors by the wounded epithelium. However, there has been limited investigation into the immediate response of the lens to wounding, particularly those induced factors that are intrinsic to the lens and its associated resident immune cells. Using an established chick embryo ex vivo cataract surgery model has made it possible to determine the early immune responses of this tissue to injury, including its resident immune cells, through a transcriptome analysis. RNA-seq studies were performed to determine the gene expression profile at 1 h post wounding compared to time 0. The results provided evidence that, as occurs in other tissues, the resident immune cells of the lens rapidly acquired a molecular signature consistent with their activation. These studies also identified the expression of many inflammatory factors by the injured lens that are associated with both the induction and regulation of the immune response.
To ensure proper wound healing it is important to elucidate the signaling cues that coordinate leader and follower cell behavior to promote collective migration and proliferation for wound healing in ...response to injury. Using an ex vivo post-cataract surgery wound healing model we investigated the role of class I phosphatidylinositol-3-kinase (PI3K) isoforms in this process. Our findings revealed a specific role for p110α signaling independent of Akt for promoting the collective migration and proliferation of the epithelium for wound closure. In addition, we found an important role for p110α signaling in orchestrating proper polarized cytoskeletal organization within both leader and wounded epithelial follower cells to coordinate their function for wound healing. p110α was necessary to signal the formation and persistence of vimentin rich-lamellipodia extensions by leader cells and the reorganization of actomyosin into stress fibers along the basal domains of the wounded lens epithelial follower cells for movement. Together, our study reveals a critical role for p110α in the collective migration of an epithelium in response to wounding.
Double mask edge illumination (DM-EI) set-ups can detect differential phase and attenuation information from a sample. However, analytical separation of the two signals often requires acquiring two ...frames with inverted differential phase contrast signals. Typically, between these two acquisitions, the first mask is moved to create a different illumination condition. This can lead to potential errors which adversely affect the data collected. In this paper, we implement a single mask EI laboratory set-up that allows for a single shot retrieval of the differential phase and attenuation images, without the need for a high resolution detector or high magnification. As well as simplifying mask alignment, the advantages of the proposed set-up can be exploited in one of two ways: either the total acquisition time can be halved with respect to the DM-EI set-up or, for the same acquisition time, twice the statistics can be collected. In this latter configuration, the signal-to-noise ratio and contrast in the mixed intensity images, and the angular sensitivity of the two set-ups were compared. We also show that the angular sensitivity of the single mask set-up can be well approximated from its illumination curve, which has been modelled as a convolution between the source spatial distribution at the detector plane, the pre-sample mask and the detector point spread function (PSF). A polychromatic wave optics simulation was developed on these bases and benchmarked against experimental data. It can also be used to predict the angular sensitivity and contrast of any set-up as a function of detector PSF.
Noise is an important socioeconomic problem in industrialized countries. Development of efficient treatment options for the audiological phenomena resulting from noise-induced hearing loss requires ...in-depth understanding of the underlying damage mechanisms causing peripheral and central nervous changes. Mechanical damage, ischemia and excitotoxicity are mainly responsible for noise-induced cell death and biophysical changes in the cochlea. Auditory synaptopathy is an additional consequence. Besides these cochlear pathologies, noise exposure leads to extensive changes within the central auditory pathway. Overstimulation causes early cell loss in the ventral cochlear nucleus just after noise exposure, which is in accordance with enhancement of apoptotic mechanisms within the corresponding timeframe. In contrast to the cell loss in lower auditory structures due to overstimulation, the later significant reduction of cell density in higher auditory structures is due to sensory deprivation. Changes in network homeostasis seem to partially compensate structural losses by modulation of spontaneous activity. However, central nervous processing of auditory information is permanently impaired by the neuroplastic changes. Unfortunately, the various noise-induced peripheral and central pathologies are difficult to treat. New therapeutic approaches are required, particularly for treatment of central nervous processing disorders and auditory synaptopathy, which contribute to audiological phenomena such as tinnitus, hyperacusis and poor speech perception in noise.
Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin ...structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis.
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•UTX/KDM6B decondenses nascent chromatin structure for myofibroblast differentiation•Inhibiting UTX/KDM6B condenses chromatin to block fibrotic transcriptome activation•UTX/KDM6B inhibition blocks myofibroblast emergence and fibrotic extracellular matrix (ECM) production•Targeting UTX/KDM6B has potential therapeutic application in lens and lung fibrosis
Epigenetics; Molecular mechanism of gene regulation; Molecular physiology; Transcriptomics
The purpose of the MU-RAY project is to develop an innovative approach to the study of volcanoes and their monitoring based on a particle physics approach. The test site is Vesuvio: one of the higher ...risk volcanoes in the world. In this context, muon radiography is an innovative method of enormous impact. This is an imaging technique which relies on the measurement, by means of a cosmic ray telescope, of the absorption in the volcano of muons with near-horizontal trajectories, produced by the interactions of cosmic rays with the atmosphere. Since 2003 this technique has been successfully used on volcanoes in Japan, providing pictures of their vertices with resolutions much better than those obtained with the traditional techniques based on gravimeters. Researchers from Naples and Florence are currently involved in the construction and testing of a prototype telescope based on the use of bars of plastic scintillator with a triangular section whose scintillation light is collected by special fibres (wave length shifters) and transported to SiPM (Silicon photomultipliers). A complete prototype telescope, consisting of three xy scintillation planes and 1m2 active area has been assembled and is now under test.
The MU-RAY detector for muon radiography of volcanoes Anastasio, A.; Ambrosino, F.; Basta, D. ...
Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment,
12/2013, Letnik:
732
Journal Article, Conference Proceeding
Recenzirano
The MU-RAY detector has been designed to perform muon radiography of volcanoes. The possible use on the field introduces several constraints. First the electric power consumption must be reduced to ...the minimum, so that the detector can be solar-powered. Moreover it must be robust and transportable, for what concerns the front-end electronics and data acquisition. A 1m2 prototype has been constructed and is taking data at Mt. Vesuvius. The detector consists of modules of 32 scintillator bars with wave length shifting fibers and silicon photomultiplier read-out. A dedicated front-end electronics has been developed, based on the SPIROC ASIC. An introduction to muon radiography principles, the MU-RAY detector description and results obtained in laboratory will be presented.
Cochlear implant surgery has become a successful procedure for deaf patients to restore their hearing again. Some of the patients, however, complain of persisting dizziness after the surgery which ...can have a major impact on their quality of life. Neurotological tests of the vestibular system were applied in a total of 18 cochlear implantees pre- and postoperatively. In addition, vestibular evoked myogenic potentials were evoked intraoperatively to investigate possible interferences of the electrically stimulated cochlear implant electrode (eVEMP) with vestibular receptor cells of the saccule in more detail. After cochlear implantation, the saccular function was impaired in the majority of the patients. However, eVEMPs could be recorded intraoperatively in all patients by intracochlear, high-level electrical stimulation via the cochlear implant electrode. In essence, acute, short-term dizziness after cochlear implantation seems to result primarily from a transient vestibular deficit of various origins. In contrast to this, chronic, persisting dizziness after cochlear implant surgery is largely based on a dysfunction of the saccular macula which is an integral component of the otolith system. This saccular impairment is induced most likely by the insertion trauma of the cochlear implant electrode when advancing it into the inner ear. A possible coactivation of the inferior vestibular nerve by the electrical stimulation might play an additional role in the pathogenesis of the persisting postsurgical dizziness.
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