The mammalian inner ear consists of diverse cell types with important functions. Gene mutations in these diverse cell types have been found to underlie different forms of genetic hearing loss. Targeting these mutations for gene therapy development represents a future therapeutic strategy to treat hearing loss. Adeno-associated viral (AAV) vectors have become the vector of choice for gene delivery in animal models in vivo. To identify AAV vectors that target inner ear cell subtypes, we systemically screened 12 AAV vectors with different serotypes (AAV1, 2, 5, 6, 6.2, 7, 8, 9, rh.8, rh.10, rh.39, and rh.43) that carry a reporter gene GFP in neonatal and adult mice by microinjection in vivo. We found that most AAVs infect both neonatal and adult inner ear, with different specificities and expression levels. The inner ear cochlear sensory epithelial region, which includes auditory hair cells and supporting cells, is most frequently targeted for gene delivery. Expression of the transgene is sustained, and neonatal inner ear delivery does not adversely affect hearing. Adult inner ear injection of AAV has a similar infection pattern as the younger inner ear, with the exception that outer hair cell death caused by the injection procedure can lead to hearing loss. In the adult, more so than in the neonatal mice, cell types infected and efficiency of infection are correlated with the site of injection. Most infected cells survive in neonatal and adult inner ears. The study adds to the list of AAV vectors that transduce the mammalian inner ear efficiently, providing the tools that are important to study inner ear gene function and for the development of gene therapy to treat hearing loss.
This study aims to explore the role of fatty acid binding protein 4 (FABP4) in diabetic retinopathy (DR), and to elucidate the potential regulatory mechanism. We firstly developed a mouse model of DR by injection with streptozocin (STZ) into C57BL/6 male mice and a cell model of DR by induction of high glucose (HG) to ARPE-19 cells. BMS309403, an inhibitor of FABP4, was employed for treatment. The blood glucose in vivo was monitored and the histological changes of retinal tissues were observed by hematoxylin and eosin staining and Evans blue assay. The expression level of FABP4 was detected by western blot and Immunohistochemical staining. The critical factors related to lipid peroxidation and oxidative stress were detected using their commercial kits, respectively. Prussian blue staining, iron content assay and thiobarbituric acid-reactive substances (TBARS) assay were conducted to evaluate ferroptosis. As a result, FABP4 was elevated in retina and serum of STZ-induced mice and in HG-induced ARPE-19 cells. BMS309403 treatment notably alleviated reduced blood glucose, reduced histological damage, and vascular permeability. In addition, BMS309403 treatment inhibited lipid peroxidation, oxidative stress, and ferroptosis both in vivo and in vitro. Furthermore, BMS309403 promoted the activation of peroxisome proliferator-activated receptor γ (PPARγ). GW9662 (an inhibitor of PPARγ) or Erastin (an inducer of ferroptosis) partially weakened the suppressive effects of BMS309403 on HG-induced lipid peroxidation, oxidative stress and ferroptosis. Taken together, FABP4 inhibition alleviates lipid peroxidation and oxidative stress in DR by regulating PPARγ-mediated ferroptosis.
Abstract CD47‐SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47‐SIRPα axis is associated with on‐target off‐tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano‐degrader is developed to inhibit CD47‐SIRPα axis in a site‐specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano‐degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high‐affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor‐mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47‐SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano‐degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.
To define a spatial position of the cochlea in the skull base and to design an appropriate method of skull radiography for demonstration of the multichannel intracochlear electrode array.Measure the angle between the basal turn of the cochlear and the median sagittal line on the axial plane CT from 26 children candidates of cochlear implant and 32 adults.The angle between the axis of the cochlear and the median sagittal line varied from 40 degrees to 68 degrees, the average is 52.66 degrees. The average angle in children is 52.52 degrees (s = 7.07) and 52.80 degrees (s = 5.78) in the adults. The difference between the two group has no significance (P > 0.05).The plain radiography cochlear view gives a clear image of the whole intracochlear electrode array and each individual electrode, it is useful for evaluating the depth and exact position of the electrodes, managing frequency mapping and optimizing speech processing strategies, it can be widely used in cochlear implant clinics and research.
The optothermal spectrum of infrared MPA of CF3CDC12 obtained by using optothermal cell with a platinum filament as a detector is reported here. It is found that the absorption peak at 944 cm-1 in infrared linear absorption spectrum splits into two peaks at 947 cm-1 and 927cm-1 in MPA spectrum. This phenomenon could be related to-the coupling of normal vibrations produced by Coriolis forces and anharmonisity. So one could select a more suitable excited wavelength according to this new result in laser separation of deuterium isotop. The absoption peak at 986 cm-1 in infrared linear absorption spectrum shows a red shift of 6cm-1 in MPA spectrum. This is due to the anhamonicity of vibrational levels of the molecule.
ObjectiveTo investigate the clinical ch aracteristics and therapeutic results of malignant tumors of ceruminous glands of external auditory canal. MethodsRetrospective analysis of 13 cases of surgically treated malignant tumors of ceruminous glands of external auditory canal. Resultsof 13 cases, 11 were followed up for more than 5 years, 2 cases for more than 3 years. Among the 13 cases, 4 cases were lost during the follow up, while 7 cases alive and tumor free and 2 cases died of recurrences. ConclusionRadical resection of the external auditory canal and/or partial temporal bone resection are proposed in some advanced cases for malignant tumors of ceruminous glands of external auditory canal. Post-operative radiotherapy is indicated as a part of treatment. Long term follow up should be advocated for all patients.
A low energy neutral lithium beam source with energy about 6 keV and a neutral beam equivalent current of 20 μA/cm2 has been developed in ASIPP in order to measure the density gradient and the fluctuations in the edge plasma of the HT-6M tokamak. In the source, lithium ions are extracted from a solid emitter (β-eucryptite), focused in a two-tube immersion lens, and neutralized in a charge-exchange cell with sodium. This source operates in pulsed mode. The pulse length is adjustable from 10 to 100 ms.
We establish a technique for the determination of the phase difference between even and odd parity continuum wave functions in atoms. This determination is based upon our detailed measurements of a quantum mechanical interference between two photoionization processes using a two-color laser field. We present our measurement of the phase difference between the continuum p and d waves in atomic rubidium, which is in good agreement with the expected value.
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