Rescue of auditory function by a single Administration of AAV-TMPRSS3 Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3A306T/A306T mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation

A clustering based transfer function for volume rendering using gray-gradient mode histogram

Volume rendering is an emerging technique widely used in the medical field to visualize human organs using tomography image slices. In volume rendering, sliced medical images are transformed into attributes, such as color and opacity through transfer function. Thus, the design of the transfer function directly affects the result of medical images visualization. A well-designed transfer function can improve both the image quality and visualization speed. In one of our previous paper, we designed a multi-dimensional transfer function based on region growth to determine the transparency of a voxel, where both gray threshold and gray change threshold are used to calculate the transparency. In this paper, a new approach of the transfer function is proposed based on clustering analysis of gray-gradient mode histogram, where volume data is represented in a two-dimensional histogram. Clustering analysis is carried out based on the spatial information of volume data in the histogram, and the transfer function is automatically generated by means of clustering analysis of the spatial information. The dataset of human thoracic is used in our experiment to evaluate the performance of volume rendering using the proposed transfer function. By comparing with the original transfer function implemented in two popularly used volume rendering systems, visualization toolkit (VTK) and RadiAnt DICOM Viewer, the effectiveness and performance of the proposed transfer function are demonstrated in terms of the rendering efficiency and image quality, where more accurate and clearer features are presented rather than a blur red area. Furthermore, the complex operations on the two-dimensional histogram are avoided in our proposed approach and more detailed information can be seen from our final visualized image

Interlayer transmission of magnons in dynamic spin valve structures

Magnonic devices are promising alternatives to conventional charge-current-driven spintronic devices. As the basic unit of spintronic devices, the spin valve is of limited use in magnonics because its dynamics is rarely studied. Here, we investigate the interlayer transmission of magnons in dynamic spin valve structures using the time-resolved magneto-optical Kerr effect. Interaction between magnons and the interfacial dissipation are studied by comparing three samples with different spin valve structures. Magnons with different intrinsic frequencies have strong interactions. In contrast, magnons with similar intrinsic frequencies have relatively weak interactions. Interfacial dissipations of magnons are increased by rare earth insertion, which can reduce the interactions between magnons indirectly. This work extends the application of spin valve structures to magnonic devices beyond their conventional use

The effect of growth sequence on magnetization damping in Ta/CoFeB/MgO structures

Magnetization damping is a key parameter to control the critical current and the switching speed in magnetic random access memory, and here we report the effect of the growth sequence on the magnetic dynamics properties of perpendicularly magnetized Ta/CoFeB/MgO structures. Ultrathin CoFeB films have been grown between Ta and MgO but with different stack sequences, i.e. substrate/Ta/CoFeB/MgO/Ta and substrate/Ta/MgO/CoFeB/Ta. The magnetization dynamics induced by femtosecond laser was investigated by using all-optical pump-probe measurements. We found that the Gilbert damping constant was modulated by reversing stack structures, which offers the potential to tune the damping parameter by the growth sequence. The Gilbert damping constant was enhanced from 0.017 for substrate/Ta/CoFeB/MgO/Ta to 0.027 for substrate/Ta/MgO/CoFeB/Ta. We believe that this enhancement originates from the increase of intermixing at the CoFeB/Ta when the Ta atom layer was grown after the CoFeB layer

Critical success criteria for B2B E-commerce systems in Chinese medical supply chain.

The paper presents an exploratory investigation to determine and prioritise the critical success criteria, which can measure and guide the successful application and performance improvement of business to business e-commerce system (BBECS) in a medical supply chain's selling and buying functions, in the context of global business expansion. The research reveals that the buying and the selling functions have different prioritisations on the majority of the determined critical success measuring criteria. These criteria are categorised into three Critical Success Measuring Criteria Groups, for the selling and the buying functions, respectively, guiding medical supply chain members in harnessing the full advantage of a BBECS. For the selling function, the top critical success measuring criteria are as follows: integrating information searching/transmission and application processes, ensuring the reliability and timeliness of technical support, ensuring recognition and acceptance of e-commerce processes, displaying the organisation's business focus and product/service provisions online, securing a large scale/amount of business transactions, adjusting production outputs and inventory levels and having more registered users than competitors do. The top critical success measuring criteria for the buying function are as follows: securing the establishment of business relationships between businesses, displaying the measures ensuring mutual trust and cooperation online, ensuring employees' recognition of the benefit of e-commerce in increasing revenue, ensuring the contribution to the development and realisation of corporate strategy, achieving cost reduction for the organisation, making the purchase of famous brand products available/doable, securing a large scale/amount of business transactions, and ensuring the attainability of products/services at a lower price

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(−9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(−9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA

GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment

Background: Mutations in GJB2 are the most common molecular defects responsible for autosomal recessive nonsyndromic hearing impairment (NSHI). The mutation spectra of this gene vary among different ethnic groups. Methods: In order to understand the spectrum and frequency of GJB2 mutations in the Chinese population, the coding region of the GJB2 gene from 2063 unrelated patients with NSHI was PCR amplified and sequenced. Results: A total of 23 pathogenic mutations were identified. Among them, five (p.W3X, c.99delT, c.155_c.158delTCTG, c.512_c.513insAACG, and p.Y152X) are novel. Three hundred and seven patients carry two confirmed pathogenic mutations, including 178 homozygotes and 129 compound heterozygotes. One hundred twenty five patients carry only one mutant allele. Thus, GJB2 mutations account for 17.9% of the mutant alleles in 2063 NSHI patients. Overall, 92.6% (684/739) of the pathogenic mutations are frame-shift truncation or nonsense mutations. The four prevalent mutations; c.235delC, c.299_c.300delAT, c.176_c.191del16, and c.35delG, account for 88.0% of all mutantalleles identified. The frequency of GJB2 mutations (alleles) varies from 4% to 30.4% among different regions of China. It also varies among different sub-ethnic groups. Conclusion: In some regions of China, testing of the three most common mutations can identify at least one GJB2 mutant allele in all patients. In other regions such as Tibet, the three most common mutations account for only 16% the GJB2 mutant alleles. Thus, in this region, sequencing of GJB2 would be recommended. In addition, the etiology of more than 80% of the mutant alleles for NSHI in China remains to be identified. Analysis of other NSHI related genes will be necessary

HFCF-Net:A hybrid-feature cross fusion network for COVID-19 lesion segmentation from CT volumetric images

BACKGROUND: The coronavirus disease 2019 (COVID‐19) spreads rapidly across the globe, seriously threatening the health of people all over the world. To reduce the diagnostic pressure of front‐line doctors, an accurate and automatic lesion segmentation method is highly desirable in clinic practice. PURPOSE: Many proposed two‐dimensional (2D) methods for sliced‐based lesion segmentation cannot take full advantage of spatial information in the three‐dimensional (3D) volume data, resulting in limited segmentation performance. Three‐dimensional methods can utilize the spatial information but suffer from long training time and slow convergence speed. To solve these problems, we propose an end‐to‐end hybrid‐feature cross fusion network (HFCF‐Net) to fuse the 2D and 3D features at three scales for the accurate segmentation of COVID‐19 lesions. METHODS: The proposed HFCF‐Net incorporates 2D and 3D subnets to extract features within and between slices effectively. Then the cross fusion module is designed to bridge 2D and 3D decoders at the same scale to fuse both types of features. The module consists of three cross fusion blocks, each of which contains a prior fusion path and a context fusion path to jointly learn better lesion representations. The former aims to explicitly provide the 3D subnet with lesion‐related prior knowledge, and the latter utilizes the 3D context information as the attention guidance of the 2D subnet, which promotes the precise segmentation of the lesion regions. Furthermore, we explore an imbalance‐robust adaptive learning loss function that includes image‐level loss and pixel‐level loss to tackle the problems caused by the apparent imbalance between the proportions of the lesion and non‐lesion voxels, providing a learning strategy to dynamically adjust the learning focus between 2D and 3D branches during the training process for effective supervision. RESULT: Extensive experiments conducted on a publicly available dataset demonstrate that the proposed segmentation network significantly outperforms some state‐of‐the‐art methods for the COVID‐19 lesion segmentation, yielding a Dice similarity coefficient of 74.85%. The visual comparison of segmentation performance also proves the superiority of the proposed network in segmenting different‐sized lesions. CONCLUSIONS: In this paper, we propose a novel HFCF‐Net for rapid and accurate COVID‐19 lesion segmentation from chest computed tomography volume data. It innovatively fuses hybrid features in a cross manner for lesion segmentation, aiming to utilize the advantages of 2D and 3D subnets to complement each other for enhancing the segmentation performance. Benefitting from the cross fusion mechanism, the proposed HFCF‐Net can segment the lesions more accurately with the knowledge acquired from both subnets