用于电子点火的单片智能IGBT解决方案

市场对内置保护功能的更复杂器件的需求,促使半导体公司去开发智能技术:采用与分立器件相同的工艺,增加基本元器件.     

Quantification of the Immune Content in Neuroblastoma: Deep Learning and Topological Data Analysis in Digital Pathology

We introduce here a novel machine learning (ML) framework to address the issue of the quantitative assessment of the immune content in neuroblastoma (NB) specimens. First, the EUNet, a U-Net with an EfficientNet encoder, is trained to detect lymphocytes on tissue digital slides stained with the CD3 T-cell marker. The training set consists of 3782 images extracted from an original collection of 54 whole slide images (WSIs), manually annotated for a total of 73,751 lymphocytes. Resampling strategies, data augmentation, and transfer learning approaches are adopted to warrant reproducibility and to reduce the risk of overfitting and selection bias. Topological data analysis (TDA) is then used to define activation maps from different layers of the neural network at different stages of the training process, described by persistence diagrams (PD) and Betti curves. TDA is further integrated with the uniform manifold approximation and projection (UMAP) dimensionality reduction and the hierarchical density-based spatial clustering of applications with noise (HDBSCAN) algorithm for clustering, by the deep features, the relevant subgroups and structures, across different levels of the neural network. Finally, the recent TwoNN approach is leveraged to study the variation of the intrinsic dimensionality of the U-Net model. As the main task, the proposed pipeline is employed to evaluate the density of lymphocytes over the whole tissue area of the WSIs. The model achieves good results with mean absolute error 3.1 on test set, showing significant agreement between densities estimated by our EUNet model and by trained pathologists, thus indicating the potentialities of a promising new strategy in the quantification of the immune content in NB specimens. Moreover, the UMAP algorithm unveiled interesting patterns compatible with pathological characteristics, also highlighting novel insights into the dynamics of the intrinsic dataset dimensionality at different stages of the training process. All the experiments were run on the Microsoft Azure cloud platform.     

ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19?

Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin-angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis.     

Antibiotic resistance and microbial composition along the manufacturing process of Mozzarella di Bufala Campana

The use of antibiotics as growth promoters in livestock, banned in all EU member states in January 2006, has led to selection of antibiotic resistant strains within environmental bacteria, including gram-positive, non pathogenic bacteria that colonize the GI tract of humans and animals. In Italy and in other Mediterranean countries, fermented foods employing environmental bacteria pre-existing in the raw substrates, rather than industrial starters of defined genotype, represent a significant proportion of cheese and meat products carrying the official PDO designation (Protected Designation of Origin). Our study focused on the microbiological and molecular analysis of lactobacilli and of other lactic acid bacteria (LABs) isolated from the Italian PDO product water buffalo Mozzarella cheese, with the aim of identifying genes responsible for tetracycline, erythromycin and kanamycin resistance. We isolated over 500 LAB colonies from retail products, as well as from raw milk and natural whey starters employed in their production. Microbiological analysis showed that about 50% of these isolates were represented by lactobacilli, which were further characterized in terms of species and strain composition, as well as by determining phenotypic and genotypic antibiotic resistance. To overcome the limits of culture-dependent approaches that select only cultivable species, we have also extracted total DNA from the whole microbiome present in the cheese and investigated the presence of specific antibiotic resistance genes with molecular approaches. Genetic determinants of antibiotic resistance were identified almost exclusively in bacteria isolated from the raw, unprocessed substrates, while the final, marketed products did not contain phenotypically resistant lactobacilli, i.e. displaying MIC values above the microbiological breakpoint. Overall, our results suggest that the traditional procedures necessary for manufacturing of this typical cheese, such as high temperature treatments, lead to a final product with low bacterial counts, lower biodiversity and lack of significant presence of antibiotic resistant lactobacilli.     

Aquaporin-1 Facilitates Transmesothelial Water Permeability: In Vitro and Ex Vivo Evidence and Possible Implications in Peritoneal Dialysis

We previously showed that mesothelial cells in human peritoneum express the water channel aquaporin 1 (AQP1) at the plasma membrane, suggesting that, although in a non-physiological context, it may facilitate osmotic water exchange during peritoneal dialysis (PD). According to the three-pore model that predicts the transport of water during PD, the endothelium of peritoneal capillaries is the major limiting barrier to water transport across peritoneum, assuming the functional role of the mesothelium, as a semipermeable barrier, to be negligible. We hypothesized that an intact mesothelial layer is poorly permeable to water unless AQP1 is expressed at the plasma membrane. To demonstrate that, we characterized an immortalized cell line of human mesothelium (HMC) and measured the osmotically-driven transmesothelial water flux in the absence or in the presence of AQP1. The presence of tight junctions between HMC was investigated by immunofluorescence. Bioelectrical parameters of HMC monolayers were studied by Ussing Chambers and transepithelial water transport was investigated by an electrophysiological approach based on measurements of TEA⁺ dilution in the apical bathing solution, through TEA⁺-sensitive microelectrodes. HMCs express Zo-1 and occludin at the tight junctions and a transepithelial vectorial Na⁺ transport. Real-time transmesothelial water flux, in response to an increase of osmolarity in the apical solution, indicated that, in the presence of AQP1, the rate of TEA⁺ dilution was up to four-fold higher than in its absence. Of note, we confirmed our data in isolated mouse mesentery patches, where we measured an AQP1-dependent transmesothelial osmotic water transport. These results suggest that the mesothelium may represent an additional selective barrier regulating water transport in PD through functional expression of the water channel AQP1.     

Epigenetic Deregulation of MicroRNAs in Rhabdomyosarcoma and Neuroblastoma and Translational Perspectives

Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed.     

Ca2+ homeostasis in the agonist-sensitive internal store: functional interactions between mitochondria and the ER measured In situ in intact cells

OBJECTIVE: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease. DESIGN: Retrospective review. SETTING: University medical center transplant service. PATIENTS: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996. RESULTS: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34). CONCLUSIONS: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.     

Role of endoplasmic reticulum aminopeptidases in health and disease: from infection to cancer

Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are essential for the maturation of a wide spectrum of proteins involved in various biological processes. In the ER, these enzymes work in concert to trim peptides for presentation on MHC class I molecules. Loss of ERAPs function substantially alters the repertoire of peptides presented by MHC class I molecules, critically affecting recognition of both NK and CD8(+) T cells. In addition, these enzymes are involved in the modulation of inflammatory responses by promoting the shedding of several cytokine receptors, and in the regulation of both blood pressure and angiogenesis. Recent genome-wide association studies have identified common variants of ERAP1 and ERAP2 linked to several human diseases, ranging from viral infections to autoimmunity and cancer. More recently, inhibition of ER peptide trimming has been shown to play a key role in stimulating innate and adaptive anti-tumor immune responses, suggesting that inhibition of ERAPs might be exploited for the establishment of innovative therapeutic approaches against cancer. This review summarizes data currently available for ERAP enzymes in ER peptide trimming and in other immunological and non-immunological functions, paying attention to the emerging role played by these enzymes in human diseases.     

Magneto-plasmonic heterodimers: Evaluation of different synthesis approaches

Nanomedicine has gained huge attention in recent years with new approaches in medical diagnosis and therapy. Particular consideration has been devoted to the nanoparticles (NPs) in theranostic field with specific interest for magnetic and gold NPs (MNPs and GNPs) due to their peculiar properties under exposition to electromagnetic fields. In this paper, we aim to develop magneto-plasmonic heterodimer by combining MNPs and GNPs through a facile and reproducible synthesis and to investigate the influence of different synthesis parameters on their response to magnetic and optical stimuli. In particular, various syntheses were performed by changing the functionalization step and using or not a reducing agent to obtain stable NP suspensions with tailored properties. The obtained heterodimers were characterized through physical, chemical, optical, and magnetic analysis, in order to evaluate their size, shape, plasmonic properties, and superparamagnetic behavior. The results revealed that the shape and dimensions of the nanocomposites can be tuned by MNPs surface functionalization, as well as by the use of a reducing agent, giving rise to nanoplatform suitable for biomedical application, exploiting the gold absorbing peak in the specific gold absorbing range of GNPs, while maintaining the superparamagnetic behavior typical of the MNPs. The obtained nanocomposites can be proposed as potential candidates for cancer theranostics.     

法国蒙彼利埃Georges-Freche酒店管理学校

Georges-Freche学校建在蒙彼利埃东侧玛丽安港区3.95英亩(1.66hm2)的用地上,它改变了当地的景观,并赋予这一区域新的特色。建筑是水平延展的,多变的形式、紧凑的体量、雕塑般的形态存在于同一个实体上,独特的空间贯穿建筑内外。学校的功能空间主要包括两栋主楼(由穿过种植树木的中央庭院的天桥相连)、学生宿舍75张床位布置在3层楼内)、管理人员住房(10间公寓布置在5层楼内)、健身房、跑道及户外运