Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare disease with autosomal recessive inheritance, caused mostly by bi-allelic gene mutations that impair motile cilia structure and function. Currently, there are no causal treatments for PCD. In many disease models, translational readthrough of premature termination codons (PTC-readthrough) induced by aminoglycosides has been proposed as an effective way of restoring functional protein expression and reducing disease symptoms. However, variable outcomes of pre-clinical trials and toxicity associated with long-term use of aminoglycosides prompt the search for other compounds that might overcome these problems. Because a high proportion of PCD-causing variants are nonsense mutations, readthrough therapies are an attractive option. We tested a group of chemical compounds with known PTC-readthrough potential (ataluren, azithromycin, tylosin, amlexanox, and the experimental compound TC007), collectively referred to as non-aminoglycosides (NAGs). We investigated their PTC-readthrough efficiency in six PTC mutations found in Polish PCD patients, in the context of cell and cilia health, and in comparison to the previously tested aminoglycosides. The NAGs did not compromise the viability of the primary nasal respiratory epithelial cells, and the ciliary beat frequency was retained, similar to what was observed for gentamicin. In HEK293 cells transfected with six PTC-containing inserts, the tested compounds stimulated PTC-readthrough but with lower efficiency than aminoglycosides. The study allowed us to select compounds with minimal negative impact on cell viability and function but still the potential to induce PTC-readthrough.     

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ET_B) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ET_B receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ET_B receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ET_B-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ET_B receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ET_B receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.     

In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

Lactobacillus plantarum BC299 can alleviate dextran sulphate sodium-induced colitis by regulating immune response and modulating gut microbiota

It is well known that probiotics are effective in relieving inflammatory bowel disease (IBD). However, their exact mechanism is still unclear. Herein, we evaluated the effect of novel Lactobacillus plantarum BC299 on dextran sodium sulphate (DSS)-induced colitis model mice and investigated the molecular mechanism. We found BC299 could regulate immune response and reduce immunosuppression by enhancing the expression of Th1 T cells in cyclophosphamide-induced immunosuppressive model mice. Meanwhile, DSS-induced colitis model mice were furtherly constructed. The results displayed BC299 can restore bodyweight and relieve colon morphology of colitis mice. Real-time quantitative polymerase chain reaction results demonstrated BC299 can regulate immune response by reducing the expression of TNF-α and IL-1β mRNA and increasing the expression of IL-10 and TGF-β mRNA. Moreover, BC299 administration reshaped and increased the diversity of gut microbiota in IBD mice. Therefore, BC299 can alleviate colitis by regulating immune response and modulating gut microbiota.     

FogMed: A Fog-Based Framework for Disease Prognosis Based Medical Sensor Data Streams

Recently, an increasing number of works start investigating the combination of fog computing and electronic health (ehealth) applications. However, there are still numerous unresolved issues worth to be explored. For instance, there is a lack of investigation on the disease prediction in fog environment and only limited studies show, how the Quality of Service (QoS) levels of fog services and the data stream mining techniques influence each other to improve the disease prediction performance (e.g., accuracy and time efficiency). To address these issues, we propose a fog-based framework for disease prediction based on Medical sensor data streams, named FogMed. This framework aims to improve the disease prediction accuracy by achieving two objectives: QoS guarantee of fog services and anomaly prediction of Medical data streams. We build a virtual FogMed environment and conduct comprehensive experiments on the public ECG dataset to validate the performance of FogMed. The experiment results show that it performs better than the cloud computing model for processing tasks with different complexities in terms of time efficiency.     

基于多通道的ICU脑血管疾病死亡风险预测模型

死亡风险预测指根据病人临床体征监测数据来预测未来一段时间的死亡风险。对于ICU病患，通过死亡风险预测可以有针对性地对病人做出临床诊断，以及合理安排有限的医疗资源。基于临床使用的MEWS和Glasgow昏迷评分量表，针对ICU病人临床监测的17项生理参数，提出一种基于多通道的ICU脑血管疾病死亡风险预测模型。引入多通道概念应用于BiLSTM模型，用于突出每个生理参数对死亡风险预测的作用。采用Attention机制用于提高模型预测精度。实验数据来自MIMIC [Ⅲ]数据库，从中提取3?080位脑血管疾病患者的16?260条记录用于此次研究，除了六组超参数实验之外，将所提模型与LSTM、Multichannel-BiLSTM、逻辑回归（logistic regression）和支持向量机（support vector machine, SVM）四种模型进行了对比分析，准确率Accuracy、灵敏度Sensitive、特异性Specificity、AUC-ROC和AUC-PRC作为评价指标，实验结果表明，所提模型性能优于其他模型，AUC值达到94.3%。     

Spontaneous cervical epidural hematoma in a patient with end-stage renal disease

Spontaneous spinal epidural hematoma (SEH) is extremely rare in patients with end-stage renal disease (ESRD). We report a case of a 71-year-old man with ESRD presented with progressive left limb weakness. Magnetic resonance imaging (MRI) revealed spinal cervical SEH involving C3-5 level. The patient received emergent decompression laminectomy with the evacuation of the epidural hematoma.     

MRMR Based Feature Vector Design for Efficient Citrus Disease Detection

In recent times, the images and videos have emerged as one of the most important information source depicting the real time scenarios. Digital images nowadays serve as input for many applications and replacing the manual methods due to their capabilities of 3D scene representation in 2D plane. The capabilities of digital images along with utilization of machine learning methodologies are showing promising accuracies in many applications of prediction and pattern recognition. One of the application fields pertains to detection of diseases occurring in the plants, which are destroying the widespread fields. Traditionally the disease detection process was done by a domain expert using manual examination and laboratory tests. This is a tedious and time consuming process and does not suffice the accuracy levels. This creates a room for the research in developing automation based methods where the images captured through sensors and cameras will be used for detection of disease and control its spreading. The digital images captured from the field's forms the dataset which trains the machine learning models to predict the nature of the disease. The accuracy of these models is greatly affected by the amount of noise and ailments present in the input images, appropriate segmentation methodology, feature vector development and the choice of machine learning algorithm. To ensure the high rated performance of the designed system the research is moving in a direction to fine tune each and every stage separately considering their dependencies on subsequent stages. Therefore the most optimum solution can be obtained by considering the image processing methodologies for improving the quality of image and then applying statistical methods for feature extraction and selection. The training vector thus developed is capable of presenting the relationship between the feature values and the target class. In this article, a highly accurate system model for detecting the diseases occurring in citrus fruits using a hybrid feature development approach is proposed. The overall improvement in terms of accuracy is measured and depicted.     

Grid Search for Predicting Coronary Heart Disease by Tuning Hyper-Parameters

Diagnosing the cardiovascular disease is one of the biggest medical difficulties in recent years. Coronary cardiovascular (CHD) is a kind of heart and blood vascular disease. Predicting this sort of cardiac illness leads to more precise decisions for cardiac disorders. Implementing Grid Search Optimization (GSO) machine training models is therefore a useful way to forecast the sickness as soon as possible. The state-of-the-art work is the tuning of the hyperparameter together with the selection of the feature by utilizing the model search to minimize the false-negative rate. Three models with a cross-validation approach do the required task. Feature Selection based on the use of statistical and correlation matrices for multivariate analysis. For Random Search and Grid Search models, extensive comparison findings are produced utilizing retrieval, F1 score, and precision measurements. The models are evaluated using the metrics and kappa statistics that illustrate the three models’ comparability. The study effort focuses on optimizing function selection, tweaking hyperparameters to improve model accuracy and the prediction of heart disease by examining Framingham datasets using random forestry classification. Tuning the hyperparameter in the model of grid search thus decreases the erroneous rate achieves global optimization.     

地方病高发区成井用胶质水泥浆的试验研究

通过地方病高发区成井用胶质水泥浆的试验研究，以普通水泥和膨润土为基本材料，同时添加改善材料性能的外加剂，研制了一种用于高砷、高氟、高矿化度地区水井成井的止水材料，具有流动性好、抗渗性高、不收缩、完全无毒、价格低廉等特点，特别是其高抗渗性和不收缩性非常适合地方病区成井时隔离劣质含水层，保证优质含水层与劣质含水层互不串通、不渗漏、不污染。