Miracle-dz/UniFAR-FTUs huggingface dataset:
An asymmetric bulge enhances artificial microRNA‐mediated virus resistance

RNA silencing is a host defense mechanism against viruses in plants (Ding and Voinnet, 2007). As a counter defense mechanism, viruses have adapted ways to overcome the host RNA silencing pathway, such as viral suppressors of RNA silencing (VSR) (Incarbone and Dunoyer, 2013). Artificial miRNAs (amiRNAs) have been widely used as antiviral agents in plants as reported by (Carbonell et al., 2019; Khalid et al., 2017; Kis et al., 2016) among others. This article is protected by copyright. All rights reserved.
Rare disease specialists and clinical pharmacologists unite: Increase collection of longitudinal data!

There is an increasing demand for clinical trials in rare diseases, defined according to the EU as affecting less than 1 in 2000. In this editorial, we will discuss the background of this increasing demand, the reasons why most rare diseases are currently not ready for clinical research, and how clinical pharmacologists, clinical geneticists, and other rare disease specialists can prepare for clinical research for rare diseases. By our definition, a disease is “ready for clinical research” if there is sufficient clinical data to allow confident planning of clinical trials to investigate a potential treatment strategy. This requires the availability of clinically relevant and well‐characterized endpoints, longitudinal data on these endpoints, and in many cases fit‐for‐purpose biomarkers. Although there are larger‐scale efforts underway to collect such data for groups of diseases (for example, for diseases affecting bone, joints, or blood vessels—www.rudystudy.org), or more general, for example, through the European Reference Networks via the Clinical Patient Management System (CPMS), unfortunately, most efforts to collect longitudinal data still start when there is a potential therapeutic treatment, causing significant delays.
Nir2 Is an Effector of VAPs Necessary for Efficient Hepatitis C Virus Replication and Phosphatidylinositol 4-Phosphate Enrichment at the Viral Replication Organelle

Hepatitis C virus (HCV) is known for its ability to modulate phosphoinositide signaling pathways for its replication. Elevated levels of phosphatidylinositol 4-phosphate [PI(4)P] in HCV replication organelles (ROs) recruits lipid transfer proteins (LTPs), like oxysterol-binding protein (OSBP). OSBP exchanges PI(4)P with cholesterol, thus removing PI(4)P from the HCV RO. Here, we found that the phosphatidylinositol transfer protein Nir2 acts as an LTP and may replenish PI at the HCV RO by interacting with VAMP-associated proteins (VAPs), enabling continuous viral replication during chronic infection. Therefore, the coordination of OSBP, Nir2, and VAPs completes our understanding of the phosphoinositide cycle between the ER and HCV ROs. ABSTRACT The endoplasmic reticulum (ER)-resident proteins vesicle-associated membrane protein (VAMP)-associated protein A and B (VAPA and VAPB) have been reported to be necessary for efficient hepatitis C virus (HCV) replication, but the specific mechanisms are not well understood. VAPs are known to recruit lipid transfer proteins to the ER, including oxysterol binding protein (OSBP), which has been previously shown to be necessary for cholesterol delivery to the HCV replication organelle in exchange for phosphatidylinositol 4-phosphate [PI(4)P]. Here, we show that VAPA and VAPB are redundant for HCV infection and that dimerization is not required for their function. In addition, we identify the phosphatidylinositol transfer protein Nir2 as an effector of VAPs to support HCV replication. We propose that Nir2 functions to replenish phosphoinositides at the HCV replication organelle to maintain elevated steady-state levels of PI(4)P, which is removed by OSBP. Thus, Nir2, along with VAPs, OSBP, and the phosphatidylinositol 4-kinase, completes a cycle of phosphoinositide flow between the ER and viral replication organelles to drive ongoing viral replication. IMPORTANCE Hepatitis C virus (HCV) is known for its ability to modulate phosphoinositide signaling pathways for its replication. Elevated levels of phosphatidylinositol 4-phosphate [PI(4)P] in HCV replication organelles (ROs) recruits lipid transfer proteins (LTPs), like oxysterol-binding protein (OSBP). OSBP exchanges PI(4)P with cholesterol, thus removing PI(4)P from the HCV RO. Here, we found that the phosphatidylinositol transfer protein Nir2 acts as an LTP and may replenish PI at the HCV RO by interacting with VAMP-associated proteins (VAPs), enabling continuous viral replication during chronic infection. Therefore, the coordination of OSBP, Nir2, and VAPs completes our understanding of the phosphoinositide cycle between the ER and HCV ROs.
A microtitre chemiluminescence sensor for detection of pyrethroids based on dual-dummy-template molecularly imprinted polymer and computational simulation.

The residues of pyrethroids in foods of animal origin are dangerous to the consumers, so this study presented a chemiluminescence sensor for determination of pyrethroids in chicken samples. A dual-dummy-template molecularly imprinted polymer capable of recognizing 10 pyrethroids was synthesized. The results of computation simulation showed that the specific 3D conformations of the templates had important influences on the polymer's recognition ability. The polymer was used to prepare a sensor on conventional 96-well microplates, and the sample solution was added into the wells for direct absorption. The absorbed analytes were initiated with the bis(2,4,6-trichlorophenyl)oxalate-H2 O2 -imidazole system, and the chemiluminescence intensity was used for analyte quantification. Results showed that one assay was finished within 12 min, and this sensor could be reused four times. The limits of detection for the 10 analytes were in the range o0.3-6.0 pg/ml, and the recoveries from the standards of fortified blank chicken samples were in the range 70.5-99.7%.
[Proinflammatory cytokine content in the saliva of children suffering from chronic tonsillitis].

INTRODUCTION We have examined 92 children aged between 6 and 15, suffering from chronic tonsillitis (CT). Tumor necrosis factor (TNF-α) and interleukin 1β and 6 (IL-1β and IL-6) contents have been defined in saliva. The control set comprised 17 healthy children. Cytokine content was defined with the enzyme multiplied immunoassay sets (Vektor Best Ltd., Russia) by enzyme-linked immunosorbent assay. The statistic analysis and data processing were carried out with statistic analysis programs (version 3.2, R Foundation for Statistical Computing, Vienna, Austria). RESULTS The content of cytokines TNF-α, IL-1, IL-6 in CT children's saliva was high against the healthy children, yet the statistically significant differences were only noted for IL-6. In the CT group the median value of this factor (12.5) was significantly higher than in the control set (6.72) (p=0.01 in Mann-Whitney assessment). IL-6 was chosen as the basic factor for the mathematic model; its combinations in the form of a multi-factor logistic regression were given consideration. From out of the three possible models there was just one that had all the coefficients statistically significantly different from zero (TNF-α - IL-6). It was chosen as the basic diagnostic model for chronic tonsillitis. The created model's sensitivity is 80.4%, while its specificity is 82.4%. DISCUSSION The revealed IL-6 dominance in saliva at CT can be is attributable to permanent antigenic challenge characteristic of the toxic allergic CT since, as previously shown, there are living proliferating microorganisms in the palatal tonsil tissues and their blood- and lymph vessels at CT. CONCLUSION The conducted ROC-analysis has demonstrated high sensitivity and specificity of the mathematical model, which enabled us to recommend determination of IL-6 in the saliva of the children suffering from CT as an additional diagnostic criterion.
Adaptive Consensus Tracking Control of Uncertain Nonlinear Multiagent Systems With Predefined Accuracy

In this article, we consider the leader–follower consensus control problem of uncertain multiagent systems, aiming to achieve the improvement of system steady state and transient performance. To this end, a new adaptive neural control approach is proposed with a novel design of the Lyapunov function, which is generated with a class of positive functions. Guided by this idea, a series of smooth functions is incorporated into backstepping design and Lyapunov analysis to develop a performance-oriented controller. It is proved that the proposed controller achieves a perfect asymptotic consensus performance and a tunable $L_{2}$ transient performance of synchronization errors, whereas most existing results can only ensure the stability. Simulation demonstrates the obtained results.
Inhomogeneous Molecular Distributions and Cytochrome Types and Redox States in Fungal Cells Revealed by Raman Hyperspectral Imaging Using Multivariate Curve Resolution-Alternating Least Squares.

Hyphae of filamentous fungi consist of compartments that are distinct both spatially and functionally, thereby forming a unique multicellular system. Much work has been done mainly using fluorescence imaging to reveal what biomolecules are present in those different hyphal sections and what physiological roles they play. Nevertheless, a holistic understanding of hyphal functions including the polarized growth of hyphae is still lacking because of the difficulty in simultaneous acquisition of spatial and chemical information on various molecular components in living hyphae. Here, we used a multivariate curve resolution-alternating least-squares (MCR-ALS) analysis of Raman hyperspectral imaging data to study in vivo the spatial distributions and chemical properties of major cellular components in the tip, basal, and branching regions of the model fungus Aspergillus nidulans. The MCR-ALS Raman imaging method visualized, without any labeling, the characteristic distributions of cytochromes as well as other components including polysaccharides, non-cytochrome proteins, nucleic acids, lipids, and ergosterol in the hyphal regions studied. Furthermore, the intrinsic Raman spectra derived for the first time from the MCR-ALS analysis enabled us to gain otherwise unobtainable chemical insights into those visualized components. We show variations in the relative abundance of cytochromes b and c and in their redox states (reduced vs. oxidized form) among the three different representative compartments of A. nidulans hyphae, which could potentially be associated with specific physiological activities and functions of hyphae. The present results demonstrate that our MCR-ALS Raman imaging can serve as a useful tool complementary to the conventional approaches, for elucidating the diverse roles of filamentous fungi at the molecular level.
Evolutionary Dynamics of the Lineage 2 West Nile Virus That Caused the Largest European Epidemic: Italy 2011–2018

Lineage 2 West Nile virus (WNV) caused a vast epidemic in Europe in 2018, with the highest incidence being recorded in Italy. To reconstruct the evolutionary dynamics and epidemiological history of the virus in Italy, 53 envelope gene and 26 complete genome sequences obtained from human and animal samples were characterised by means of next-generation sequencing. Phylogenetic analysis revealed two Italian strains originating between 2010 and 2012: clade A, which apparently became extinct in 2013–2014, and clade B, which was responsible for the 2018 epidemic. The mean genetic distances in clade B increased over time and with the distance between sampling locations. Bayesian birth-death and coalescent skyline plots of the clade B showed that the effective number of infections and the effective reproduction number (Re) increased between 2015 and 2018. Our data suggest that WNV-2 entered Italy in 2011 as a result of one or a few penetration events. Clade B differentiated mainly as a result of genetic drift and purifying selection, leading to the appearance of multiple locally circulating sub-clades for different times. Phylodynamic analysis showed a current expansion of the infection among reservoir birds and/or vectors.
Implementation and 2‐year outcomes of the first FDA‐approved implantable apheresis vascular access device

Patients requiring chronic apheresis treatments typically lack sufficient peripheral venous access to support long‐term therapy. Historically, central venous tunneled catheters, septum‐bearing subcutaneous ports, and fistulas were used to obtain required blood flow rates for apheresis procedures. In 2017, the US Food and Drug Administration approved the first intravascular device specifically designed for apheresis therapy, the PowerFlow Implantable Apheresis IV Port.
Muco-Obstructive Lung Diseases. Reply.

To the Editor: The review article by Boucher (May 16 issue)1 does not include a discussion of asthma as a muco-obstructive lung disease. In a subgroup of patients with asthma, clinically significant mucus plugging is detected on highresolution computed tomographic imaging. This condition is characterized clinically by severe airf low obstruction and a lack of response to both bronchodilators and systemic glucocorticoids.2 Mucus-derived obstruction is an important asthma phenotype because it may predict more persistent obstruction than that which is usually encountered and involve a treatment approach that is similar to that for other mucoobstructive diseases. Furthermore, overall mucin concentrations have been found to be higher both in patients with stable asthma and in those with asthma exacerbations than in healthy persons, although the predominant mucin in patients with asthma is MUC5AC,3 and goblet-cell hyperplasia has been associated with neutrophilic asthma, which shares many similarities with chronic obstructive pulmonary disease (COPD). 4 Finally, hypertonic saline, which is frequently used in patients with other muco-obstructive lung diseases, has been shown to increase ciliary clearance in patients with asthma and is an underused therapy in this population.5
The Janus Face of Tumor Microenvironment Targeted by Immunotherapy

The tumor microenvironment (TME) is a complex entity where host immune and non-immune cells establish a dynamic crosstalk with cancer cells. Through cell-cell interactions, which are mediated by key signals, such as the PD-1/PD-L1 axis, as well as the release of soluble mediators, this articulated process defines the nature of TME determining tumor development, prognosis, and response to therapy. Specifically, tumors are characterized by cellular plasticity that allows for the microenvironment to polarize towards inflammation or immunosuppression. Thus, the dynamic crosstalk among cancer, stromal, and immune components crucially favors the dominance of one of the Janus-faced contexture of TME crucial to the outcome of tumor development and therapeutic response. However, mostly, TME is dominated by an immunosuppressive landscape that blocks antitumor immunity and sustain tumor progression. Hence, in most cases, the immunosuppressive components of TME are highly competent in suppressing tumor-specific CD8+ T lymphocytes, the effectors of cancer destruction. In this complex context, immunotherapy aims to arm the hidden Janus face of TME disclosing and potentiating antitumor immune signals. Herein, we discuss recent knowledge on the immunosuppressive crosstalk within TME, and share perspectives on how immunotherapeutic approaches may exploit tumor immune signals to generate antitumor immunity.
Topographic modeling of early human osteoarthritis in sheep

Early osteoarthritis induced in a clinically relevant ovine model progresses in a highly specific spatiotemporal pattern resembling human OA. Deciphering degeneration Aging and injury are known to contribute to osteoarthritis, a disease characterized by the breakdown of cartilage. Here, Oláh et al. induced meniscal injury in sheep and created detailed maps of disease progression. They found that cartilage and bone breakdown occurred first in the injured region before spreading throughout the joint. Patterns of degeneration observed in the sheep 6 months after injury mirrored pathology observed in human osteoarthritis. This large animal model of osteoarthritis could be useful for furthering our understanding of disease progression and for testing potential therapies. Articular cartilage damage occurring during early osteoarthritis (OA) is a key event marking the development of the disease. Here, we modeled early human OA by gathering detailed spatiotemporal data from surgically induced knee OA development in sheep. We identified a specific topographical pattern of osteochondral changes instructed by a defined meniscal injury, showing that both cartilage and subchondral bone degeneration are initiated from the region adjacent to the damage. Alterations of the subarticular spongiosa arising locally and progressing globally disturbed the correlations of cartilage with subchondral bone seen at homeostasis and were indicative of disease progression. We validated our quantitative findings against human OA, showing a similar pattern of early OA correlating with regions of meniscal loss and an analogous late critical disturbance within the entire osteochondral unit. This translational model system can be used to elucidate mechanisms of OA development and provides a roadmap for investigating regenerative therapies.
Pay Attention to Them: Deep Reinforcement Learning-Based Cascade Object Detection

This paper proposes a novel and effective approach, namely pay attention to them (PAT), to general object detection, which integrates the bottom-up single-shot convolutional neural networks (CNNs) and a top-down operating strategy. PAT starts by routinely applying a CNN regression detector to the entire input image. It then conducts refinement, which locates a sub-region that probably contains relevant objects through an intelligent agent built with an attentional mechanism and zooms it in to launch the detector again. This refining step is repeated in a cascaded way, where all the bounding boxes produced are scaled according to the original resolution and the sub-marginal and overlapping parts are wiped out to generate the final output. Due to such progressive processing, PAT improves the detection accuracy, especially for the objects of small sizes. Extensive experiments are conducted on the Pascal VOC and MS COCO benchmarks, and the results show that PAT is able to improve the representative baseline detectors, i.e., single shot multibox detector, YOLOv2, and Faster regions with CNN features, with remarkable accuracy gains [about 2%–5% mean Average Precision (mAP)], which demonstrates its competency.
Mobile Apps for the Care Management of Chronic Kidney and End-Stage Renal Diseases: Systematic Search in App Stores and Evaluation

Background Numerous free and low-cost mobile apps for the care management of kidney disease have become available in recent years. Although these appear to be promising tools, they have not been evaluated comparatively based on standard mobile app metrics, and thus, limited evidence is available regarding their efficacy. This study systematically cataloged and assessed mobile apps designed to assist medication compliance and nutrition tracking that are useful to the chronic kidney disease (CKD) and the end-stage renal disease (ESRD) patients who are on dialysis. Objective The objective of this study was to comprehensively evaluate mobile apps used for medication compliance and nutrition tracking for possible use by CKD and ESRD patients. Methods A systematic review framework was applied to the search, screening, and assessment of apps identified and downloaded from the iOS and Android app stores. We selected apps using 13 relevant search terms, narrowed down based on a set of inclusion and exclusion criteria, and then used the Mobile App Rating Scale (MARS), a widely adopted app evaluation tool to assess the effectiveness of apps. The internal consistency and interrater reliability were tested using Cronbach alpha and interclass correlation coefficients (ICCs), respectively. Results The MARS total score had excellent internal consistency (Cronbach alpha=.90) and a moderate level of interrater reliability (2-way mixed ICC 0.65). Overall, 11 out of the 12 reviewed apps met the minimum acceptable score of 3.0 in MARS rating. The 3 apps with the highest combined scores were My Kidneys, My Health Handbook (MARS=4.68); My Food Coach (MARS=4.48); and National Kidney Foundation Malaysia (MARS=4.20). The study identified 2 general weaknesses in the existing apps: the apps fell short of accommodating advanced interactive features such as providing motivational feedback and promoting family member and caregiver participations in the app utilization. Conclusions The MARS rating system performed well in the app evaluation. The 3 highest ranked apps scored consistently high across the 5 dimensions specified in MARS. These apps were developed in collaboration with reputable organizations and field experts, demonstrating the importance of expert guidance in developing medical apps.
Matrix-degrading protease ADAMTS-5 cleaves inter-α-inhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients

Destruction of the cartilage matrix in joints is an important feature of arthritis. Proteolytic degradation of cartilage glycoproteins can contribute to the loss of matrix integrity. Human inter-α-inhibitor (IαI), which stabilizes the extracellular matrix, is composed of the light-chain serine proteinase inhibitor bikunin and two homologous heavy chains (HC1 and HC2) covalently linked through chondroitin 4-sulfate. Inflammation promotes the transfer of HCs from chondroitin 4-sulfate to hyaluronan by tumor necrosis factor–stimulated gene-6 protein (TSG-6). This reaction generates a covalent complex between the heavy chains and hyaluronan that can promote leukocyte invasion. This study demonstrates that both IαI and the HC–hyaluronan complex are substrates for the extracellular matrix proteases ADAMTS-5 and matrix metalloprotease (MMP) -3, -7, and -13. The major cleavage sites for all four proteases are found in the C terminus of HC2. ADAMTS-5 and MMP-7 displayed the highest activity toward HC2. ADAMTS-5 degradation products were identified in mass spectrometric analysis of 29 of 33 arthropathic patients, indicating that ADAMTS-5 cleavage occurs in synovial fluid in arthritis. After cleavage, free HC2, together with TSG-6, is able to catalyze the transfer of heavy chains to hyaluronan. The release of extracellular matrix bound HC2 is likely to increase the mobility of the HC2/TSG-6 catalytic unit and consequently increase the rate of the HC transfer reaction. Ultimately, ADAMTS-5 cleavage of HC2 could alter the physiological and mechanical properties of the extracellular matrix and contribute to the progression of arthritis.