Miracle-dz/UniFAR-FTUs huggingface dataset:
The CFTR Corrector, VX-809 (Lumacaftor), Rescues ABCA4 Trafficking Mutants: a Potential Treatment for Stargardt Disease.

BACKGROUND/AIMS Mutations in ABCA4 cause Stargardt macular degeneration, which invariably ends in legal blindness. We studied two common mutants, A1038V (in NBD1) and G1961E (in NBD2), with the purpose of exploring how they interact with the cell's quality control mechanism. The study was designed to determine how these mutants can be rescued. METHODS We expressed wt and mutant ABCA4 in HEK293 cells and studied the effect of the mutations on trafficking and processing and the ability of correctors to rescue them. We used a combination of western blotting, confocal microscopy and surface biotinylation coupled with pulldown of plasma membrane proteins. RESULTS G1961E is sensitive to inhibitors of the aggresome, tubacin and the lysosome, bafilomycin A. Both mutants cause a reduction in heat shock protein, Hsp27. Incubation of HEK293 cells expressing the mutants with VX-809, an FDA approved drug for the treatment of cystic fibrosis, increased the levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the levels of both mutants at the plasma membrane suggesting that trafficking had been restored. Transfecting additional Hsp27 to the cells also increased the steady state levels of both mutants. However, in combination with VX-809 the addition of Hsp27 caused a dramatic increase in the protein expression particularly in the G1961 mutant which increased approximately 5-fold. CONCLUSION Our results provide a new mechanism for the rescue of ABCA4 trafficking mutants based on the restoration of Hsp27. Our results provide a pathway for the treatment of Stargardt disease.
Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

Metastatic disease is caused by the ability of cancer cells to reach distant organs and form secondary lesions at new locations. Dissemination of cancer cells depends on their migration plasticity – an ability to switch between motility modes driven by distinct molecular machineries. One of such switches is mesenchymal‐to‐amoeboid transition. Although mesenchymal migration of individual cells requires Arp2/3‐dependent actin polymerisation, amoeboid migration is characterised by a high level of actomyosin contractility and often involves the formation of membrane blebs. The acquisition of amoeboid motility by mesenchymal cells is often associated with enhanced metastasis.
Efficacy of Glecaprevir and Pibrentasvir in Patients with Genotype 1 Hepatitis C Virus Infection with Treatment Failure after NS5A Inhibitor Plus Sofosbuvir Therapy.

BACKGROUND/AIMS Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS We performed a phase 3b, open label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n=78, group A) or 16 weeks (n=49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n=21, group C) or G/P for 16 weeks (n=29, group D). The primary endpoint was a sustained virologic response 12 weeks after treatment (SVR12). Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions (RASs) in NS3 and NS5A. RESULTS Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with an SVR12 in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 patients with HCV genotype 1a infection (7.3%), 6 in group A (7.9%), 3 in group B (6.1%), 3 in group C (14.3%), and 1 in group D (3.4%). Most patients had baseline RASs in NS5A. Treatment-emergent RASs in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced an SVR12 in more than 90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov no: NCT03092375.
Lung segmentation method with dilated convolution based on VGG-16 network

Abstract Lung cancer has become one of the life-threatening killers. Lung disease need to be assisted by CT images taken doctor's diagnosis, and the segmented CT image of the lung parenchyma is the first step to help doctor diagnosis. For the problem of accurately segmenting the lung parenchyma, this paper proposes a segmentation method based on the combination of VGG-16 and dilated convolution. First of all, we use the first three parts of VGG-16 network structure to convolution and pooling the input image. Secondly, using multiple sets of dilated convolutions make the network has a large enough receptive field. Finally, the multi-scale convolution features are fused, and each pixel is predicted using MLP to segment the parenchymal region. Experimental results were produced over state of the art on 137 images which key metrics Dice similarity coefficient (DSC) is 0.9867. Experimental results show that this method can effectively segment the lung parenchymal area, and compared to other conventional methods better.
Do compensatory health beliefs predict behavioural intention in a multiple health behaviour change context? Evidence in individuals with cardiovascular diseases?

ABSTRACT Multiple health behaviour change (MHBC) represents one of the best ways to prevent reoccurrence of cardiovascular events. However, few individuals with cardiovascular diseases engage in this process. The present study examined the role of compensatory health beliefs (CHB; i.e., belief that a healthy behaviour compensates an unhealthy one) as a drag to engagement in this process. Some studies have shown that CHBs predict intention to engage in healthy behaviours, but no study has investigated CHBs in individuals who actually need to change multiple health behaviours. The goal was to better understand the role of CHBs in intentions formation process among individuals with cardiac diseases in an MHBC context. One hundred and four patients completed a questionnaire at the beginning of their cardiac rehabilitation program. Results showed that: (1) CHBs negatively predicted intentions (2) but only for participants with high self-efficacy or low risk perception; (3) CHBs predictions differed depending on the nature of the compensating behaviour, and were more predictive when medication intake was the compensating one. Findings only partially confirmed previous research conducted on healthy individuals who were not in an MHBC process, and emphasized the importance of considering CHBs for individuals in this process.
Delay-Sensitive Multicast in Inter-Datacenter WAN Using Compressive Latency Monitoring

Multicast routing in inter-datacenter wide area networks is to compute a multicast tree from a source datacenter to multiple destination datacenters. Software-defined networking enables optimal delay-sensitive routing for multicast sessions in inter-datacenter WANs. Delay-sensitive routing requires the controller to obtain the up-to-date latency of every link. However, the communication overhead and time for collecting the latency information of all links can be prohibitively high for the controller to perform real-time scheduling in a WAN. Inspired by the sparsity of link load information in WANs, we propose compressive latency monitoring, a real-time method for collecting a near-accurate latency information of all links. The controller only needs to collect the latency information of a small subset of significant links and then estimates the latency information of insignificant links. We use real-world network topologies to simulate multicast routing both under the compressive latency monitoring and global latency monitoring. Simulation results show that the compressive latency monitoring can achieve nearly good network throughput performance as the global monitoring with much less communication overhead and in a more timely fashion.
Combined Ankle/Knee Stretching and Pivoting Stepping Training for Children With Cerebral Palsy

Although various treatment methods have been investigated to reduce spasticity and intoeing gait in children with cerebral palsy (CP), methods to concurrently reduce an intoeing gait and associated ankle/knee stiffness and spasticity according to a child’s specific needs are lacking. This study aimed to develop a training program to improve walking function and transverse-plane (pivoting) neuromuscular control and reduce spasticity and intoeing gait deviations. Eight children with diplegic CP and intoeing gait participated in this 6-week combined robotic ankle and/or knee intelligent stretching and pivoting neuromuscular control training program (Subject-specific Stretching and Pivoting Off-axis Neuromuscular control Training, [SS-POINT]). The effects of SS-POINT were evaluated using neuromechanical, functional, and clinical outcome measures and compared to those for eight children with CP and intoeing gait who participated in pivoting neuromuscular control training (POINT) alone in a previous study. <inline-formula> <tex-math notation="LaTeX">$\textit {Results}$ </tex-math></inline-formula>: After the SS-POINT program, subjects with CP showed reduced knee stiffness and intoeing angle, and improvements in both joint and leg functions in terms of ankle and knee active range of motion, ankle dorsiflexor strength, proprioception, walking speed, balance, and minimum pivoting angle. Furthermore, improvements in proprioceptive acuity and minimum pivoting angle after the SS-POINT were greater than those after the POINT. <inline-formula> <tex-math notation="LaTeX">$\textit {Conclusion}$ </tex-math></inline-formula>: The SS-POINT approach can be used as a subject-specific training program for improving leg and walking functions and reducing intoeing during gait. <inline-formula> <tex-math notation="LaTeX">$\textit {Significance}$ </tex-math></inline-formula>: This approach can serve as an individualized intervention at the joint and walking levels to maximize intervention effects by adjusting training targets, sequences, and intensities to meet the individual needs of children with CP.
Expression and functional analyses of ephrin type-A receptor 2 in mouse spermatogonial stem cells†

Abstract Spermatogonial stem cells (SSCs) undergo continuous self-renewal division in response to self-renewal factors. The present study identified ephrin type-A receptor 2 (EPHA2) on mouse SSCs and showed that supplementation of glial cell-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), which are both SSC self-renewal factors, induced EPHA2 expression in cultured SSCs. Spermatogonial transplantation combined with magnetic-activated cell sorting or fluorescence-activated cell sorting also revealed that EPHA2 was expressed in SSCs. Additionally, ret proto-oncogene (RET) phosphorylation levels decreased following the knockdown (KD) of Epha2 expression via short hairpin ribonucleic acid (RNA). Although the present immunoprecipitation experiments did not reveal an association between RET with EPHA2, RET interacted with FGFR2. The Epha2 KD decreased the proliferation of cultured SSCs and inhibited the binding of cultured SSCs to laminin-coated plates. The Epha2 KD also significantly reduced the colonization of testis cells by spermatogonial transplantation. EPHA2 was also expressed in human GDNF family receptor alpha 1-positive spermatogonia. The present results indicate that SSCs express EPHA2 and suggest that it is a critical modifier of self-renewal signals in SSCs. Summary sentence Mouse spermatogonial stem cells express EPHA2.
Equity–Efficiency Trade-offs Associated With Alternative Approaches to Deceased Donor Kidney Allocation: A Patient-level Simulation

Supplemental Digital Content is available in the text. Background. The number of patients waiting to receive a kidney transplant outstrips the supply of donor organs. We sought to quantify trade-offs associated with different approaches to deceased donor kidney allocation in terms of quality-adjusted life years (QALYs), costs, and access to transplantation. Methods. An individual patient simulation model was developed to compare 5 different approaches to kidney allocation, including the 2006 UK National Kidney Allocation Scheme (NKAS) and a QALY maximization approach designed to maximize health gains from a limited supply of donor organs. We used various sources of patient-level data to develop multivariable regression models to predict survival, health state utilities, and costs. We simulated the allocation of kidneys from 2200 deceased donors to a waiting list of 5500 patients and produced estimates of total lifetime costs and QALYs for each allocation scheme. Results. Among patients who received a transplant, the QALY maximization approach generated 48 045 QALYs and cost £681 million, while the 2006 NKAS generated 44 040 QALYs and cost £625 million. When also taking into consideration outcomes for patients who were not prioritized to receive a transplant, the 2006 NKAS produced higher total QALYs and costs and an incremental cost-effectiveness ratio of £110 741/QALY compared with the QALY maximization approach. Conclusions. Compared with the 2006 NKAS, a QALY maximization approach makes more efficient use of deceased donor kidneys but reduces access to transplantation for older patients and results in greater inequity in the distribution of health gains between patients who receive a transplant and patients who remain on the waiting list.
A survey of Canadian healthcare professionals’ practices regarding reactive balance training

ABSTRACT Background: Perturbation-based balance training (PBT) is a relatively new type of balance training that aims to improve control of reactions to a loss of balance. This study aimed to determine the prevalence of use of PBT in clinical practice, and the most significant barriers and facilitators to implementing PBT in practice. Methods: Health-care professionals across Canada (primarily physiotherapists and kinesiologists) who provide balance training to individuals with balance impairments and/or increased fall risk completed a questionnaire that asked about knowledge and use of PBT in practice. Results: Overall, 76.3% of participants (299/392) reported that they had used PBT in their practices, with 22.4% (88/392) reporting regular PBT use. Lack of knowledge of PBT appeared to be the most significant barrier for those not currently using PBT in their practices, whereas individuals who were familiar with PBT and open to using it in practice experienced barriers related to training, knowledge, human resources, client characteristics, and the practice setting. More than 90% of respondents were interested in learning more about almost all aspects of PBT. Conclusions: These findings could be used to inform development of future educational strategies to increase uptake of PBT in rehabilitation practice.
Mapping connectomes with diffusion MRI: Deterministic or probabilistic tractography?

In the Discussion section of the manuscript entitled “Mapping connectomes with Diffusion MRI: deterministic or probabilistic tractography? ”,1 Sarwar and colleagues briefly mention a class of methods that aim to imbue a tractogram reconstruction with quantitative properties, by modulating the contribution of individual streamlines in such a manner that the tractogram becomes concordant with the underlying image data.2-5 They state that, while such methods “can potentially improve the accuracy of connectome reconstruction”, one particular method (Spherical‐deconvolution Informed Filtering of Tractograms, SIFT)2 “can potentially yield spurious between‐group differences” when the densities of specific pathways are compared quantitatively across subjects. They additionally present a hypothetical fiber phantom intended to support this statement. Here we demonstrate that the empirical behavior suggested to be problematic by Sarwar and colleagues is in fact the best possible behavior of that particular algorithm given the limitations of the demonstration data provided to it; moreover, given appropriate application and interpretation of such methods, quantification of absolute fiber connectivity can be achieved in this phantom, thus refuting the basis for their dismissal of such approaches for improving tractography quantification. The top row, left column of Figure 1A is a replication of both the Fiber Orientation Distribution (FOD) field and reconstructed streamlines from the aforementioned “toy example” phantom, which we have labeled “Patient. ” In the top row, right column of Figure 1A, we have duplicated this phantom without incorporation of the simulated pathology or imbalance in streamline count between the 2 bundles; this we have labeled “Control. ” Sarwar and colleagues describe the application of the SIFT method to the “Patient” phantom only. They correctly identify the fact that the SIFT method removes 2 streamlines from the lower unaffected bundle to match the tractogram to the underlying FODs (Figure 1A, bottom‐left). They then, however, erroneously conclude that: “Therefore, if the SIFT‐adjusted streamline count for Bundle 2 is compared between groups with and without pathology in Bundle 1, a spurious reduction in the streamline count will be found in Bundle 2 when in fact the true pathology is circumscribed to Bundle 1. ” Comparing this result with application of the SIFT method to the “Control” phantom (Figure 1A, bottom‐right), it is clear that comparing absolute streamlines counts within a specific bundle across subjects, when the total number of streamlines in the tractograms of those subjects varies markedly for methodological reasons, would lead to erroneous inferences only because doing so would be inappropriate. Robust representation of this phantom and reconstruction using SIFT requires the following 2 modifications:
Implement Of Network User Virtual Identity Merging Based on Spark

With the rapid development of Internet, people show growing dependence on network communications. Each user has a lot of network virtual identities because of the explosive increase of network applications. Compared with previous work, our study proposes an algorithm to find virtual identities which belong to the same natural person. On the other hand, in view of massive data from users’ access records, our study is based on a quick, general engine with ease of use for large-scale data processing platform and clustering system called Spark.
New Reconstructed Database for Cost Reduction in Indoor Fingerprinting Localization

Location fingerprinting is a technique widely suggested for challenging indoor positioning. Despite the significant benefits of this technique, it needs a considerable amount of time and energy to measure the Received Signal Strength (RSS) at Reference Points (RPs) and build a fingerprinting database to achieve an appropriate localization accuracy. Reducing the number of RPs can reduce this cost, but it noticeably degrades the accuracy of positioning. In order to alleviate this problem, this paper takes the interior architecture of the indoor area and signal propagation effects into account and proposes two novel recovery methods for creating the reconstructed database instead of the measured one. They only need a few numbers of RPs to reconstruct the database and even are able to produce a denser database. The first method is a new zone-based path-loss propagation model which employs fingerprints of different zones separately and the second one is a new interpolation method, zone-based Weighted Ring-based (WRB). The proposed methods are compared with the conventional path-loss model and six interpolation functions. Two different test environments along with a benchmarking testbed, and various RPs configurations are also utilized to verify the proposed recovery methods, based on the reconstruction errors and the localization accuracies they provide. The results indicate that by taking only 11% of the initial RPs, the new zone-based path-loss model decreases the localization error up to 26% compared to the conventional path-loss model and the proposed zone-based WRB method outperforms all the other interpolation methods and improves the accuracy by 40%.
An Adversarial Feature Distillation Method for Audio Classification

The audio classification task aims to discriminate between different audio signal types. In this task, deep neural networks have achieved better performance than the traditional shallow architecture-based machine-learning method. However, deep neural networks often require huge computational and storage requirements that hinder the deployment in embedded devices. In this paper, we proposed a distillation method which transfers knowledge from well-trained networks to a small network, and the method can compress model size while improving audio classification precision. The contributions of the proposed method are two folds: a multi-level feature distillation method was proposed and an adversarial learning strategy was employed to improve the knowledge transfer. The extensive experiments are conducted on three audio classification tasks, audio scene classification, general audio tagging, and speech command recognition. The experimental results demonstrate that: the small network can provide better performance while achieves the calculated amount of floating-point operations per second (FLOPS) compression ratio of 76:1 and parameters compression ratio of 3:1.
Repositório ISCTE-IUL

— This research work's core objective is to categorise and understand the barriers to strategic implementation, focusing, then, through an inquiry, in the most voted of them, to make a deeper analysis on one of the variables. To that end, this document begins with a literature review and begins to identify the importance that strategic communication has in the process of propagating a given individual idea or, in the terms that interests us most, within of an organization whether ascending or descending, horizontal or vertical. In the organizational arena, business and communication are two inseparable issues. Then it is explained more deeply in what barriers to strategic implementation consists, in its variances of application and how it is immersed in the multiple possibilities that can cause the collapse of the plans orchestrated by the companies. In the end, as a theoretical complement, a questionnaire was designed for a relatively large number of people who were confronted with the topics under discussion throughout this article.