Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are the second most common form of congenital muscular dystrophy. Currently, there is no effective treatment available. COL6-CMDs are caused by recessive or dominant mutations in one of the three genes encoding for the α chains of collagen type VI (COL6A1, COL6A2, and COL6A3). One of the most common mutations in COL6-CMD patients is a de novo deep intronic c.930+189C > T mutation in COL6A1 gene. This mutation creates a cryptic donor splice site and induces incorporation of a novel in-frame pseudo-exon in the mature transcripts. In this study, we systematically evaluated the splice switching approach using antisense oligonucleotides (ASOs) to correct this mutation. Fifteen ASOs were designed using the RNA-tiling approach to target the misspliced pseudo-exon and its flanking sequences. The efficiency of ASOs was evaluated at RNA, protein, and structural levels in skin fibroblasts established from four patients carrying the c.930+189C > T mutation. We identified two additional lead ASO candidates that efficiently induce pseudo-exon exclusion from the mature transcripts, thus allowing for the restoration of a functional collagen VI microfibrillar matrix. Our findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common intronic mutation

Look ahead to improve QoE in DASH streaming

[EN] When a video is encoded with constant quality, the resulting bitstream will have variable bitrate due to the inherent nature of the video encoding process. This paper proposes a video Adaptive Bitrate Streaming (ABR) algorithm, called Look Ahead, which takes into account this bitrate variability in order to calculate, in real time, the appropriate quality level that minimizes the number of interruptions during the playback. The algorithm is based on the Dynamic Adaptive Streaming over HTTP (DASH) standard for on-demand video services. In fact, it has been implemented and integrated into ExoPlayer v2, the latest version of the library developed by Google to play DASH contents. The proposed algorithm is compared to the Müller and Segment Aware Rate Adaptation (SARA) algorithms as well as to the default ABR algorithm integrated into ExoPlayer. The comparison is carried out by using the most relevant parameters that affect the Quality of Experience (QoE) in video playback services, that is, number and duration of stalls, average quality of the video playback and number of representation switches. These parameters can be combined to define a QoE model. In this sense, this paper also proposes two new QoE models for the evaluation of ABR algorithms. One of them considers the bitrate of every segment of each representation, and the second is based on VMAF (Video Multimethod Assessment Fusion), a Video Quality Assessment (VQA) method developed by Netflix. The evaluations presented in the paper reflect: first, that Look Ahead outperforms the Müller, SARA and the ExoPlayer ABR algorithms in terms of number and duration of video playback stalls, with hardly decreasing the average video quality; and second, that the two QoE models proposed are more accurate than other similar models existing in the literature.This work is supported by the PAID-10-18 Program of the Universitat Politecnica de Valencia (Ayudas para contratos de acceso al sistema espanol de Ciencia, Tecnologia e Innovacion, en estructuras de investigacion de la Universitat Politecnica de Valencia) and by the Project 20180810 from the Universitat Politecnica de Valencia ("Tecnologias de distribucion y procesado de informacion multimedia y QoE").Belda Ortega, R.; De Fez Lava, I.; Arce Vila, P.; Guerri Cebollada, JC. (2020). Look ahead to improve QoE in DASH streaming. 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(2019)ISO/IEC 23009–1:2014 (2014) Dynamic adaptive streaming over HTTP (DASH) - Part 1: media presentation description and segment formats.Juluri P, Tamarapalli V, Medhi D (2015) SARA: segment aware rate adaptation algorithm for dynamic adaptive streaming over HTTP. Proc. of the IEEE Int. Conf. On Commun. Workshop (ICCW), London, UK: 1765-1770. https://doi.org/10.1109/ICCW.2015.7247436 .Juluri P, Tamarapalli V, Medhi D (2016) QoE management in DASH systems using the segment aware rate adaptation algorithm. Proc. of the IEEE/IFIP Netw. Oper. And Manag. Symp. (NOMS), Istanbul, Turkey: 129-136. https://doi.org/10.1109/NOMS.2016.7502805 .Kua J, Armitage G, Branch P (2017) A survey of rate adaptation techniques for dynamic adaptive streaming over HTTP. IEEE Commun Surv & Tutor 19(3):1842–1866. https://doi.org/10.1109/COMST.2017.2685630Lee S, Youn K, Chung K (2015) Adaptive video quality control scheme to improve QoE of MPEG DASH. Proc. of IEEE Int. Conf. On Consum. Electron. (ICCE), Las Vegas, NV, USA: 126-127. https://doi.org/10.1109/ICCE.2015.7066348 .Li S, Zhang F, Ma L, Ngan K (2011) Image quality assessment by separately evaluating detail losses and additive impairments. IEEE Trans. on Multimed. 13-5:935–949. https://doi.org/10.1109/TMM.2011.2152382Liu C, Bouazizi I, Gabbouj M (2011) Rate adaptation for adaptive HTTP streaming. Proc. of the second annual ACM Conf. On multimed. Syst. (MMSys), San Jose, CA, USA: 169-174. https://doi.org/10.1145/1943552.1943575 .Medium webpage (2016) Toward a practical perceptual video quality metric. Available online at: https://medium.com/netflix-techblog/toward-a-practical-perceptual-video-quality-metric-653f208b9652 . Accessed: Jun. 2019.Mobile Video Service Performance Study (2015) HUAWEI white paper. Available online at: http://www.ctiforum.com/uploadfile/2015/0701/20150701091255294.pdf .Mok RKP, Luo X, Chan EWW, Chang RKC (2012) QDASH: a QoE-aware DASH system. Proc. of multim. Syst. Conf. (MMSys), Chapel Hill, NC, USA: 11-22. https://doi.org/10.1145/2155555.2155558Moldovan C, Hagn K, Sieber C, Kellerer W, Hoßfeld T (2017) Keep calm and don’t switch: about the relationship between switches and quality in HAS. Proc. of the Int. Teletraffic Congr. (ITC), Genoa, Italy: pp. 1-6. https://doi.org/10.23919/ITC.2017.8065802Müller C, Lederer S, Timmerer C (2012) An evaluation of dynamic adaptive streaming over HTTP in vehicular environments. Proc. of the 4th workshop on mob. Video (MoVid), Chapel Hill, NC, USA: 37-42. https://doi.org/10.1145/2151677.2151686Nguyen T, Vu T, Nguyen DV, Ngoc NP, and Thang TC (2015) QoE optimization for adaptive streaming with multiple VBR videos. Proc. of the Int. Conf. On comp., Manag. And Telecommun. (ComManTel), DaNang, Vietnam: 189-193. https://doi.org/10.1109/ComManTel.2015.7394285 .Qin Y, H. Shuai, Pattipati K R, Qian F, Sen S, Wang B, Yue C (2018) ABR Streaming of VBR-encoded videos: characterization, challenges, and solutions. Proc. of ACM CoNext 2018, Heraklion, Greece: 366–378. https://doi.org/10.1145/3281411.3281439 .Samain J, Carofiglio G, Muscariello L, Papalini M, Sardara M, Tortelli M, Rossi D (2017) Dynamic adaptive video streaming: towards a systematic comparison of ICN and TCP/IP. IEEE Trans on Multimed 19(10):2166–2181. https://doi.org/10.1109/TMM.2017.2733340Sheikh H, Bovik A (2006) Image information and visual quality. IEEE Trans on Image Process 15(2):430–444. https://doi.org/10.1109/TIP.2005.859378Shuai Y, Herfet T (2016). A buffer dynamic stabilizer for low-latency adaptive video streaming. Proc. of the Int. Conf. on Consum. Electron., Berlin: 1–5. https://doi.org/10.1109/ICCE-Berlin.2016.7684742 .Tavakoli S, Egger S, Seufert M, Schatz R, Brunnström K, García N (2016) Perceptual quality of HTTP adaptive streaming strategies: cross-experimental analysis of multi-laboratory and crowdsourced subjective studies. 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Exact ground states for the four-electron problem in a Hubbard ladder

The exact ground state of four electrons in an arbitrary large two leg Hubbard ladder is deduced from nine analytic and explicit linear equations. The used procedure is described, and the properties of the ground state are analyzed. The method is based on the construction in r-space of the different type of orthogonal basis wave vectors which span the subspace of the Hilbert space containing the ground state. In order to do this, we start from the possible microconfigurations of the four particles within the system. These microconfigurations are then rotated, translated and spin-reversed in order to build up the basis vectors of the problem. A closed system of nine analytic linear equations is obtained whose secular equation, by its minimum energy solution, provides the ground state energy and the ground state wave function of the model.Comment: 10 pages, 7 figure

Advances in ophthalmic drug delivery

Various strategies for ocular drug delivery are considered; from basic formulation techniques for improving availability of drugs; viscosity enhancers and mucoadhesives aid drug retention and penetration enhancers promote drug transport into the eye. The use of drug loaded contact lenses and ocular inserts allows drugs to be better placed where they are needed for more direct delivery. Developments in ocular implants gives a means to overcome the physical barriers that traditionally prevented effective treatment. Implant technologies are under development allowing long term drug delivery from a single procedure, these devices allow posterior chamber diseases to be effectively treated. Future developments could bring artificial corneas to eliminate the need for donor tissue and one-off implantable drug depots lasting the patient’s lifetime

Primary psoas abscess extending to thigh adductors: case report

<p>Abstract</p> <p>Background</p> <p>Psoas abscess is a rare condition consisting of pyomyositis of the psoas. The worldwide incidence was 12 cases per 100,000 per year in 1992, but the current incidence is unknown. Psoas abscess can descend along the psoas sheath and reach the inner upper third of the thigh, but only infrequently does it penetrate the sheath and involve the thigh adductors. Because of insidious clinical presentation, the diagnosis of psoas abscess is a challenge. Delayed diagnosis can result in poor prognosis.</p> <p>Case presentation</p> <p>A 45-year-old male with no significant past medical history presented with pain in the left thigh, and limitation of movement at the left hip and knee joint for one month. Ultrasound, CT, and MRI revealed a liquid mass in the left psoas. Percutaneous drainage of this mass yielded 300 ml pus from the psoas. After surgery, the patient reported relief of pain; however, ten days after removal of the drainage tube, the patient complained of persistent pain in his left thigh. CT revealed that the psoas abscess had extended inferiorly, and involved the entire set of adductors of the left thigh. Open surgical drainage was performed at the flank and at the thigh, yielding 350 ml of pus from the thigh. After open drainage and adequate antibiotic therapy, the patient made a good recovery. Follow-up CT confirmed complete resolution of the abscess.</p> <p>Conclusions</p> <p>Large psoas abscess can penetrate the psoas sheath, and descend to thigh adductors even after percutaneous drainage. Appropriate treatment includes open surgical drainage along with antibiotic therapy.</p

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Expression of a Serine Protease Gene prC Is Up-Regulated by Oxidative Stress in the Fungus Clonostachys rosea: Implications for Fungal Survival

BACKGROUND: Soil fungi face a variety of environmental stresses such as UV light, high temperature, and heavy metals. Adaptation of gene expression through transcriptional regulation is a key mechanism in fungal response to environmental stress. In Saccharomyces cerevisiae, the transcription factors Msn2/4 induce stress-mediated gene expression by binding to the stress response element. Previous studies have demonstrated that the expression of extracellular proteases is up-regulated in response to heat shock in fungi. However, the physiological significance of regulation of these extracellular proteases by heat shock remains unclear. The nematophagous fungus Clonostachys rosea can secret an extracellular serine protease PrC during the infection of nematodes. Since the promoter of prC has three copies of the stress response element, we investigated the effect of environmental stress on the expression of prC. METHODOLOGY/PRINCIPAL FINDINGS: Our results demonstrated that the expression of prC was up-regulated by oxidants (H(2)O(2) or menadione) and heat shock, most likely through the stress response element. After oxidant treatment or heat shock, the germination of conidia in the wild type strain was significantly higher than that in the prC mutant strain in the presence of nematode cuticle. Interestingly, the addition of nematode cuticle significantly attenuated the production of reactive oxygen species (ROS) induced by oxidants and heat shock in the wild type strain, but not in prC mutant strain. Moreover, low molecule weight (<3 kD) degradation products of nematode cuticle suppressed the inhibitory effect of conidial germination induced by oxidants and heat shock. CONCLUSIONS/SIGNIFICANCE: These results indicate that PrC plays a protective role in oxidative stress in C. rosea. PrC degrades the nematode cuticle to produce degradation products, which in turn offer a protective effect against oxidative stress by scavenging ROS. Our study reveals a novel strategy for fungi to adapt to environmental stress

Cardiac Potassium Channels: Physiological Insights for Targeted Therapy.

The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K(+) channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K(+) channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them

Higher media multi-tasking activity is associated with smaller gray-matter density in the anterior cingulate cortex

Media multitasking, or the concurrent consumption of multiple media forms, is increasingly prevalent in today’s society and has been associated with negative psychosocial and cognitive impacts. Individuals who engage in heavier media-multitasking are found to perform worse on cognitive control tasks and exhibit more socio-emotional difficulties. However, the neural processes associated with media multi-tasking remain unexplored. The present study investigated relationships between media multitasking activity and brain structure. Research has demonstrated that brain structure can be altered upon prolonged exposure to novel environments and experience. Thus, we expected differential engagements in media multitasking to correlate with brain structure variability. This was confirmed via Voxel-Based Morphometry (VBM) analyses: Individuals with higher Media Multitasking Index (MMI) scores had smaller gray matter density in the anterior cingulate cortex (ACC). Functional connectivity between this ACC region and the precuneus was negatively associated with MMI. Our findings suggest a possible structural correlate for the observed decreased cognitive control performance and socio-emotional regulation in heavy media-multitaskers. While the cross-sectional nature of our study does not allow us to specify the direction of causality, our results brought to light novel associations between individual media multitasking behaviors and ACC structure differences