Nonsense-mediated RNA decay and its bipolar function in cancer

AbstractNonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future.

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From disease modelling to personalised therapy in patients with CEP290 mutations

F1000Research ◽

10.12688/f1000research.11553.1 ◽

2017 ◽

Vol 6 ◽

pp. 669 ◽

Cited By ~ 3

Author(s):

Elisa Molinari ◽

Shalabh Srivastava ◽

John A. Sayer ◽

Simon A. Ramsbottom

Keyword(s):

Disease Severity ◽

Genetic Diseases ◽

Therapeutic Benefit ◽

Disease Modelling ◽

Centrosomal Protein ◽

Common Cause ◽

Nonsense Mediated Decay ◽

Premature Termination Codons ◽

Exon Usage ◽

Personalised Therapy

Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. When transcripts containing these changes are generated, they are usually rapidly removed by the cell through the process of nonsense-mediated decay. Here we discuss observed changes in transcripts of the centrosomal protein CEP290 resulting not from degradation, but from changes in exon usage. We also comment on a landmark paper (Drivas et al. Sci Transl Med. 2015) where modelling this process of exon usage may be used to predict disease severity in CEP290 ciliopathies, and how understanding this process may potentially be used for therapeutic benefit in the future.

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The Ocular Gene Delivery Landscape

Biomolecules ◽

10.3390/biom11081135 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1135

Author(s):

Bhubanananda Sahu ◽

Isha Chug ◽

Hemant Khanna

Keyword(s):

Gene Therapy ◽

Genetic Diseases ◽

Gene Therapies ◽

Advantages And Disadvantages ◽

Fda Approval ◽

New Information ◽

Efficient Delivery ◽

Delivery Routes ◽

History Of ◽

Different Parts

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy.

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Advantages and Disadvantages of Using Magnetic Nanoparticles for the Treatment of Complicated Ocular Disorders

Pharmaceutics ◽

10.3390/pharmaceutics13081157 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1157

Author(s):

Elena K. Schneider-Futschik ◽

Felisa Reyes-Ortega

Keyword(s):

Magnetic Field ◽

Magnetic Nanoparticles ◽

Therapeutic Efficacy ◽

Genetic Diseases ◽

Systemic Exposure ◽

Drug Carriers ◽

Three Dimensions ◽

Target Point ◽

Advantages And Disadvantages ◽

Ocular Disorders

Nanomaterials provide enormous opportunities to overcome the limitations of conventional ocular delivery systems, such as low therapeutic efficacy, side effects due to the systemic exposure, or invasive surgery. Apart from the more common ocular disorders, there are some genetic diseases, such as cystic fibrosis, that develop ocular disorders as secondary effects as long as the disease progresses. These patients are more difficult to be pharmacologically treated using conventional drug routes (topically, systemic), since specific pharmacological formulations can be incompatible, display increased toxicity, or their therapeutic efficacy decreases with the administration of different kind of chemical molecules. Magnetic nanoparticles can be used as potent drug carriers and magnetic hyperthermia agents due to their response to an external magnetic field. Drugs can be concentrated in the target point, limiting the damage to other tissues. The other advantage of these magnetic nanoparticles is that they can act as magnetic resonance imaging agents, allowing the detection of the exact location of the disease. However, there are some drawbacks related to their use in drug delivery, such as the limitation to maintain efficacy in the target organ once the magnetic field is removed from outside. Another disadvantage is the difficulty in maintaining the therapeutic action in three dimensions inside the human body. This review summarizes all the application possibilities related to magnetic nanoparticles in ocular diseases.

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State-of-the-Art Software-Based Remote Attestation: Opportunities and Open Issues for Internet of Things

Sensors ◽

10.3390/s21051598 ◽

2021 ◽

Vol 21 (5) ◽

pp. 1598

Author(s):

Sigurd Frej Joel Jørgensen Ankergård ◽

Edlira Dushku ◽

Nicola Dragoni

Keyword(s):

Internet Of Things ◽

Smart Cities ◽

Cyber Attacks ◽

Resource Constrained ◽

Remote Attestation ◽

Comprehensive Overview ◽

Research Issues ◽

Advantages And Disadvantages ◽

Iot Devices ◽

Specialized Hardware

The Internet of Things (IoT) ecosystem comprises billions of heterogeneous Internet-connected devices which are revolutionizing many domains, such as healthcare, transportation, smart cities, to mention only a few. Along with the unprecedented new opportunities, the IoT revolution is creating an enormous attack surface for potential sophisticated cyber attacks. In this context, Remote Attestation (RA) has gained wide interest as an important security technique to remotely detect adversarial presence and assure the legitimate state of an IoT device. While many RA approaches proposed in the literature make different assumptions regarding the architecture of IoT devices and adversary capabilities, most typical RA schemes rely on minimal Root of Trust by leveraging hardware that guarantees code and memory isolation. However, the presence of a specialized hardware is not always a realistic assumption, for instance, in the context of legacy IoT devices and resource-constrained IoT devices. In this paper, we survey and analyze existing software-based RA schemes (i.e., RA schemes not relying on specialized hardware components) through the lens of IoT. In particular, we provide a comprehensive overview of their design characteristics and security capabilities, analyzing their advantages and disadvantages. Finally, we discuss the opportunities that these RA schemes bring in attesting legacy and resource-constrained IoT devices, along with open research issues.

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Emerging Applications of Nanotechnology in Healthcare Systems: Grand Challenges and Perspectives

Pharmaceuticals ◽

10.3390/ph14080707 ◽

2021 ◽

Vol 14 (8) ◽

pp. 707

Author(s):

Sumaira Anjum ◽

Sara Ishaque ◽

Hijab Fatima ◽

Wajiha Farooq ◽

Christophe Hano ◽

...

Keyword(s):

Targeted Drug Delivery ◽

Technological Progress ◽

Review Paper ◽

Genetic Diseases ◽

Healthcare Sector ◽

Human Right ◽

New Generation ◽

Immense Potential ◽

Near Future ◽

Shed Light

Healthcare, as a basic human right, has often become the focus of the development of innovative technologies. Technological progress has significantly contributed to the provision of high-quality, on-time, acceptable, and affordable healthcare. Advancements in nanoscience have led to the emergence of a new generation of nanostructures. Each of them has a unique set of properties that account for their astonishing applications. Since its inception, nanotechnology has continuously affected healthcare and has exerted a tremendous influence on its transformation, contributing to better outcomes. In the last two decades, the world has seen nanotechnology taking steps towards its omnipresence and the process has been accelerated by extensive research in various healthcare sectors. The inclusion of nanotechnology and its allied nanocarriers/nanosystems in medicine is known as nanomedicine, a field that has brought about numerous benefits in disease prevention, diagnosis, and treatment. Various nanosystems have been found to be better candidates for theranostic purposes, in contrast to conventional ones. This review paper will shed light on medically significant nanosystems, as well as their applications and limitations in areas such as gene therapy, targeted drug delivery, and in the treatment of cancer and various genetic diseases. Although nanotechnology holds immense potential, it is yet to be exploited. More efforts need to be directed to overcome these limitations and make full use of its potential in order to revolutionize the healthcare sector in near future.

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Deep Cerebral Perforators: Anatomical Distribution and Clinical Symptoms: An Overview

Stroke ◽

10.1161/strokeaha.120.034096 ◽

2021 ◽

Author(s):

Valerie Vogels ◽

Ruben Dammers ◽

Martine van Bilsen ◽

Victor Volovici

Keyword(s):

Clinical Symptoms ◽

Imaging Techniques ◽

Published Data ◽

Comprehensive Overview ◽

Large Variability ◽

Anatomical Distribution ◽

Anatomic Distribution ◽

Anterior Choroidal ◽

Near Future ◽

Choroidal Artery

The anatomic distribution of the deep cerebral perforators is considered either a given or subject to enormous variability. Most published overviews on this topic only report findings from a limited number of anatomic dissections, and no attempt has been made to date to provide a comprehensive overview of all published data. A comprehensive literature search was performed on MEDLINE, Embase, and Google Scholar with the help of an information specialist. Three types of studies were included: (1) articles that described the anatomy and distribution territories of perforator groups arising from the arteries of the circle of Willis; (2) studies that evaluated the anatomy of the deep cerebral perforators using imaging techniques; and (3) studies that evaluated either microsurgically or radiologically confirmed perforator occlusion and reported the (magnetic resonance imaging–confirmed) distribution territory of the infarction together with a description of the clinical symptoms associated as a result of the infarction. A total of 2715 articles were screened and 53 were included. Of these, 40 dealt with the anatomic and imaging anatomy of perforator groups (37 reported results of dissections and 3 results of imaging studies), with a total of 2421 hemispheres investigated. Another 13 articles with 680 patients were included that evaluated perforator infarction territories. The deep cerebral perforator distribution shows large variability with poor concordance rates among reported studies, with the exception of the posterior communicating and anterior choroidal artery perforators. Despite the assumption that cerebral perforator anatomy is a given, studies show large variability in the anatomic distribution of various perforator groups. Perforator anatomy and relationships between perforator groups, as well as potential collateral circulation in these territories should be prioritized as a research topic in cerebrovascular disease in the near future.

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Actively translated uORFs reduce translation and mRNA stability independent of NMD in Arabidopsis

10.1101/2021.09.16.460672 ◽

2021 ◽

Cited By ~ 1

Author(s):

Hsin-Yen Larry Wu ◽

Polly Yingshan Hsu

Keyword(s):

Gene Expression ◽

Mrna Stability ◽

Gene Expression Regulation ◽

Regulatory Elements ◽

Expression Regulation ◽

Ribosome Profiling ◽

Translation Efficiency ◽

Nonsense Mediated Decay ◽

Protein Levels ◽

Eukaryotic Genes

ABSTRACTUpstream ORFs (uORFs) are widespread cis-regulatory elements in the 5’ untranslated regions of eukaryotic genes. Translation of uORFs could negatively regulate protein synthesis by repressing main ORF (mORF) translation and by reducing mRNA stability presumably through nonsense-mediated decay (NMD). While the above expectations were supported in animals, they have not been extensively tested in plants. Using ribosome profiling, we systematically identified 2093 Actively Translated uORFs (ATuORFs) in Arabidopsis seedlings and examined their roles in gene expression regulation by integrating multiple genome-wide datasets. Compared with genes without uORFs, we found ATuORFs result in 38%, 14%, and 43% reductions in translation efficiency, mRNA stability, and protein levels, respectively. The effects of predicted but not actively translated uORFs are much weaker than those of ATuORFs. Interestingly, ATuORF-containing genes are also expressed at higher levels and encode longer proteins with conserved domains, features that are common in evolutionarily older genes. Moreover, we provide evidence that uORF translation in plants, unlike in vertebrates, generally does not trigger NMD. We found ATuORF-containing transcripts are degraded through 5’ to 3’ decay, while NMD targets are degraded through both 5’ to 3’ and 3’ to 5’ decay, suggesting uORF-associated mRNA decay and NMD have distinct genetic requirements. Furthermore, we showed ATuORFs and NMD repress translation through separate mechanisms. Our results reveal that the potent inhibition of uORFs on mORF translation and mRNA stability in plants are independent of NMD, highlighting a fundamental difference in gene expression regulation by uORFs in the plant and animal kingdoms.

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Role of Molecular Docking in Computer-Aided Drug Design and Development

Advances in Medical Technologies and Clinical Practice - Applied Case Studies and Solutions in Molecular Docking-Based Drug Design ◽

10.4018/978-1-5225-0362-0.ch001 ◽

2016 ◽

pp. 1-28

Author(s):

Rahul Agarwal ◽

Ashutosh Singh ◽

Subhabrata Sen

Keyword(s):

Molecular Docking ◽

Drug Design ◽

Protein Binding ◽

Design And Development ◽

Advantages And Disadvantages ◽

Computer Aided ◽

Drug Designing ◽

Near Future

Molecular Docking is widely used in CADD (Computer-Aided Drug Designing), SBDD (Structure-Based Drug Designing) and LBDD (Ligand-Based Drug Designing). It is a method used to predict the binding orientation of one molecule with the other and used for any kind of molecule based on the interaction like, small drug molecule with its protein target, protein – protein binding or a DNA – protein binding. Docking is very much popular technique due to its reliable prediction properties. This book chapter will provide an overview of diverse docking methodologies present that are used in drug design and development. There will be discussion on several case studies, pertaining to each method, followed by advantages and disadvantages of the discussed methodology. It will typically aim professionals in the field of cheminformatics and bioinformatics, both in academia and in industry and aspiring scientists and students who want to take up this as a profession in the near future. We will conclude with our opinion on the effectiveness of this technology in the future of pharmaceutical industry.

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Comparison of oil press for jatropha oil – a review

Research in Agricultural Engineering ◽

10.17221/22/2013-rae ◽

2016 ◽

Vol 61 (No. 1) ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

A.N. Siregar ◽

J.A. Ghani ◽

C.H.C. Haron ◽

M. Rizal ◽

Z. Yaakob ◽

...

Keyword(s):

Oil Recovery ◽

Oil Extraction ◽

Biodiesel Production ◽

South East Asia ◽

Jatropha Oil ◽

Extraction Techniques ◽

Advantages And Disadvantages ◽

Jatropha Seeds ◽

Mechanical Extraction ◽

Near Future

As petrol will soon be exhausted in the near future, Jatropha is going to be one of the substitute candidates for future biodiesel production. Countries of South-East Asia, such as Malaysia, they are going to start the establishment of Jatropha plantations assuming that Jatropha will be the main resource for biodiesel production. A press is commonly used to extract oils from Jatropha. An oil press can be manually driven or engine-powered. In this paper, we will review some available advances focused on mechanical extraction techniques, covering three types of press for Jatropha oil extraction. We have found that major points like operating principles, oil extraction levels, advantages and disadvantages of each press and important factors to increase oil recovery. Based on the study, three types of press are: ram press, which is ineffective; strainer press, which is able to produce more oil than others and cylinder-hole press, which is the best due to its capacity in extracting oil from Jatropha seeds for about 89.4% of oil yields.

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A survey on identification and quantification of alternative polyadenylation sites from RNA-seq data

Briefings in Bioinformatics ◽

10.1093/bib/bbz068 ◽

2019 ◽

Vol 21 (4) ◽

pp. 1261-1276 ◽

Cited By ~ 7

Author(s):

Moliang Chen ◽

Guoli Ji ◽

Hongjuan Fu ◽

Qianmin Lin ◽

Congting Ye ◽

...

Keyword(s):

Gene Expression Regulation ◽

Simulated Data ◽

Alternative Polyadenylation ◽

Transcriptome Profiling ◽

Systematic Evaluation ◽

Data Sets ◽

Rna Seq ◽

Comprehensive Overview ◽

Computational Approaches ◽

The Status

Abstract Alternative polyadenylation (APA) has been implicated to play an important role in post-transcriptional regulation by regulating mRNA abundance, stability, localization and translation, which contributes considerably to transcriptome diversity and gene expression regulation. RNA-seq has become a routine approach for transcriptome profiling, generating unprecedented data that could be used to identify and quantify APA site usage. A number of computational approaches for identifying APA sites and/or dynamic APA events from RNA-seq data have emerged in the literature, which provide valuable yet preliminary results that should be refined to yield credible guidelines for the scientific community. In this review, we provided a comprehensive overview of the status of currently available computational approaches. We also conducted objective benchmarking analysis using RNA-seq data sets from different species (human, mouse and Arabidopsis) and simulated data sets to present a systematic evaluation of 11 representative methods. Our benchmarking study showed that the overall performance of all tools investigated is moderate, reflecting that there is still lot of scope to improve the prediction of APA site or dynamic APA events from RNA-seq data. Particularly, prediction results from individual tools differ considerably, and only a limited number of predicted APA sites or genes are common among different tools. Accordingly, we attempted to give some advice on how to assess the reliability of the obtained results. We also proposed practical recommendations on the appropriate method applicable to diverse scenarios and discussed implications and future directions relevant to profiling APA from RNA-seq data.

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