The role of miRNA in diagnostics

Whilst the promise of RNA interference (RNAi) continues to expand in the therapeutic environment, the utility of the endogenous RNAi mechanism, microRNAs (miRNA), in diagnostics has been proven with the successful commercialization of a biopsy assay for the identification of cancer of unknown primary origin (CUP). The implications and consequences in personalized medicine arising from this highly sensitive and specific approach are substantial, however, the true potential is only beginning to be understood, as reports of disease-specific miRNA signatures in circulating lymphocytes, blood plasma/ serum, lung sputum, saliva and urine have been described, even in diseases where no diagnostic tools exist. This review summarizes the various approaches in miRNA biomarker discovery in addition to key findings in the field with the highest potential for clinical development

Low Complexity All-Pass Based Polyphase Decimation Filters for ECG Monitoring

This paper presents a low complexity high efficiency decimation filter which can be employed in EletroCardioGram (ECG) acquisition systems. The decimation filter with a decimation ratio of 128 works along with a third order sigma delta modulator. It is designed in four stages to reduce cost and power consumption. The work reported here provides an efficient approach for the decimation process for high resolution biomedical data conversion applications by employing low complexity two-path all-pass based decimation filters. The performance of the proposed decimation chain was validated by using the MIT-BIH arrhythmia database and comparative simulations were conducted with the state of the art

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition

microRNA expression in the aging mouse lung

BACKGROUND: MicroRNAs (miRNAs) are a novel class of short double stranded RNA that mediate the post-transcriptional regulation of gene expression. Previous studies have implicated changes in miRNA expression in the regulation of development and the induction of diseases such as cancer. However, although miRNAs have been implicated in the process of aging in C. elegans, nothing is known of their role in mammalian tissues. RESULTS: To address this question, we have used a highly-sensitive, semi-quantitative RT-PCR based approach to measure the expression profile of 256 of the 493 currently identified miRNAs in the lungs from 6 month (adult) and 18 month (aged) old female BALB/c mice. We show that, despite the characteristic changes in anatomy and gene expression associated with lung aging, there were no significant changes in the expression of 256 miRNAs. CONCLUSION: Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding gene

Egg parasitoids of the genus Trichogramma (Hymenoptera, Trichogrammatidae) in olive groves of the Mediterranean region

A survey of egg parasitoids of the genus Trichogramma (Hymenoptera, Trichogrammatidae) was carried out in olive groves in Portugal, Greece, Egypt, and Tunisia during the years 2002–2004. Parasitoids were obtained either by exposing sentinel eggs (Sitotroga cerealella Olivier or Ephestia kuehniella Zeller) on olive trees or by collecting eggs of lepidopterous olive pests. Parasitized egg samples were reared separately in the laboratory for emergence of parasitoids. These were further reared in separate lines and processed by morphological and molecular biology techniques for species characterization. The recorded fauna of Trichogramma parasitoids in olive groves was species poor and consisted of species mainly known from the Mediterranean region. Trichogramma bourarachae Pintureau and Babault was found in Tunisia and Egypt, T. cordubensis Vargas and Cabello, and T. euproctidis Girault in Egypt, Trichogramma cacoeciae Marchal in Portugal, Greece, Egypt, Tunisia and Trichogramma nerudai Pintureau and Gerding in Portugal. Apart from that, Trichogramma oleae Voegele´ and Pointel was collected in Tunisia. This species is probably not indigenous, but has established after several releases of a French strain were made in recent years. For selected strains, the sequence of the internal transcribed spacer 2 (ITS-2) region of rDNA was determined and deposited in the GenBank database. Differences in important biological attributes were found among collected strains of T. bourarachae, suggesting the existence of biotypes. The results contribute to the limited knowledge on distribution and biodiversity of the genus Trichogramma in the Mediterranean region. They can be helpful for the preservation and use of indigenous Trichogramma species in biological control of lepidopterous pests in olive and other local crops

Transcriptome analysis shows activation of circulating CD8 T cells in patients with severe asthma

Background: Although previous studies have implicated tissue CD4 T cells in the development and maintenance of the inflammatory response in asthmatic patients, little is known about the role of CD8 T cells. There is now accumulating evidence that microRNAs and other noncoding RNAs are important regulators of T-cell function. Objectives: We sought to use transcriptomics to determine the activation state of circulating CD4 and CD8 T cells in patients with nonsevere and severe asthma. Methods: mRNA and noncoding RNA expression in circulating T cells was measured by means of microarray, quantitative real-time PCR, or both. Results: Comparison of mRNA expression showed widespread changes in the circulating CD8 but not CD4 T cells from patients with severe asthma. No changes were observed in the CD4 and CD8 T cells in patients with nonsevere asthma versus those in healthy control subjects. Bioinformatics analysis showed that the changes in CD8 T-cell mRNA expression were associated with multiple pathways involved in T-cell activation. As with mRNAs, we also observed widespread changes in expression of noncoding RNA species, including natural antisense, pseudogenes, intronic long noncoding RNAs (lncRNAs), and intergenic lncRNAs in CD8 T cells from patients with severe asthma. Measurement of the microRNA expression profile showed selective downregulation of miR-28-5p in CD8 T cells and reduction of miR-146a and miR-146b in both CD4 and CD8 T cells. Conclusions: Severe asthma is associated with the activation of circulating CD8 T cells but not CD4 T cells. This response is correlated with the downregulation of miR-146a/b and miR-28-5p, as well as changes in the expression of multiple species of lncRNA that might regulate CD8 T-cell function. © 2011 American Academy of Allergy, Asthma & Immunology

Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

MicroRNA biotherapeutics: key challenges from a drug development perspective

The endogenous mediators of RNAi, microRNA (miRNAs), have grown in our understanding to be nodal elements in molecular homeostasis. Deregulation of miRNA levels is now believed to frequently cause disease. Considerable excitement therefore surrounds efforts focusing on restoring aberrant miRNA expression as a novel approach to therapy. In Chapter 7, the current body of knowledge around miRNA function in man and clinically relevant laboratory species is critically assessed from a miRNA biotherapeutics safety and efficacy perspective. In addition, the major relevant lessons learnt from RNAi and antisense drug development efforts are discussed where these translate to the field of miRNA therapy. Special attention is paid to key elements, such as evolutionarily optimized, viral vectoring solutions and genomic organization contexts that can be exploited for tailoring ectopic miRNA expression, maturation and bioprocessing. Moreover, the knowledge gaps arising from common approaches used to interrogate miRNA mode of action are identified in support of developing robust clinical path strategies in the personalized, precision medicine era