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Functional consequences of developmentally regulated alternative splicing
Key Points
A large fraction of genes in worms, flies and vertebrates express multiple mRNAs by alternative splicing. This produces extensive mRNA structural diversity that ultimately affects protein coding potential as well as mRNA
cis
-acting elements that are determinative for translation, mRNA stability and mRNA intracellular localization.
Global analyses of alternative splicing regulation during periods of biological transition, such as during development, have revealed coordinated and conserved networks of alternative splicing.
Several splicing regulatory networks controlled by individual RNA-binding proteins have been identified by combining recent advances in genome-wide analyses of alternative splicing with the identification of RNA binding sites
in vivo
.
A high proportion of RNA-binding proteins that regulate alternative splicing are themselves regulated by alternative splicing and are subject to auto- and crossregulatory feedback. This type of regulation includes alternative splicing linked with nonsense-mediated decay (AS–NMD), which results in mRNA downregulation.
Diverse physiological processes are regulated in a determinative fashion by alternative splicing patterns, including meiosis in budding yeast, neuronal arborization in the
Drosophila melanogaster
brain, and stem cell determination in vertebrates.
The regulation of gene expression by alternative splicing is intricately linked with transcription, the epigenetic state of chromatin, and subsequent RNA processing events, such as 3′ end formation, mRNA export and mRNA translation efficiency.
Recent transcriptomics studies have revealed extensive mRNA diversity generated by alternative splicing. An emerging theme is the existence of regulatory networks through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, involving robust and coordinated alternative splicing transitions.
Genome-wide analyses of metazoan transcriptomes have revealed an unexpected level of mRNA diversity that is generated by alternative splicing. Recently, regulatory networks have been identified through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, which involve robust and coordinated alternative splicing transitions. The regulation of splicing in yeast, worms, flies and vertebrates affects a variety of biological processes. The functional classes of genes that are regulated by alternative splicing include both those with widespread homeostatic activities and those with cell-type-specific functions. Alternative splicing can drive determinative physiological change or can have a permissive role by providing mRNA variability that is used by other regulatory mechanisms.
Journal Article
The marauders : a novel
\"When the BP oil spill devastates the Gulf coast, those who made a living by shrimping find themselves in dire straits. For the oddballs and lowlifes who inhabit the sleepy, working class bayou town of Jeannette, these desperate circumstances serve as the catalyst that pushes them to enact whatever risky schemes they can dream up to reverse their fortunes. At the center of it all is Gus Lindquist, a pill-addicted, one-armed treasure hunter obsessed with finding the lost treasure of pirate Jean Lafitte\"--Amazon.com.
Book
Reporting reliability, convergent and discriminant validity with structural equation modeling: A review and best-practice recommendations
Many constructs in management studies, such as perceptions, personalities, attitudes, and behavioral intentions, are not directly observable. Typically, empirical studies measure such constructs using established scales with multiple indicators. When the scales are used in a different population, the items are translated into other languages or revised to adapt to other populations, it is essential for researchers to report the quality of measurement scales before using them to test hypotheses. Researchers commonly report the quality of these measurement scales based on Cronbach’s alpha and confirmatory factor analysis results. However, these results are usually inadequate and sometimes inappropriate. Moreover, researchers rarely consider sampling errors for these psychometric quality measures. In this best practice paper, we first critically review the most frequently-used approaches in empirical studies to evaluate the quality of measurement scales when using structural equation modeling. Next, we recommend best practices in assessing reliability, convergent and discriminant validity based on multiple criteria and taking sampling errors into consideration. Then, we illustrate with numerical examples the application of a specifically-developed R package, measureQ, that provides a one-stop solution for implementing the recommended best practices and a template for reporting the results. measureQ is easy to implement, even for those new to R. Our overall aim is to provide a best-practice reference for future authors, reviewers, and editors in reporting and reviewing the quality of measurement scales in empirical management studies.
Journal Article
The roles of RNA processing in translating genotype to phenotype
Key Points
Gene expression involves a cascade of chromosomal, transcriptional and post-transcriptional events. Genomic variants produce differences between individuals in terms of transcriptional and post-transcriptional events at equal frequency.
Common genetic variation between individuals contributes to phenotypic diversity. Single-nucleotide variants can have functional consequences by affecting RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency.
Genomic variants affect RNA processing by altering the binding sites of sequence-specific RNA-binding proteins, by disrupting RNA structures required for processing or by introducing RNA structures that prevent RNA processing.
Comparisons of genomic and transcriptomic sequences from a large number of individuals from diverse backgrounds will not only identify functional variants that are relevant to human health, but also catalogue the
cis
-acting elements that are required for basal and regulated RNA processing.
Analysis of the effects of genomic variants on post-transcriptional regulation of gene expression is made possible by the recent rapid expansion of high-throughput experimental approaches and associated computational analyses.
Genetic variants can produce phenotypic traits through effects on RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency.
A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.
Journal Article
Contactless steam generation and superheating under one sun illumination
Steam generation using solar energy provides the basis for many sustainable desalination, sanitization, and process heating technologies. Recently, interest has arisen for low-cost floating structures that absorb solar radiation and transfer energy to water via thermal conduction, driving evaporation. However, contact between water and the structure leads to fouling and pins the vapour temperature near the boiling point. Here we demonstrate solar-driven evaporation using a structure not in contact with water. The structure absorbs solar radiation and re-radiates infrared photons, which are directly absorbed by the water within a sub-100 μm penetration depth. Due to the physical separation from the water, fouling is entirely avoided. Due to the thermal separation, the structure is no longer pinned at the boiling point, and is used to superheat the generated steam. We generate steam with temperatures up to 133 °C, demonstrating superheated steam in a non-pressurized system under one sun illumination.
Solar steam generation is limited by fouling of solar converters, and the steam temperature is usually pinned to 100 °C. Here, both limitations are overcome in a system utilizing a solar absorber and light down-converter to achieve radiative heating, which does not require physical contact between absorber and water.
Journal Article
Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated the therapeutic potential for calcium channel modulation to block the synergistic effects and rescue myopathy.
Journal Article