Over the past decade there has been increased awareness of the potential role of alternative splicing in the etiology of cancer. In particular, advances in RNA-Sequencing technology and analysis has ...led to a wave of discoveries in the last few years regarding the causes and functional relevance of alternative splicing in cancer. Here we discuss the current understanding of the connections between splicing and cancer, with a focus on the most recent findings. We also discuss remaining questions and challenges that must be addressed in order to use our knowledge of splicing to guide the diagnosis and treatment of cancer.
School of Biomedical Sciences, University of Queensland, Brisbane, Australia
The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ...ion channels. Functional receptors of this family comprise five subunits and are important targets for neuroactive drugs. The GlyR is best known for mediating inhibitory neurotransmission in the spinal cord and brain stem, although recent evidence suggests it may also have other physiological roles, including excitatory neurotransmission in embryonic neurons. To date, four -subunits ( 1 to 4) and one -subunit have been identified. The differential expression of subunits underlies a diversity in GlyR pharmacology. A developmental switch from 2 to 1 is completed by around postnatal day 20 in the rat. The -subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin. The last few years have seen a surge in interest in these receptors. Consequently, a wealth of information has recently emerged concerning GlyR molecular structure and function. Most of the information has been obtained from homomeric 1 GlyRs, with the roles of the other subunits receiving relatively little attention. Heritable mutations to human GlyR genes give rise to a rare neurological disorder, hyperekplexia (or startle disease). Similar syndromes also occur in other species. A rapidly growing list of compounds has been shown to exert potent modulatory effects on this receptor. Since GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons, these agents may provide lead compounds for the development of muscle relaxant and peripheral analgesic drugs.
Address for reprint requests and other correspondence: J. W. Lynch, School of Biomedical Sciences, Univ. of Queensland, Brisbane QLD 4072, Australia (E-mail: j.lynch{at}uq.edu.au )
To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use.
Published data on hERG ...(or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans.
Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels.
The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.
The symmetry energy describes how the energy of nuclear matter rises as one goes away from equal numbers of neutrons and protons. This is very important to describe neutron rich matter in ...astrophysics. This article reviews our knowledge of the symmetry energy from theoretical calculations, nuclear structure measurements, heavy-ion collisions, and astronomical observations. We then present a roadmap to make progress in areas of relevance to the symmetry energy that promotes collaboration between the astrophysics and the nuclear physics communities.
Summary
Most mammalian pre‐mRNAs are alternatively spliced in a manner that alters the resulting open reading frame. Consequently, alternative pre‐mRNA splicing provides an important RNA‐based layer ...of protein regulation and cellular function. The ubiquitous nature of alternative splicing coupled with the advent of technologies that allow global interrogation of the transcriptome have led to an increasing awareness of the possibility that widespread changes in splicing patterns contribute to lymphocyte function during an immune response. Indeed, a few notable examples of alternative splicing have clearly been demonstrated to regulate T‐cell responses to antigen. Moreover, several proteins key to the regulation of splicing in T cells have recently been identified. However, much remains to be done to truly identify the spectrum of genes that are regulated at the level of splicing in immune cells and to determine how many of these are controlled by currently known factors and pathways versus unknown mechanisms. Here, we describe the proteins, pathways, and mechanisms that have been shown to regulate alternative splicing in human T cells and discuss what is and is not known about the genes regulated by such factors. Finally, we highlight unifying themes with regards to the mechanisms and consequences of alternative splicing in the adaptive immune system and give our view of important directions for future studies.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Adverse socioeconomic circumstances in childhood may confer a greater risk for adult cardiovascular disease (CVD). The purpose of this review is to systematically evaluate evidence for an association ...between socioeconomic circumstances during childhood and specific CVD subtypes, independent of adult socioeconomic conditions.
We systematically retrieved individual-level studies of morbidity and mortality from CVD and specific CVD subtypes linked to early life influences, including coronary heart disease (CHD), ischemic and hemorrhagic stroke, peripheral vascular disease, markers of atherosclerosis (carotid intima-media thickness and stenosis), and rheumatic heart disease. Indicators of socioeconomic position in childhood varied, although most studies relied on father's occupation.
We located 40 studies (24 prospective, 11 case–control, and 5 cross-sectional) reported in 50 publications. Thirty-one studies (19 prospective, 7 case–control, and all 5 cross-sectional) found a robust inverse association between childhood circumstances and CVD risk, although findings sometimes varied among specific outcomes, socioeconomic measures, and sex. Case–control studies reported mixed results. The association was stronger for stroke and, in particular, hemorrhagic stroke, than for CHD. Childhood socioeconomic conditions remained important predictors of CVD, even in younger cohorts.
Childhood and adulthood socioeconomic circumstances are important determinants of CVD risk. The specific contribution of childhood and adulthood characteristics varies across different CVD subtypes. Disease-specific mechanisms are likely to explain the childhood origins of these adult health inequalities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hyperekplexia is a rare neurological disorder characterized by neonatal hypertonia, exaggerated startle responses to unexpected stimuli and a variable incidence of apnoea, intellectual disability and ...delays in speech acquisition. The majority of motor defects are successfully treated by clonazepam. Hyperekplexia is caused by hereditary mutations that disrupt the functioning of inhibitory glycinergic synapses in neuromotor pathways of the spinal cord and brainstem. The human glycine receptor α1 and β subunits, which predominate at these synapses, are the major targets of mutations. International genetic screening programs, that together have analysed several hundred probands, have recently generated a clear picture of genotype-phenotype correlations and the prevalence of different categories of hyperekplexia mutations. Focusing largely on this new information, this review seeks to summarise the effects of mutations on glycine receptor structure and function and how these functional alterations lead to hyperekplexia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Collisions involving 112Sn and 124Sn nuclei have been simulated with the improved quantum molecular dynamics transport model. The results of the calculations reproduce isospin diffusion data from two ...different observables and the ratios of neutron and proton spectra. By comparing these data to calculations performed over a range of symmetry energies at saturation density and different representations of the density dependence of the symmetry energy, constraints on the density dependence of the symmetry energy at subnormal density are obtained. The results from the present work are compared to constraints put forward in other recent analyses.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in ...units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.
Pre-mRNA splicing is catalyzed through the activity of the spliceosome, a dynamic enzymatic complex. Forcing aberrant interactions within the spliceosome can reduce splicing efficiency and alter ...splice site choice; however, it is unknown whether such alterations are naturally exploited mechanisms of splicing regulation. Here, we demonstrate that hnRNP L represses CD45 exon 4 by recruiting hnRNP A1 to a sequence upstream of the 5′ splice site. Together, hnRNP L and A1 induce extended contacts between the 5′ splice site-bound U1 snRNA and neighboring exonic sequences that, in turn, inhibit stable association of U6 snRNA and subsequent catalysis. Importantly, analysis of several exons regulated by hnRNP L shows a clear relationship between the potential for binding of hnRNP A1 and U1 snRNA and the effect of hnRNP L on splicing. Together, our results demonstrate that conformational perturbations within the spliceosome are a naturally occurring and generalizable mechanism for controlling alternative splicing decisions.
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► HnRNP L recruits hnRNP A1 and U1 snRNA to sequences upstream of the 5′ splice site ► HnRNP L-induced extended base pairing of U1 snRNA inhibits exchange for U6 snRNA ► Local traps in spliceosome assembly are naturally exploited mechanisms of regulation ► Extended base pairing of U1 may account for much of regulation by hnRNPs L and A1
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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