Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention

© 2018 Elsevier B.V. Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the CLK1, CLK2, CLK3 and CLK4 genes. The expression of CLK1 is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLKT1 (arising from exon 4 skipping) and CLKT2 (arising from intron 4 retention). We examined CLK1 alternative splicing in a range of cancer cell lines, and report widespread and highly variable rates of exon 4 skipping and intron 4 retention. We also examined the effect of severe environmental stress including heat shock, osmotic shock, and exposure to the alkaloid drug harmine on CLK1 alternative splicing in DU145 prostate cancer cells. All treatments rapidly reduced exon 4 skipping and intron 4 retention, shifting the balance towards full-length CLK1 expression. We also found that the inhibition of CLK1 with the benzothiazole TG003 reduced exon 4 skipping and intron 4 retention suggesting an autoregulatory mechanism. CLK1 inhibition with TG003 also resulted in modified alternative splicing of five cancer-associated genes

The S. pombe translation initiation factor eIF4G is sumoylated and associates with the SUMO protease Ulp2

SUMO is a small post-translational modifier, that is attached to lysine residues in target proteins. It acts by altering proteinprotein interactions, protein localisation and protein activity. SUMO chains can also act as substrates for ubiquitination, resulting in proteasome-mediated degradation of the target protein. SUMO is removed from target proteins by one of a number of specific proteases. The processes of sumoylation and desumoylation have well documented roles in DNA metabolism and in the maintenance of chromatin structure. To further analyse the role of this modification, we have purified protein complexes containing the S. pombe SUMO protease, Ulp2. These complexes contain proteins required for ribosome biogenesis, RNA stability and protein synthesis. Here we have focussed on two translation initiation factors that we identified as co-purifying with Ulp2, eIF4G and eIF3h. We demonstrate that eIF4G, but not eIF3h, is sumoylated. This modification is increased under conditions that produce cytoplasmic stress granules. Consistent with this we observe partial co-localisation of eIF4G and SUMO in stressed cells. Using HeLa cells, we demonstrate that human eIF4GI is also sumoylated; in vitro studies indicate that human eIF4GI is modified on K1368 and K1588, that are located in the C-terminal eIF4A- and Mnk-binding sites respectively

Adult Non-Cystic Fibrosis Bronchiectasis Is Characterised by Airway Luminal Th17 Pathway Activation

Copyright © 2015 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Non-cystic fibrosis (CF) bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation. METHODS: Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF), and gene expression of IL-17A, IL-1β, IL-8 and IL-23 determined from endobronchial biopsies (EBx) in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL-17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined. RESULTS: BALF levels of all Th17 cytokines (median (IQR) pg/mL) were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23) vs. 0.27 (0.24, 0.35), 95% CI 1.05 to 2.21, p<0.0001) and IL-23 (9.48 (4.79, 15.75) vs. 0.70 (0.43, 1.79), 95% CI 4.68 to 11.21, p<0.0001). However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls) in bronchiectasis EBx was significantly higher than control for IL1β (4.12 (1.24, 8.05) vs 1 (0.13, 2.95), 95% CI 0.05 to 4.07, p = 0.04) and IL-8 (3.75 (1.64, 11.27) vs 1 (0.54, 3.89), 95% CI 0.32 to 4.87, p = 0.02) and BALF IL-8 and IL-1α levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1α. CONCLUSIONS AND CLINICAL RELEVANCE: Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity

Orbital Orientations of Exoplanets: HAT-P-4b is Prograde and HAT-P-14b is Retrograde

We present observations of the Rossiter-McLaughlin effect for two exoplanetary systems, revealing the orientations of their orbits relative to the rotation axes of their parent stars. HAT-P-4b is prograde, with a sky-projected spin-orbit angle of lambda = -4.9 +/- 11.9 degrees. In contrast, HAT-P-14b is retrograde, with lambda = 189.1 +/- 5.1 degrees. These results conform with a previously noted pattern among the stellar hosts of close-in giant planets: hotter stars have a wide range of obliquities and cooler stars have low obliquities. This, in turn, suggests that three-body dynamics and tidal dissipation are responsible for the short-period orbits of many exoplanets. In addition, our data revealed a third body in the HAT-P-4 system, which could be a second planet or a companion star.Comment: AJ, in press [8 pages

Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2013: the Influenza Complications Alert Network

The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 14 sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with confirmed influenza, estimates vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2013 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals, with influenza confirmed by nucleic acid testing. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 5 April to 31 October 2013, 631 patients were admitted with confirmed influenza at the 14 FluCAN sentinel hospitals. Of these, 31% were more than 65 years of age, 9.5% were Indigenous Australians, 4.3% were pregnant and 77% had chronic co-morbidities. Influenza B was detected in 30% of patients. Vaccination coverage was estimated at 81% in patients more than 65 years of age but only 49% in patients aged less than 65 years with chronic comorbidities. Vaccination effectiveness against hospitalisation with influenza was estimated at 50% (95% confidence interval: 33%, 63%,

Pion interferometry in Au+Au collisions at sNN\sqrt{\mathrm{s}_{_{\mathrm{NN}}}} = 200 GeV

We present a systematic analysis of two-pion interferometry in Au+Au collisions at $\sqrt{s_{NN}}$ = 200 GeV using the STAR detector at RHIC. We extract the HBT radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianess of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast wave parameterizations. The expansion of the source and its relation with the initial energy density distribution is studied.Comment: 21 pages, 30 figures. As published in Physics Review

Strengthening global-change science by integrating aeDNA with paleoecoinformatics

Ancient environmental DNA (aeDNA) data are close to enabling insights into past global-scale biodiversity dynamics at unprecedented taxonomic extent and resolution. However, achieving this potential requires solutions that bridge bioinformatics and paleoecoinformatics. Essential needs include support for dynamic taxonomic inferences, dynamic age inferences, and precise stratigraphic depth. Moreover, aeDNA data are complex and heterogeneous, generated by dispersed researcher networks, with methods advancing rapidly. Hence, expert community governance and curation are essential to building high-value data resources. Immediate recommendations include uploading metabarcoding-based taxonomic inventories into paleoecoinformatic resources, building linkages among open bioinformatic and paleoecoinformatic data resources, harmonizing aeDNA processing workflows, and expanding community data governance. These advances will enable transformative insights into global-scale biodiversity dynamics during large environmental and anthropogenic changes

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

The Environmental History of Cetaceans in Portugal: Ten Centuries of Whale and Dolphin Records

The history between cetaceans and humans is documented throughout time not only in reports, descriptions, and tales but also in legal documents, laws and regulations, and tithes. This wealth of information comes from the easy spotting and identification of individuals due to their large size, surface breathing, and conspicuous above water behaviour. This work is based on historical sources and accounts accounting for cetacean presence for the period between the 12th and 17th centuries, as well as scientific articles, newspapers, illustrations, maps, non-published scientific reports, and other grey literature from the 18th century onwards. Information on whale use in Portugal's mainland has been found since as early as the 12th century and has continued to be created throughout time. No certainty can be given for medieval and earlier events, but both scavenging of stranded whales or use of captured ones may have happened. There is an increasing number of accounts of sighted, stranded, used, or captured cetaceans throughout centuries which is clearly associated with a growing effort towards the study of these animals. Scientific Latin species denominations only started to be registered from the 18th century onwards, as a consequence of the evolution of natural sciences in Portugal and increasing interest from zoologists. After the 19th century, a larger number of observations were recorded, and from the 20th century to the present day, regular scientific records have been collected. Research on the environmental history of cetaceans in Portugal shows a several-centuries-old exploitation of whales and dolphins, as resources mainly for human consumption, followed in later centuries by descriptions of natural history documenting strandings and at sea encounters. Most cetaceans species currently thought to be present in Portuguese mainland waters were at some point historically recorded

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co