Dma/RNF8 proteins are evolutionarily conserved E3 ubiquitin ligases that target septins.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tThe budding yeast proteins Dma1 and Dma2 are members of the unique FHA-RING domain protein family and are linked to mitotic regulation and septin organization by ill-defined mechanisms. We show that Dma2 has ubiquitin ligase activity, and that septins Shs1 and Cdc11 are likely direct in vivo targets. We further propose that human RNF8, rather than Chfr, is the mammalian Dma homolog. As in yeast, RNF8 localizes to the centrosomes and cell division sites and promotes ubiquitylation of the septin SEPT7, whose depletion increases cell division anomalies. Together, these findings reveal evolutionary and functional conservation of Dma proteins, and suggest that RNF8 maintains genome stability through independent, yet analogous, nuclear and cytoplasmic ubiquitylation activities.HFSP fellowshipCRUKERCEuropean Community’s Seventh Framework ProgramWellcome Trus

RNF8 links nucleosomal and cytoskeletal ubiquitylation of higher order protein structures.

PublishedCommentJournal ArticleN/

Phylogenetic Implications of a Unique 5.8S nrDNA Insertion in Cyperaceae

The purpose of this study was to assess the phylogenetic utility of a large insertion (3 bp) in the 5.8S gene of nuclear ribosomal DNA (nrDNA) in Cyperaceae and selected Juncaceae. This was done by reconstructing the character evolution of the insertion on a phylogeny derived from rbcL sequences. Results suggest that the insertion was gained once at the base of Cyperaceae followed by multiple losses in its most-derived taxa. Despite several homoplastic losses (CI = 0.20), the pattern of insertion loss (RI = 0.88), and base pair variation within the insertion were useful for defining sedge clades at various taxonomic levels. For example, whereas a loss of the insertion appeared to characterize a major terminal clade within Cyperaceae, both an insertion loss and sequence variation were consistent with infrageneric clades previously discovered in an ITS phylogeny of Eleocharis. The presence/absence of the insertion also supported previous conclusions based on morphological and molecular data that tribe Scirpeae and Scirpus s.l. are polyphyletic. In the context of our current understanding of Cyperaceae relationships, evolutionary patterns related to this insertion provide additional support for groups defined in prior phylogenetic analyses. The present analysis also suggests that the controversial position of Oxychloe andina (Juncaceae) in previous rbcL analyses, as sister to Cyperaceae (Y12978) or as nested within Cyperaceae (U49222), is due to the fact that Y12978 is a Juncaceae/Cyperaceae chimera, whereas U49222 is the sequence of a Cyperaceae contaminant. When U49222 is excluded from analyses and the Cyperaceae portion of Y12978 is removed, Juncaceae and Cyperaceae are monophyletic with Oxychloe positioned within a Juncaceae clade of single-flowered genera

Chromatin Profiles of Chromosomally Integrated Human Herpesvirus-6A

Human herpesvirus-6A (HHV-6A) and 6B (HHV-6B) are two closely related betaherpesviruses that are associated with various diseases including seizures and encephalitis. The HHV-6A/B genomes have been shown to be present in an integrated state in the telomeres of latently infected cells. In addition, integration of HHV-6A/B in germ cells has resulted in individuals harboring this inherited chromosomally integrated HHV-6A/B (iciHHV-6) in every cell of their body. Until now, the viral transcriptome and the epigenetic modifications that contribute to the silencing of the integrated virus genome remain elusive. In the current study, we used a patient-derived iciHHV-6A cell line to assess the global viral gene expression profile by RNA-seq, and the chromatin profiles by MNase-seq and ChIP-seq analyses. In addition, we investigated an in vitro generated cell line (293-HHV-6A) that expresses GFP upon the addition of agents commonly used to induce herpesvirus reactivation such as TPA. No viral gene expression including miRNAs was detected from the HHV-6A genomes, indicating that the integrated virus is transcriptionally silent. Intriguingly, upon stimulation of the 293-HHV-6A cell line with TPA, only foreign promoters in the virus genome were activated, while all HHV-6A promoters remained completely silenced. The transcriptional silencing of latent HHV-6A was further supported by MNase-seq results, which demonstrate that the latent viral genome resides in a highly condensed nucleosome-associated state. We further explored the enrichment profiles of histone modifications via ChIP-seq analysis. Our results indicated that the HHV-6 genome is modestly enriched with the repressive histone marks H3K9me3/H3K27me3 and does not possess the active histone modifications H3K27ac/H3K4me3. Overall, these results indicate that HHV-6 genomes reside in a condensed chromatin state, providing insight into the epigenetic mechanisms associated with the silencing of the integrated HHV-6A genome

Perceptions of climate change across the Canadian forest sector: the key factors of institutional and geographical environment

Assessing the perception of key stakeholders within the forest sector is critical to evaluating their readiness to engage in adapting to climate change. Here, we report the results of the most comprehensive survey carried out in the Canadian forestry sector to date regarding perceptions of climate change. A total of 1158 individuals, representing a wide range of stakeholders across the five most important forestry provinces in Canada, were asked about climate change, its impact on forest ecosystems, and the suitability of current forest management for addressing future impacts. Overall, we found that respondents were more concerned about climate change than the general population. More than 90% of respondents agreed with the anthropogenic origins of climate change, and > 50% considered it a direct threat to their welfare. Political view was the main driver of general beliefs about the causes of climate change and its future consequences, while the province of origin proved to be the best predictor of perceived current impacts on forest ecosystems and its associated risks; and type of stakeholder was the main driver of perceived need for adaptation. Industrial stakeholders were the most skeptical about the anthropogenic cause(s) of climate change (18% disagreed with this statement, compared to an average of 8% in the other stakeholders), its impacts on forest ecosystems (28% for industry vs. 10% for other respondents), and the need for new management practices (18% vs. 7%). Although the degree of awareness and the willingness to implement adaptive practices were high even for the most skeptical groups, our study identified priority sectors or areas for action when designing awareness campaigns. We suggest that the design of a strategic framework for implementing climate adaptation within the Canadian forest sector should focus on the relationship between climate change and changes in disturbance regimes, and above all on the economic consequences of these changes, but it should also take into account the positions shown by each of the actors in each province.This project was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC) through a strategic grant 430393- 12. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Implications of the antiplatelet therapy gap left with discontinuation of prasugrel in Canada

Background The current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. Methods Five members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. Results Several clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. Conclusions The discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy.Introduction Dans ses lignes directrices actuelles sur la thérapie antiplaquettaire, la Société canadienne de cardiologie recommande l’utilisation du ticagrélor ou du prasugrel plutôt que l’utilisation du clopidogrel comme antagonistes des récepteurs plaquettaires P2Y12 de première intention dans le traitement des patients qui présentent un risque modéré à élevé de syndromes coronariens aigus. Depuis peu, le distributeur a cessé la distribution d’Effient (prasugrel) au Canada. Méthodes Cinq membres du comité des lignes directrices 2018 sur la thérapie antiplaquettaire de la Société canadienne de cardiologie ont entrepris une revue indépendante fondée sur les données probantes pour dresser le profil des patients pour lesquels le prasugrel devrait être la meilleure option parmi les antagonistes des récepteurs P2Y12 et se pencher sur les traitements alternatifs en l'absence de prasugrel. Résultats Plusieurs scénarios cliniques où le prasugrel devrait être indiqué sont recensés et abordés. Les réflexions sur les solutions de rechange au traitement, notamment une revue des lignes directrices nationales et internationales en matière de désescalade des antagonistes des récepteurs P2Y12, sont présentées. Conclusions La cessation de la distribution du prasugrel pose problème aux cliniciens. Les cliniciens doivent tenir compte des facteurs clés pour déterminer le meilleur traitement de remplacement

Shunt dysfunction patterns after transjugular intrahepatic portosystemic shunt creation using a combination of a generic stent-graft and bare-stents.

Even though transjugular intrahepatic portosystemic shunt (TIPS) using Fluency Stent-grafts provides good shunt patency rates, shunt dysfunction is a great concern after TIPS creation, occurring in up to 20% of cases within one year. The objective of this study was to describe shunt dysfunction patterns after TIPS creation using a combination of generic stent-grafts/bare-stents. Single-center retrospective study of all TIPS revisions between January 2005 and December 2020. TIPS revision angiograms were analyzed for stents' positions, stenoses' diameters, and stenoses' locations. Out of 99 TIPS, a total of 33 TIPS revisions were included. The median time to TIPS revision was 10.4 months. Angiograms showed four patterns of TIPS dysfunction-associated features (DAF), defined as follows: Type 1 was defined as stenosis located after the stent end in the hepatic vein (HV), type 2 as intra-stent stenosis located in the hepatic vein, type 3 as intra-stent stenosis or a kink in the parenchymal tract or the portal vein end of the TIPS, and type 4 as a complete TIPS occlusion. Types 1, 2, 3, and 4 were seen in 23 (69.7%), 5 (15.2%), 2 (6.1%), and 3 (9.1%) TIPS respectively. TIPS revision was successful in 30 (90.1%) patients with median pre- and post-TIPS revision PSG of 18.5 mmHg and 8 mmHg respectively (p < .001). Our results illustrate the four angiographic patterns of TIPS DAF after TIPS creation using a combination of generic stent-grafts/bare-stents and emphasize the need for appropriate stent length extending to the HV/inferior vena cava junction

Fundamental limitations on "warp drive" spacetimes

"Warp drive" spacetimes are useful as "gedanken-experiments" that force us to confront the foundations of general relativity, and among other things, to precisely formulate the notion of "superluminal" communication. We verify the non-perturbative violation of the classical energy conditions of the Alcubierre and Natario warp drive spacetimes and apply linearized gravity to the weak-field warp drive, testing the energy conditions to first and second order of the non-relativistic warp-bubble velocity. We are primarily interested in a secondary feature of the warp drive that has not previously been remarked upon, if it could be built, the warp drive would be an example of a "reaction-less drive". For both the Alcubierre and Natario warp drives we find that the occurrence of significant energy condition violations is not just a high-speed effect, but that the violations persist even at arbitrarily low speeds. An interesting feature of this construction is that it is now meaningful to place a finite mass spaceship at the center of the warp bubble, and compare the warp field energy with the mass-energy of the spaceship. There is no hope of doing this in Alcubierre's original version of the warp-field, since by definition the point in the center of the warp bubble moves on a geodesic and is "massless". That is, in Alcubierre's original formalism and in the Natario formalism the spaceship is always treated as a test particle, while in the linearized theory we can treat the spaceship as a finite mass object. For both the Alcubierre and Natario warp drives we find that even at low speeds the net (negative) energy stored in the warp fields must be a significant fraction of the mass of the spaceship.Comment: 18 pages, Revtex4. V2: one reference added, some clarifying comments and discussion, no physics changes, accepted for publication in Classical and Quantum Gravit