The interactome of the atypical phosphatase Rtr1 in Saccharomyces cerevisiae

The phosphatase Rtr1 has been implicated in dephosphorylation of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) during transcription elongation and in regulation of nuclear import of RNAPII. Although it has been shown that Rtr1 interacts with RNAPII in yeast and humans, the specific mechanisms that underlie Rtr1 recruitment to RNAPII have not been elucidated. To address this, we have performed an in-depth proteomic analysis of Rtr1 interacting proteins in yeast. Our studies revealed that hyperphosphorylated RNAPII is the primary interacting partner for Rtr1. To extend these findings, we performed quantitative proteomic analyses of Rtr1 interactions in yeast strains deleted for CTK1, the gene encoding the catalytic subunit of the CTD kinase I (CTDK-I) complex. Interestingly, we found that the interaction between Rtr1 and RNAPII is decreased in ctk1Δ strains. We hypothesize that serine-2 CTD phosphorylation is required for Rtr1 recruitment to RNAPII during transcription elongation

Elevation change of the Greenland Ice Sheet due to surface mass balance and firn processes, 1960–2014

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in The Cryosphere 9 (2015): 2009-2025, doi:10.5194/tc-9-2009-2015.Observed changes in the surface elevation of the Greenland Ice Sheet are caused by ice dynamics, basal elevation change, basal melt, surface mass balance (SMB) variability, and by compaction of the overlying firn. The last two contributions are quantified here using a firn model that includes compaction, meltwater percolation, and refreezing. The model is forced with surface mass fluxes and temperature from a regional climate model for the period 1960–2014. The model results agree with observations of surface density, density profiles from 62 firn cores, and altimetric observations from regions where ice-dynamical surface height changes are likely small. In areas with strong surface melt, the firn model overestimates density. We find that the firn layer in the high interior is generally thickening slowly (1–5 cm yr−1). In the percolation and ablation areas, firn and SMB processes account for a surface elevation lowering of up to 20–50 cm yr−1. Most of this firn-induced marginal thinning is caused by an increase in melt since the mid-1990s and partly compensated by an increase in the accumulation of fresh snow around most of the ice sheet. The total firn and ice volume change between 1980 and 2014 is estimated at −3295 ± 1030 km3 due to firn and SMB changes, corresponding to an ice-sheet average thinning of 1.96 ± 0.61 m. Most of this volume decrease occurred after 1995. The computed changes in surface elevation can be used to partition altimetrically observed volume change into surface mass balance and ice-dynamically related mass changes.P. Kuipers Munneke received financial support from the Netherlands Polar Programme (NPP) of the Netherlands Institute for Scientific Research (NWO). ECMWF at Reading (UK) is acknowledged for use of the Cray supercomputing system. The J. E. Box contribution is supported by Det Frie Forskningsråd grant 4002-00234 and Geocenter Denmark

Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling and activation of these neurons enhance specific motor programs whereas indirect pathway MSNs (iMSNs) are negatively coupled to PKA and inhibit competing motor programs. An imbalance in the activity of these two programs is observed following increased dopamine signaling associated with exposure to psychostimulant drugs of abuse. Alterations in MSN signaling are mediated by changes in MSN protein post-translational modifications, including phosphorylation. Whereas direct changes in specific kinases, such as PKA, regulate different effects observed in the two MSN populations, alterations in the specific activity of serine/threonine phosphatases, such as protein phosphatase 1 (PP1) are less well known. This lack of knowledge is due, in part, to unknown, cell-specific changes in PP1 targeting proteins. Spinophilin is the major PP1-targeting protein in striatal postsynaptic densities. Using proteomics and immunoblotting approaches along with a novel transgenic mouse expressing hemagglutainin (HA)-tagged spinophilin in dMSNs and iMSNs, we have uncovered cell-specific regulation of the spinophilin interactome following a sensitizing regimen of amphetamine. These data suggest regulation of spinophilin interactions in specific MSN cell types and may give novel insight into putative cell-specific, phosphatase-dependent signaling pathways associated with psychostimulants

Correction: Baucum II, Anthony J. et al. Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization. Proteomes 2018, 6, 53

The author wishes to make the following corrections to the methods section of their paper [...]. Erratum for Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization. [Proteomes. 2018

Turkey and the Gulf States in the Horn of Africa:Fluctuating dynamics of engagement, investment and influence

Since around 2015, the importance of the Gulf states, particularly Saudi Arabia, the United Arab Emirates (UAE) and Qatar, in the affair of countries in the Horn of Africa has been growing. At the same time, Turkey, which made a political choice nearly two decades ago to ‘open towards Africa’, has also strengthened its presence in the region. While the Horn of Africa is not the top foreign policy priority for the Gulf states or Turkey, its geographical proximity—part of the Gulf’s ‘near abroad’—means that the region demands consistent attention, particularly from a (maritime) security perspective.Relations between the countries in the Horn of Africa and their partners in the Gulf and wider Middle East are asymmetric in nature. While the Horn countries in focus for this study—Sudan, Ethiopia, Eritrea and Somalia—are relatively poor, politically volatile and affected by conflict, their partners across the Red Sea are comparatively wealthy, largely stable (at least internally) and increasingly asserting their positions as more proactive middle powers. For these middle power states, relations with global powers remain their geopolitical priority.Nonetheless, expansion into areas such as the Horn of Africa, where they can assert their (growing) political, financial and military strength, has become an increasingly important objective of foreign policy.The scale of resources brought to bear by Turkey and the Gulf states in their business and humanitarian ventures in the Horn of Africa is substantial. This does not, however, necessarily correspond to the priority given to the Horn of Africa by policymakers in Turkey and the Gulf. For countries in the Horn of Africa, the growing involvement of these more powerful, wealthier powers in their economies and foreign relations has offered opportunities—although not without some risks—to drive domestic (or personal) agendas, and to continue a long history of avoiding capture by those of global powers

Characterization Of A New ODA3 Allele, ODA3-6, Defective In Assembly Of The Outer Dynein Arm-Docking Complex In Chlamydomonas Reinhardtii

We have used an insertional mutagenesis approach to generate new C. reinhardtii motility mutants. Of 56 mutants isolated, one is a new allele at the ODA3 locus, called oda3-6. Similar to the previously characterized oda3 alleles, oda3-6 has a slow-jerky swimming phenotype and reduced swimming speed. The oda3-6 mutant fails to assemble the outer dynein arm motor and outer dynein arm—docking complex (ODA-DC) in the ciliary axoneme due to an insertion in the 5’ end of the DCC1 gene, which encodes the DC1 subunit of the ODA-DC. Transformation of oda3-6 with the wild-type DCC1 gene rescues the mutant swimming phenotype and restores assembly of the ODA-DC and the outer dynein arm in the cilium. This is the first oda3 mutant to be characterized at the molecular level and is likely to be very useful for further analysis of DC1 function

Pharmacogenomics polygenic risk score: Ready or not for prime time?

Pharmacogenomic Polygenic Risk Scores (PRS) have emerged as a tool to address the polygenic nature of pharmacogenetic phenotypes, increasing the potential to predict drug response. Most pharmacogenomic PRS have been extrapolated from disease-associated variants identified by genome wide association studies (GWAS), although some have begun to utilize genetic variants from pharmacogenomic GWAS. As pharmacogenomic PRS hold the promise of enabling precision medicine, including stratified treatment approaches, it is important to assess the opportunities and challenges presented by the current data. This assessment will help determine how pharmacogenomic PRS can be advanced and transitioned into clinical use. In this review, we present a summary of recent evidence, evaluate the current status, and identify several challenges that have impeded the progress of pharmacogenomic PRS. These challenges include the reliance on extrapolations from disease genetics and limitations inherent to pharmacogenomics research such as low sample sizes, phenotyping inconsistencies, among others. We finally propose recommendations to overcome the challenges and facilitate the clinical implementation. These recommendations include standardizing methodologies for phenotyping, enhancing collaborative efforts, developing new statistical methods to capitalize on drug-specific genetic associations for PRS construction. Additional recommendations include enhancing the infrastructure that can integrate genomic data with clinical predictors, along with implementing user-friendly clinical decision tools, and patient education. Ethical and regulatory considerations should address issues related to patient privacy, informed consent and safe use of PRS. Despite these challenges, ongoing research and large-scale collaboration is likely to advance the field and realize the potential of pharmacogenomic PRS

A novel GCN5b lysine acetyltransferase complex associates with distinct transcription factors in the protozoan parasite Toxoplasma gondii

Toxoplasma gondii is a protozoan parasite that has a tremendous impact on human health and livestock. High seroprevalence among humans and other animals is facilitated by the conversion of rapidly proliferating tachyzoites into latent bradyzoites that are housed in tissue cysts, which allow transmission through predation. Epigenetic mechanisms contribute to the regulation of gene expression events that are crucial in both tachyzoites as well as their development into bradyzoites. Acetylation of histones is one of the critical histone modifications that is linked to active gene transcription. Unlike most early-branching eukaryotes, Toxoplasma possesses two GCN5 homologues, one of which, GCN5b, is essential for parasite viability. Surprisingly, GCN5b does not associate with most of the well-conserved proteins found in the GCN5 complexes of other eukaryotes. Of particular note is that GCN5b interacts with multiple putative transcription factors that have plant-like DNA-binding domains denoted as AP2. To understand the function of GCN5b and its role(s) in epigenetic gene regulation of stage switching, we performed co-immunoprecipitation of GCN5b under normal and bradyzoite induction conditions. We report the greatest resolution of the GCN5b complex to date under these various culture conditions. Moreover, reciprocal co-IPs were performed with distinct GCN5b-interacting AP2 factors (AP2IX-7 and AP2XII-4) to delineate the interactomes of each putative transcription factor. Our findings suggest that GCN5b is associated with at least two distinct complexes that are characterized by two different pairs of AP2 factors, and implicate up to four AP2 proteins to be involved with GCN5b-mediated gene regulation