Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1

SAMHD1 is a host restriction factor that blocks the ability of lentiviruses such as HIV-1 to undergo reverse transcription in myeloid cells and resting T-cells. This restriction is alleviated by expression of the lentiviral accessory proteins Vpx and Vpr (Vpx/Vpr), which target SAMHD1 for proteasome-mediated degradation. However, the precise determinants within SAMHD1 for recognition by Vpx/Vpr remain unclear. Here we show that evolution of Vpx/Vpr in primate lentiviruses has caused the interface between SAMHD1 and Vpx/Vpr to alter during primate lentiviral evolution. Using multiple HIV-2 and SIV Vpx proteins, we show that Vpx from the HIV-2 and SIVmac lineage, but not Vpx from the SIVmnd2 and SIVrcm lineage, require the C-terminus of SAMHD1 for interaction, ubiquitylation, and degradation. On the other hand, the N-terminus of SAMHD1 governs interactions with Vpx from SIVmnd2 and SIVrcm, but has little effect on Vpx from HIV-2 and SIVmac. Furthermore, we show here that this difference in SAMHD1 recognition is evolutionarily dynamic, with the importance of the N- and C-terminus for interaction of SAMHD1 with Vpx and Vpr toggling during lentiviral evolution. We present a model to explain how the head-to-tail conformation of SAMHD1 proteins favors toggling of the interaction sites by Vpx/Vpr during this virus-host arms race. Such drastic functional divergence within a lentiviral protein highlights a novel plasticity in the evolutionary dynamics of viral antagonists for restriction factors during lentiviral adaptation to its hosts. © 2013 Fregoso et al

ARSB IS REQUIRED FOR BONE REMODELING

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Timing and Nature of the Deepening of the Tasmanian Gateway

Tectonic changes that produced a deep Tasmanian Gateway between Australia and Antarctica are widely invoked as the major mechanism for Antarctic cryosphere growth and Antarctic Circumpolar Current (ACC) development during the Eocene/Oligocene (E/O) transition (∼34–33 Ma). Ocean Drilling Program (ODP) Leg 189 recovered near-continuous marine sedimentary records across the E/O transition interval at four sites around Tasmania. These records are largely barren of calcareous microfossils but contain a rich record of siliceous- and organic-walled marine microfossils. In this study we integrate micropaleontological, sedimentological, geochemical, and paleomagnetic data from Site 1172 (East Tasman Plateau) to identify four distinct phases (A–D) in the E/O Tasmanian Gateway deepening that are correlative among ODP Leg 189 sites. Phase A, prior to ∼35.5 Ma: minor initial deepening characterized by a shallow marine prodeltaic setting with initial condensation episodes. Phase B, ∼35.5–33.5 Ma: increased deepening marked by the onset of major glauconitic deposition and inception of energetic bottom-water currents. Phase C, ∼33.5–30.2 Ma: further deepening to bathyal depths, with episodic erosion by increasingly energetic bottom-water currents. Phase D, \u3c30.2 Ma: establishment of stable, open-ocean, warm-temperate, oligotrophic settings characterized by siliceous-carbonate ooze deposition. Our combined evidence indicates that this early Oligocene Tasmanian Gateway deepening initially produced an eastward flow of relatively warm surface waters from the Australo-Antarctic Gulf into the southwestern Pacific Ocean. This “proto-Leeuwin” current fundamentally differs from previous regional reconstructions of eastward flowing cool water (e.g., a “proto-ACC”) during the early Oligocene and thereby represents an important new constraint for reconstructing regional- to global-scale dynamics for this major global change event

Heat and moisture budgets from airborne measurements and high-resolution model simulations

High-resolution simulations with a mesoscale model are performed to estimate heat and moisture budgets of a well-mixed boundary layer. The model budgets are validated against energy budgets obtained from airborne measurements over heterogeneous terrain in Western Germany. Time rate of change, vertical divergence, and horizontal advection for an atmospheric column of air are estimated. Results show that the time trend of specific humidity exhibits some deficiencies, while the potential temperature trend is matched accurately. Furthermore, the simulated turbulent surface fluxes of sensible and latent heat are comparable to the measured fluxes, leading to similar values of the vertical divergence. The analysis of different horizontal model resolutions exhibits improved surface fluxes with increased resolution, a fact attributed to a reduced aggregation effect. Scale-interaction effects could be identified: while time trends and advection are strongly influenced by mesoscale forcing, the turbulent surface fluxes are mainly controlled by microscale processes

Hyperresolution information and hyperresolution ignorance in modelling the hydrology of the land surface

There is a strong drive towards hyperresolution earth system models in order to resolve finer scales of motion in the atmosphere. The problem of obtaining more realistic representation of terrestrial fluxes of heat and water, however, is not just a problem of moving to hyperresolution grid scales. It is much more a question of a lack of knowledge about the parameterisation of processes at whatever grid scale is being used for a wider modelling problem. Hyperresolution grid scales cannot alone solve the problem of this hyperresolution ignorance. This paper discusses these issues in more detail with specific reference to land surface parameterisations and flood inundation models. The importance of making local hyperresolution model predictions available for evaluation by local stakeholders is stressed. It is expected that this will be a major driving force for improving model performance in the future. Keith BEVEN, Hannah CLOKE, Florian PAPPENBERGER, Rob LAMB, Neil HUNTE

The minimal kinome of Giardia lamblia illuminates early kinase evolution and unique parasite biology

Background: The major human intestinal pathogen Giardia lamblia is a very early branching eukaryote with a minimal genome of broad evolutionary and biological interest. Results: To explore early kinase evolution and regulation of Giardia biology, we cataloged the kinomes of three sequenced strains. Comparison with published kinomes and those of the excavates Trichomonas vaginalis and Leishmania major shows that Giardia's 80 core kinases constitute the smallest known core kinome of any eukaryote that can be grown in pure culture, reflecting both its early origin and secondary gene loss. Kinase losses in DNA repair, mitochondrial function, transcription, splicing, and stress response reflect this reduced genome, while the presence of other kinases helps define the kinome of the last common eukaryotic ancestor. Immunofluorescence analysis shows abundant phospho-staining in trophozoites, with phosphotyrosine abundant in the nuclei and phosphothreonine and phosphoserine in distinct cytoskeletal organelles. The Nek kinase family has been massively expanded, accounting for 198 of the 278 protein kinases in Giardia. Most Neks are catalytically inactive, have very divergent sequences and undergo extensive duplication and loss between strains. Many Neks are highly induced during development. We localized four catalytically active Neks to distinct parts of the cytoskeleton and one inactive Nek to the cytoplasm. Conclusions: The reduced kinome of Giardia sheds new light on early kinase evolution, and its highly divergent sequences add to the definition of individual kinase families as well as offering specific drug targets. Giardia's massive Nek expansion may reflect its distinctive lifestyle, biphasic life cycle and complex cytoskeleton

Identification of Hyaloperonospora arabidopsidis Transcript Sequences Expressed during Infection Reveals Isolate-Specific Effectors

Biotrophic plant pathogens secrete effector proteins that are important for infection of the host. The aim of this study was to identify effectors of the downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa) that are expressed during infection of its natural host Arabidopsis thaliana. Infection-related transcripts were identified from Expressed Sequence Tags (ESTs) derived from leaves of the susceptible Arabidopsis Ws eds1-1 mutant inoculated with the highly virulent Hpa isolate Waco9. Assembly of 6364 ESTs yielded 3729 unigenes, of which 2164 were Hpa-derived. From the translated Hpa unigenes, 198 predicted secreted proteins were identified. Of these, 75 were found to be Hpa-specific and six isolate Waco9-specific. Among 42 putative effectors identified there were three Elicitin-like proteins, 16 Cysteine-rich proteins and 18 host-translocated RXLR effectors. Sequencing of alleles in different Hpa isolates revealed that five RXLR genes show signatures of diversifying selection. Thus, EST analysis of Hpa-infected Arabidopsis is proving to be a powerful method for identifying pathogen effector candidates expressed during infection. Delivery of the Waco9-specific protein RXLR29 in planta revealed that this effector can suppress PAMP-triggered immunity and enhance disease susceptibility. We propose that differences in host colonization can be conditioned by isolate-specific effectors