Developing an Integrated Ocean Observing System for New Zealand

New Zealand (NZ) is an island nation with stewardship of an ocean twenty times larger than its land area. While the challenges facing NZ’s ocean are similar to other maritime countries, no coherent national plan exists that meets the needs of scientists, stakeholders or kaitiakitanga (guardianship) of NZ’s ocean in a changing climate. The NZ marine science community used the OceanObs’19 white paper to establish a framework and implementation plan for a collaborative NZ ocean observing system (NZ-OOS). Co-production of ocean knowledge with Māori will be embedded in this national strategy for growing a sustainable, blue economy for NZ. The strengths of an observing system for a relatively small nation come from direct connections between the science impetus through to users and stakeholders of an NZ-OOS. The community will leverage off existing ocean observations to optimize effort and resources in a system that has historically made limited investment in ocean observing. The goal of the community paper will be achieved by bringing together oceanographers, data scientists and marine stakeholders to develop an NZ-OOS that provides best knowledge and tools to the sectors of society that use or are influenced by the ocean

Primate lentiviral viral protein R and the DNA damage response: a tale of manipulation and subversion

Vpr is a 14 kDa accessory protein conserved amongst extant primate lentiviruses that is required for virus replication in vivo. Although many functions have been attributed to Vpr, its primary role, and the function under selective pressure in vivo, remains elusive. The minimal importance of Vpr in infection of activated CD4+ T cells in vitro suggests that its major importance lies in overcoming restriction to virus replication in quiescent CD4+ T cells and non-cycling myeloid cell populations, such as macrophages and dendritic cells. Previous studies from our laboratory demonstrated that HIV-1 replication is attenuated in the absence of Vpr in monocyte-derived dendritic cells (MDDCs) and macrophages, which is correlated with the ability of HIV-1 Vpr to overcome a post-integration transcriptional defect in these cells. In contrast to HIV-1 Vpr-mediated transcriptional enhancement of the viral LTR, here I describe a role for HIV-2 and SIVmac Vpr homologs in the suppression of innate immune sensing of primate lentiviral infection in monocyte-derived dendritic cells (MDDCs). Specifically, the Vpr proteins of HIV-2 and SIVmac, but not that of HIV-1, suppress innate immune detection and induction of type I and type III IFN at two distinct stages of the viral life cycle: prior to and during integration. We posit that HIV-2/SIVmac-lineage Vpr homologs gained this function upon the acquisition of Vpx, a Vpr paralog in the lentiviral genome, that targets the retroviral restriction factor SAMHD1 for proteasomal degradation. Mutational analysis shows that suppression of pre-integration innate immune sensing by HIV-2/SIVmac Vpr homologs is tied to their interaction with the DNA damage response protein human Uracil DNA glycosylase hUNG. Interestingly, the HIV-1 Vpr degrades hUNG, whilst the HIV-2/SIVmac Vpr homologs do not. This difference correlates with the inability of HIV-1 Vpr to suppress type I and III IFN responses in SIVmac Vpx supplemented infections of MDDCs. These results highlight how divergent lentiviruses have tailored interactions of their Vpr proteins with members of the DNA damage response to promote replication in diverse cellular contexts. This work also describes the conserved role of primate lentiviral Vpr homologs in the transcription of extrachromosomal or unintegrated viral DNA. This function is dependent on Vpr engagement with the host E3-ubiquitin ligase complex Cul4-DDB1-DCAF1 (DCAFCRL4) and ability to activate the DNA damage response. These findings give insight into the mechanisms driving transcription from an underappreciated and long-lived source of viral antigen, and further the field of non-integrating lentiviral vectors, a frequently used tool for the genetic modification of non-dividing cells. Together, both studies shed light on the way Vpr proteins from diverse primate lentiviruses converge in their manipulation of the DNA damage response to facilitate multiple stages of the virus lifecycle.2024-01-24T00:00:00

Identification of benzazole compounds that induce HIV-1 transcription.

Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed "shock and kill". This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents

Seasonality in Southern Ocean isoscapes

Polar marine ecosystems are particularly vulnerable to the effects of climate change. Warming temperatures, freshening seawater and disruption to sea ice formation potentially all have detrimental cascading effects on food webs. New approaches are needed to better understand spatio-temporal interactions among biogeochemical processes at the base of Southern Ocean food webs, and how these interactions vary seasonally. In marine systems, isoscapes (models of the spatial variation in the stable isotopic composition) of carbon and nitrogen identify the spatial expression of varying biogeochemical processes on nutrient utilization by phytoplankton. Isoscapes also provide a baseline for interpreting stable isotope compositions of higher trophic level animals in movement, migration and diet research. Here we produce carbon and nitrogen isoscapes across the entire Southern Ocean (>40°S) using surface particulate organic matter (POM) isotope data, collected from multiple sources over the past 50 years and throughout the annual cycle. We use Integrated Nested Laplace Approximation (INLA)-based approaches to predict mean annual isoscapes and four seasonal isoscapes using a suite of environmental data as predictor variables. Clear spatial gradients in δ13C and δ15N values were predicted across the Southern Ocean, consistent with previous statistical and mechanistic isoscape views of isotopic variability in this region. We identify strong seasonal variability in both carbon and nitrogen isoscapes, with key implications for the use of static or annual average isoscape baselines in animal studies attempting to document seasonal migratory or foraging behaviours

Isoscape Models of the Southern Ocean: Predicting Spatial and Temporal Variability in Carbon and Nitrogen Isotope Compositions of Particulate Organic Matter

Polar marine ecosystems are particularly vulnerable to the effects of climate change. Warming temperatures, freshening seawater, and disruption to sea-ice formation potentially all have cascading effects on food webs. New approaches are needed to better understand spatiotemporal interactions among biogeochemical processes at the base of Southern Ocean food webs. In marine systems, isoscapes (models of the spatial variation in the stable isotopic composition) of carbon and nitrogen have proven useful in identifying spatial variation in a range of biogeochemical processes, such as nutrient utilization by phytoplankton. Isoscapes provide a baseline for interpreting stable isotope compositions of higher trophic level animals in movement, migration, and diet research. Here, we produce carbon and nitrogen isoscapes across the entire Southern Ocean (>40°S) using surface particulate organic matter isotope data, collected over the past 50 years. We use Integrated Nested Laplace Approximation-based approaches to predict mean annual isoscapes and four seasonal isoscapes using a suite of environmental data as predictor variables. Clear spatial gradients in δ13C and δ15N values were predicted across the Southern Ocean, consistent with previous statistical and mechanistic views of isotopic variability in this region. We identify strong seasonal variability in both carbon and nitrogen isoscapes, with key implications for the use of static or annual average isoscape baselines in animal studies attempting to document seasonal migratory or foraging behaviors

Activity and selectivity of compounds that induce HIV-1 transcription.

<p>Activity and selectivity of compounds that induce HIV-1 transcription.</p

HDAC inhibition assay.

<p>Hela nuclear extract (NE) or purified HDACs were assayed for deacetylation activity in the presence of Compound <b>1</b>, Compound <b>2</b>, or known HDAC inhibitors. Data are plotted as mean ± SEM of two independent replicates and is normalized to vehicle-treated sample. Dotted line indicates 100% HDAC activity (0% inhibition). SAHA, suberanilohydroxamic acid; TSA, trichostatin A; VA, valproic acid; NaBu, sodium butyrate.</p

Compounds 1 and 2 induce HIV-1 transcription in ACH-2 and U1.

<p>Cells were treated with 30 μM of Cmpd 1 and Cmpd 2 for 24 h. RNA was prepared and HIV expression was monitored by qRT-PCR. Data are presented as the log fold induction over DMSO treated controls. Each bar represents treatments performed in triplicate. Error bars represent the standard error. These data are from an individual experiment that is representative of 3 independent experiments.</p

Induction of HIV-1 expressing cells following treatment with latency reversing agents.

<p>ACH-2 cells were not treated or treated with a final concentration of 30 μM Cmpd 1 or Cmpd 2, 10 μM SAHA, 1 mM JQ1 or 10 ng/ml PMA for 16 h. Cells were stained using anti-HIV-Gag-PE and analyzed by flow cytometry. Numbers within the profiles represent the percentage of positive cells. These profiles are from a single experiment. B) Data from four independent experiments. Y-axis is mean of % p24 positive cells. * Cmpd 1 p-value >0.005 compared to other treatments using a two-tailed t-test.</p

In vitro profiling properties of HIV-1 latency antagonists.

<p>In vitro profiling properties of HIV-1 latency antagonists.</p