Coastal Ocean Processes : a science prospectus

CoOP (Coastal Ocean Processes) is an organization meant to study major interdisciplinary scientific problems in the coastal ocean. Its goal is "to obtain a new level of quantitative understanding of the processes that dominate the transformations, transport and fates of biologically, chemically and geologically important matter on the continental margin". Central to obtaining this understanding will be advances in observing and modeling the cross-shelf component of transport. More specific objectives are to understand 1) cross-margin exchanges, 2) air sea exchanges, 3) benthic-pelagic exchanges, 4) terrestrial inputs and 5) biological and chemical transformations within the water column. CoOP research will be carried out primarly through a series of process-oriented field studies, each involving about two years of measurements. Each of these field studies is to be initiated and defined through a community workshop. In addition to the process studies, CoOP will also involve modeling, long time series, exploratory studies, remote sensing, technological innovation, data archiving and communications. A CoOP pilot study has been approved for funding by the National Science Foundation, and funding will begin in 1992. The CoOP science effort is thus already underway.Funding was provided by the National Science Foundation under Grant No. OCE-9108993

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Lead Optimization of Second-Generation Acridones As Broad-Spectrum Antimalarials

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development

Extracellular polymeric substance (EPS)-degrading enzymes reduce staphylococcal surface attachment and biocide resistance on pig skin in vivo.

Staphylococcal extracellular polymeric substances (EPS) such as extracellular DNA (eDNA) and poly-N-acetylglucosamine surface polysaccharide (PNAG) mediate numerous virulence traits including host colonization and antimicrobial resistance. Previous studies showed that EPS-degrading enzymes increase staphylococcal biocide susceptibility in vitro and in vivo, and decrease virulence in animal models. In the present study we tested the effect of EPS-degrading enzymes on staphylococcal skin colonization and povidone iodine susceptibility using a novel in vivo pig model that enabled us to colonize and treat 96 isolated areas of skin on a single animal in vivo. To quantitate skin colonization, punch biopsies of colonized areas were homogenized, diluted, and plated on agar for colony forming unit enumeration. Skin was colonized with either Staphylococcus epidermidis or Staphylococcus aureus. Two EPS-degrading enzymes, DNase I and the PNAG-degrading enzyme dispersin B, were employed. Enzymes were tested for their ability to inhibit skin colonization and detach preattached bacteria. The effect of enzymes on the susceptibility of preattached S. aureus to killing by povidone iodine was also measured. We found that dispersin B significantly inhibited skin colonization by S. epidermidis and detached preattached S. epidermidis cells from skin. A cocktail of dispersin B and DNase I detached preattached S. aureus cells from skin and increased their susceptibility to killing by povidone iodine. These findings suggest that staphylococcal EPS components such as eDNA and PNAG contribute to skin colonization and biocide resistance in vivo. EPS-degrading enzymes may be a useful adjunct to conventional skin antisepsis procedures in order to further reduce skin bioburden

Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice

<div><p>Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI^-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI^-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI^-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. <i>In vitro</i> analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.</p></div

FXII activation by α-kallikrein or FXIa in the presence of polyanions.

<p><b>(A)</b> FXII (200 nM) was incubated with vehicle (▼), 1nM FXIa (◇), or 2 nM α-kallikrein (◆). <b>(B-D)</b> FXII (200 nM) incubated with <b>(B)</b> 5 ug/ml DNA (□,➄), <b>(C)</b> 5 ug/ml RNA (○,➂) or <b>(D)</b> 20 μg/ml Poly-P (△,▲), in the presence of 1 nM FXIa (□,○,△) or 2 nM α-kallikrein (➄,➂,▲). At the indicated times, samples were tested for FXIIa activity by chromogenic assay. Error bars are +/− one standard deviation.</p

Plasma cytokine levels after CLP.

<p>Shown are plasma concentrations of TNFα, IL-1β, IL-6 and IL-10 in WT (black bars) and FXI^-/- (white bars) littermates at various times after high-grade CLP. Absolute cytokine levels are shown in the left-hand column and fold-increases in cytokines compared to sham treatment are shown in the right-hand column. Eight or nine mice were tested at each time point for each genotype for CLP, and three were used at each time point for sham surgery. Plasma TNFα <b>(</b><i>p</i> = 0.006) and IL-10 <b>(</b><i>p</i> = 0.0003) levels were significantly greater in WT mice than in FXI^-/- mice 4 hr post-CLP. Fold-increases in plasma levels of TNFα, <b>(</b><i>p</i> = 0.009), IL-1β, <b>(</b><i>p</i> = 0.009), IL-6 (<i>p</i> = 0.003) and IL-10 (<i>p</i> = 0.0003) were significantly greater in WT mice than in FXI^-/- mice 4 hr post-CLP. For IL-6, FXI^-/- mice had significantly greater fold-increases in plasma levels 8 (**<i>p</i> = 0.005) and 24 hr (**<i>p</i> = 0.04) post-CLP. Error bars represent SEM.</p