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- Lu, Lu, 1984-, et al.
(författare)
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MEPicides : α,β-Unsaturated Fosmidomycin N-acyl Analogsas inhibitors that selectively target DXR from Plasmodium falciparum, the deadliest causative parasite of human Malaria
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Fosmidomycin and FR-9000098 have been confirmed to show parasiticidal activity against Plasmodium falciparum, targeting DXR involved in the MEP pathway. We designed a construct of PfDXR that has successfully been overexpressed in E. coli BL21(DE3) C43, and purified by IMAC and SEC, with the final yield of 1.2 mg/ 8 L culture. PfDXR was concentrated to 20 mg/ml, and co-crystallized with previously tested inhibitors in the FR-9000098 scaffold in the presence of Mn2+. Three FR-9000098 analogues with double-bonded Ca-Cband/or a phenyl ring with various lengths to N1, showed inhibitory activities with IC50s roughly 50 nM. Three crystals were in triclinic P1space group, with similar dimensions in the unit cell (51Å, 56Å, 86Å, 103°, 103°, 101°). All four complex structures have been crystallographically determined at resolutions in the range 1.86 Å, 2.45 Å, 2.13Å, 2.05 Å. Given the high similarity in structures, the initial phases were determined by rigid body refinement with search model PfDXR-FN3 complex, followed by restrained refinement in refmac5. Subsequently, the ligands and surrounding amino acid residues were manually rebuilt with theqdstools in O. the Ca-Cbbonds of the three ligands were altered from a single to double bond based on the structure of FR9000098. In addition, two ligands were extended at the Cdwith a phenyl group, and with the benzyl group connected by two carbons. N-terminal NADPH binding domains from four complexes undergo minor rigid body movement, and more details of conformational changes in the flap region are discussed.
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| 2. |
- Jones, Benjamin L., 1991-, et al.
(författare)
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Human micronutrient provision by seagrass fisheries outperform coral reefs in a malnourished region
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Blue foods can help tackle hunger by providing rich sources of micronutrients such as calcium, iron, and zinc. Here, we used a novel index of nutrient multifunctionality to assess the micronutrient contributions of fish species across key components of the tropical seascape along a 3000-km stretch of coastline in East Africa. We found that micronutrient multifunctionality varied significantly throughout the tropical seascape, and that the average seagrass-associated fish is more nutritious than a reef-associated fish. The role of seagrass meadows in provisioning high levels of multiple micronutrients relative to coral reefs becomes substantial when we subset the fish communities to include only those species that are high value and targeted in the region. Key fisheries species were far more likely to occur in seagrass meadows than on coral reefs, including those that are both fished and protected, which, when coupled with overall higher per capita micronutrient content, positions seagrass meadows as an unrecognized reservoir of micronutrients to support human health.
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| 4. |
- Mas e Braga, Martim, et al.
(författare)
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Antarctic ice stream thickening under Pliocene warmth
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ice streams regulate most ice mass loss in Antarctica. Determining their response to Pliocene warmth could provide insights into their future behaviour, but is hindered by poor representation of subglacial topography in ice-sheet models. We address this limitation using a high-resolution regional model for Dronning Maud Land (East Antarctica). We show that the region’s largest ice stream, Jutulstraumen, thickens by 700 m under warm late-Pliocene conditions despite ice-shelf collapse and a retrograde bed slope, while nearby ice streams thin. While it is known that unstable retreat on a retrograde slope can be slowed under certain conditions, this finding illustrates that an ice stream can thicken and gain mass. We attribute thickening to high lateral stresses at its flux gate, which constrict ice drainage. Similar stress balances occur today in 27% of East Antarctica, and understanding how lateral stresses regulate ice-stream discharge is necessary for accurately assessing Antarctica’s sea-level rise contribution.
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