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- Allentoft, Morten E., et al.
(författare)
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Population genomics of post-glacial western Eurasia
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Tidskriftsartikel (refereegranskat)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 2. |
- Blasco, Pilar, et al.
(författare)
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Conformational Dynamics of the Lipopolysaccharide from Escherichia coli O91 Revealed by Nuclear Magnetic Resonance Spectroscopy and Molecular Simulations
- 2017
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 56:29, s. 3826-3839
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Tidskriftsartikel (refereegranskat)abstract
- The outer leaflet of the outer membrane in Gram-negative bacteria contains lipopolysaccharides (LPS) as a major component, and the outer membrane provides a physical barrier and protection against hostile environments. The enterohemorrhagic Escherichia coli of serogroup O91 has an O-antigen polysaccharide (PS) with five sugar residues in the repeating unit (RU), and the herein studied O-antigen PS contains similar to 10 RUs. H-1-C-13 HSQC-NOESY experiments on a 1-C-13-labeled PS were employed to deduce H-1-H-1 cross-relaxation rates and transglycosidic (3)J(CH) related to the psi torsional angles were obtained by H-1-H-1 NOESY experiments. Dynamical parameters were calculated from the molecular dynamics (MD) simulations of the PS in solution and compared to those from C-13 nuclear magnetic resonance (NMR) relaxation studies. Importantly, the MD simulations can reproduce the dynamical behavior of internal correlation times along the PS chain. Two-dimensional free energy surfaces of glycosidic torsion angles delineate the conformational space available to the O-antigen. Although similar with respect to populated states in solution, the O-antigen in LPS bilayers has more extended chains as a result of spatial limitations due to close packing. Calcium ions are highly abundant in the phosphate-containing core region mediating LPS LPS association that is crucial for maintaining bilayer integrity, and the negatively charged O-antigen promotes a high concentration of counterbalancing potassium ions. The ensemble of structures present for the PS in solution is captured by the NMR experiments, and the similarities between the O-antigen on its own and as a constituent of the full LPS in a bilayer environment make it possible to realistically describe the LPS conformation and dynamics from the MD simulations.
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| 3. |
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| 4. |
- Martínez-Carranza, Markel, 1992-, et al.
(författare)
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Synaptotagmin Binding to Botulinum Neurotoxins
- 2020
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 59:4, s. 491-498
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Tidskriftsartikel (refereegranskat)abstract
- Botulinum neurotoxins (BoNTs) are exceptionally toxic proteins that cause paralysis but are also extensively used as treatment for various medical conditions. Most BoNTs bind two receptors on neuronal cells, namely, a ganglioside and a protein receptor. Differences in the sequence between the protein receptors from different species can impact the binding affinity and toxicity of the BoNTs. Here we have investigated how BoNT/B, /DC, and /G, all three toxins that utilize synaptotagmin I and II (Syt-I and Syt-II, respectively) as their protein receptors, bind to Syt-I and -II of mouse/rat, bovine, and human origin by isothermal titration calorimetry analysis. BoNT/G had the highest affinity for human Syt-I, and BoNT/DC had the highest affinity for bovine Syt-II. As expected, BoNT/B, /DC, and /G showed very low levels of binding to human Syt-II. Furthermore, we carried out saturation transfer difference (STD) and STD-TOCSY NMR experiments that revealed the region of the Syt peptide in direct contact with BoNT/G, which demonstrate that BoNT/G recognizes the Syt peptide in a model similar to that in the established BoNT/B-Syt-II complex. Our analyses also revealed that regions outside the Syt peptide’s toxin-binding region are important for the helicity of the peptide and, therefore, the binding affinity.
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| 5. |
- Patel, Dhilon S., et al.
(författare)
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Escherichia coli O176 LPS structure and dynamics : A NMR spectroscopy and MD simulation study
- 2020
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Ingår i: Current Research in Structural Biology. - : Elsevier BV. - 2665-928X. ; 2, s. 79-88
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Tidskriftsartikel (refereegranskat)abstract
- A lipopolysaccharide (LPS) molecule is a key component of the bacterial outer membrane used to protect the bacterium and to interact with the environment. To gain insight into its function, the study of the LPS conformation and dynamics at the molecular and cellular levels is necessary, but these highly diverse and dynamic membrane-LPS systems are difficult to study. In this work, by using NMR spectroscopy and molecular dynamics (MD) simulations, we determined the conformational preferences of an E. coli O176 O-antigen polysaccharide at the atomic level. Moreover, we analyzed the use of non-uniform sampling (NUS) for the acquisition of high dynamic range spectra, like H-1,H-1-NOESY NMR experiments. A comparison of the effective transglycosidic distances derived from conventional uniformly sampled and NUS H-1,H-1-NOESY data showed high similarity under equal measuring time conditions. Furthermore, the experimentally derived internuclear distances of the O-antigen polysaccharide with ten repeating units (RUs) showed very good agreement to those calculated from the MD simulations of the same O-antigen polysaccharide in solution. Analysis of the LPS bilayer simulations with five and with ten RUs revealed that, although similar with respect to populated states in solution, the O-antigen in LPS bilayers had more extended chains as a result of spatial limitations due to close packing. Additional MD simulations of O-antigen polysaccharides from E. coli O6 (branched repeating unit) and O91 (negatively charged linear repeating unit) in solution and LPS bilayers were performed and compared to those of O176 (linear polymer). For all three O-antigens, the ensemble of structures present for the polysaccharides in solution were consistent with the results from their H-1,H-1-NOESY experiments. In addition, the similarities between the O-antigen on its own and as a constituent of the full LPS in bilayer environment makes it possible to realistically describe the LPS conformation and dynamics from the MD simulations.
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