A Global Population Genetic Study of Pantala flavescens

Among terrestrial arthropods, the dragonfly species Pantala flavescens is remarkable due to their nearly global distribution and extensive migratory ranges; the largest of any known insect. Capable of migrating across oceans, the potential for high rates of gene flow among geographically distant populations is significant. It has been hypothesized that P. flavescens may be a global panmictic population but no sufficient genetic evidence has been collected thus far. Through a population genetic analysis of P. flavescens samples from North America, South America, and Asia, the current study aimed to examine the extent at which gene flow is occurring on a global scale and discusses the implications of the genetic patterns we uncovered on population structure and genetic diversity of the species. This was accomplished using PCR-amplified cytochrome oxidase one (CO1) mitochondrial DNA data to reconstruct phylogenetic trees, a haplotype network, and perform molecular variance analyses. Our results suggested high rates of gene flow are occurring among all included geographic regions; providing the first significant evidence that Pantala flavescens should be considered a global panmictic population. © 2016 Troast et al

Minimum Spanning Haplotype Network.

<p>All haplotypes are based on the CO1 gene except for “India 4” which is “CO1-like”. Numbers in parentheses indicate the number of changes between haplotypes.</p

Distribution of Individuals.

<p>Distribution of <i>Pantala flavescens</i> individuals used in this study. The dotted line represents the suggested India to Africa migration route.</p

GARLI majority rule consensus tree.

<p>Tree based on CO1. Known locations of samples are indicated in parentheses.</p

MrBayes Bayesian majority rule consensus tree.

<p>Tree based on CO1. Known locations of samples are indicated in parentheses.</p

Evidence for widespread gene flow and migration in the Globe Skimmer dragonfly Pantala flavescens

The global population structure and dispersal patterns of Pantala flavescens (Fabricius, 1798) are evaluated using a geographically extensive mitochondrial DNA dataset, a more limited samples of nuclear markers, wing isotopic (δ²H) data and a literature review. No spatial or temporal haplotype structure was recovered between the samples. Isotope data suggest that most samples were immigrants at the collection locations. A literature review of migration events for the species confirms regular inter-and intra-continental migrations occur (the majority reported from Asia, Africa and Australasia), with individuals and swarms dispersing thousands of kilometers over land and oceans. Migrations coincide with prevailing winds and seasonal rains, which points to a mechanism we name the “pantropical Pantala conveyor belt”, suggesting widespread gene flow is possible for an aquatic insect with excellent flying ability linked to rapid larval development.Funding: Ware would like to acknowledge funding from NSF DBI #1564386.</p

Evidence for widespread gene flow and migration in the Globe Skimmer dragonfly Pantala flavescens

The global population structure and dispersal patterns of Pantala flavescens (Fabricius, 1798) are evaluated using a geographically extensive mitochondrial DNA dataset, a more limited samples of nuclear markers, wing isotopic (δ²H) data and a literature review. No spatial or temporal haplotype structure was recovered between the samples. Isotope data suggest that most samples were immigrants at the collection locations. A literature review of migration events for the species confirms regular inter-and intra-continental migrations occur (the majority reported from Asia, Africa and Australasia), with individuals and swarms dispersing thousands of kilometers over land and oceans. Migrations coincide with prevailing winds and seasonal rains, which points to a mechanism we name the “pantropical Pantala conveyor belt”, suggesting widespread gene flow is possible for an aquatic insect with excellent flying ability linked to rapid larval development.Funding: Ware would like to acknowledge funding from NSF DBI #1564386.</p

A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking (Phase), rigid receptor docking (Glide), and protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. We provide an in-depth description of our novel methodology and present results for 41 targets consisting of 415 cross-docking cases divided amongst a training and test set. For both the training and test-set, we compute binding modes with a ligand-heavy atom RMSD to within 2.5 Å or better in over 90% of cross-docking cases compared to less than 70% of cross-docking cases using our previously published induced-fit docking algorithm and less than 41% using rigid receptor docking. Applications of the predicted ligand-receptor structure in free energy perturbation calculations is demonstrated for both public data and in active drug discovery projects, both retrospectively and prospectively

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h