The evolution of seafloor spreading behind the tip of the westward propagating Cocos-Nazca spreading center

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 21(6), (2020): e2020GC008957, doi:10.1029/2020GC008957.At the Galapagos triple junction in the equatorial Pacific Ocean, the Cocos‐Nazca spreading center does not meet the East Pacific Rise (EPR) but, instead, rifts into 0.4 Myr‐old lithosphere on the EPR flank. Westward propagation of Cocos‐Nazca spreading forms the V‐shaped Galapagos gore. Since ~1.4 Ma, opening at the active gore tip has been within the Cocos‐Galapagos microplate spreading regime. In this paper, bathymetry, magnetic, and gravity data collected over the first 400 km east of the gore tip are used to examine rifting of young lithosphere and transition to magmatic spreading segments. From inception, the axis shows structural segmentation consisting of rifted basins whose bounding faults eventually mark the gore edges. Rifting progresses to magmatic spreading over the first three segments (s1–s3), which open between Cocos‐Galapagos microplate at the presently slow rates of ~19–29 mm/year. Segments s4–s9 originated in the faster‐spreading (~48 mm/year) Cocos‐Nazca regime, and well‐defined magnetic anomalies and abyssal hill fabric close to the gore edges show the transition to full magmatic spreading was more rapid than at present time. Magnetic lineations show a 20% increase in the Cocos‐Nazca spreading rate after 1.1 Ma. The near‐axis Mantle Bouguer gravity anomaly decreases eastward and becomes more circular, suggesting mantle upwelling, increasing temperatures, and perhaps progression to a developed melt supply beneath segments. Westward propagation of individual Cocos‐Nazca segments is common with rates ranging between 12 and 54 mm/year. Segment lengths and lateral offsets between segments increase, in general, with distance from the tip of the gore.E. M. and H. S. are grateful to the National Science Foundation for funding this work and to InterRidge and the University of Leeds for providing support for a number of the international students and scholars who were able to participate on the cruise. We are also grateful for the extraordinary work of the Captain and crew of R/V Sally Ride , whose efficiency and good cheer made the cruise such a success. We thank M. Ligi and two anonymous reviewers for their comments which greatly improved the manuscript. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.2020-11-1

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The Evolution of Seafloor Spreading Behind the Tip of the Westward Propagating Cocos‐Nazca Spreading Center

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 21(6), (2020): e2020GC008957, doi:10.1029/2020GC008957.At the Galapagos triple junction in the equatorial Pacific Ocean, the Cocos‐Nazca spreading center does not meet the East Pacific Rise (EPR) but, instead, rifts into 0.4 Myr‐old lithosphere on the EPR flank. Westward propagation of Cocos‐Nazca spreading forms the V‐shaped Galapagos gore. Since ~1.4 Ma, opening at the active gore tip has been within the Cocos‐Galapagos microplate spreading regime. In this paper, bathymetry, magnetic, and gravity data collected over the first 400 km east of the gore tip are used to examine rifting of young lithosphere and transition to magmatic spreading segments. From inception, the axis shows structural segmentation consisting of rifted basins whose bounding faults eventually mark the gore edges. Rifting progresses to magmatic spreading over the first three segments (s1–s3), which open between Cocos‐Galapagos microplate at the presently slow rates of ~19–29 mm/year. Segments s4–s9 originated in the faster‐spreading (~48 mm/year) Cocos‐Nazca regime, and well‐defined magnetic anomalies and abyssal hill fabric close to the gore edges show the transition to full magmatic spreading was more rapid than at present time. Magnetic lineations show a 20% increase in the Cocos‐Nazca spreading rate after 1.1 Ma. The near‐axis Mantle Bouguer gravity anomaly decreases eastward and becomes more circular, suggesting mantle upwelling, increasing temperatures, and perhaps progression to a developed melt supply beneath segments. Westward propagation of individual Cocos‐Nazca segments is common with rates ranging between 12 and 54 mm/year. Segment lengths and lateral offsets between segments increase, in general, with distance from the tip of the gore.E. M. and H. S. are grateful to the National Science Foundation for funding this work and to InterRidge and the University of Leeds for providing support for a number of the international students and scholars who were able to participate on the cruise. We are also grateful for the extraordinary work of the Captain and crew of R/V Sally Ride , whose efficiency and good cheer made the cruise such a success. We thank M. Ligi and two anonymous reviewers for their comments which greatly improved the manuscript. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.2020-11-1

Impaired Viral Entry Cannot Explain Reduced CD4+ T Cell Susceptibility to HIV Type 1 in Certain Highly Exposed Individuals

Rare individuals report repeated unprotected HIV-1 sexual exposures, yet remain seronegative for years. We investigated the possibility that reduced in vitro CD4+ T cell susceptibility to HIV-1 infection protects such highly exposed seronegative (ES) individuals. Susceptibility to three R5-tropic HIV-1 isolates, regardless of inoculating dose, was remarkably similar between 81 ES and 33 low-risk controls. In 94% (99/105) of donors, we observed a 1.36 log-unit range in HIV-1JR-CSF production, with similar results for HIV-11192. The median frequency of intracellular Gag+ T cells after single-round infection was similar in ES (5.2%) and controls (7.2%), p = 0.456. However, in repeated testing, CD4+ T cells from two controls (6.1%) and four ES (4.9%) exhibited a 10- to 2500-fold reduction in HIV-1 production and required 5- to 12-fold greater HIV-11192 and HIV-1JR-CSF inocula to establish infection (TCID50). Reduced viral entry cannot explain the low producer phenotype; no differences in CCR5 receptor density or β-chemokine production were observed. In conclusion, we have identified a remarkably narrow range of HIV-1 susceptibility in seronegative donors regardless of risk activity, which can be applied as a benchmark to assess vaccine-induced antiviral effector activities. However, CD4+ T cells from a subset of individuals demonstrated reduced HIV-1 susceptibility unexplained by impaired entry, lending support to the possibility that cellular restriction of HIV-1 may account for continued seronegativity in some of those having repeated sexual exposure. Identifying the host-virus interactions responsible for diminished in vitro susceptibility may contribute to the development of novel therapeutic strategies

A 3.9-Centimorgan-Resolution Human Single-Nucleotide Polymorphism Linkage Map and Screening Set

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)–based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic’s commonly used microsatellite-based screening set