Identification of Structural Variation in Chimpanzees Using Optical Mapping and Nanopore Sequencing.

Recent efforts to comprehensively characterize great ape genetic diversity using short-read sequencing and single-nucleotide variants have led to important discoveries related to selection within species, demographic history, and lineage-specific traits. Structural variants (SVs), including deletions and inversions, comprise a larger proportion of genetic differences between and within species, making them an important yet understudied source of trait divergence. Here, we used a combination of long-read and -range sequencing approaches to characterize the structural variant landscape of two additional Pan troglodytes verus individuals, one of whom carries 13% admixture from Pan troglodytes troglodytes. We performed optical mapping of both individuals followed by nanopore sequencing of one individual. Filtering for larger variants (>10 kbp) and combined with genotyping of SVs using short-read data from the Great Ape Genome Project, we identified 425 deletions and 59 inversions, of which 88 and 36, respectively, were novel. Compared with gene expression in humans, we found a significant enrichment of chimpanzee genes with differential expression in lymphoblastoid cell lines and induced pluripotent stem cells, both within deletions and near inversion breakpoints. We examined chromatin-conformation maps from human and chimpanzee using these same cell types and observed alterations in genomic interactions at SV breakpoints. Finally, we focused on 56 genes impacted by SVs in >90% of chimpanzees and absent in humans and gorillas, which may contribute to chimpanzee-specific features. Sequencing a greater set of individuals from diverse subspecies will be critical to establish the complete landscape of genetic variation in chimpanzees

Genetic adaptations to SIV across chimpanzee populations

Central and eastern chimpanzees are infected with Simian Immunodeficiency Virus (SIV) in the wild, typically without developing acute immunodeficiency. Yet the recent zoonotic transmission of chimpanzee SIV to humans, which were naïve to the virus, gave rise to the Human Immunodeficiency Virus (HIV), which causes AIDS and is responsible for one of the deadliest pandemics in human history. Chimpanzees have been infected with SIV for tens of thousands of years and have likely evolved to reduce its pathogenicity, becoming semi-natural hosts that largely tolerate the virus. In support of this view, central and eastern chimpanzees show evidence of positive selection in genes involved in SIV/HIV cell entry and immune response to SIV, respectively. We hypothesise that the population first infected by SIV would have experienced the strongest selective pressure to control the lethal potential of zoonotic SIV, and that population genetics will reveal those first critical adaptations. With that aim we used population genomics to investigate signatures of positive selection in the common ancestor of central-eastern chimpanzees. The genes with signatures of positive selection in the ancestral population are significantly enriched in SIV-related genes, especially those involved in the immune response to SIV and those encoding for host genes that physically interact with SIV/HIV (VIPs). This supports a scenario where SIV first infected the central-eastern ancestor and where this population was under strong pressure to adapt to zoonotic SIV. Interestingly, integrating these genes with candidates of positive selection in the two infected subspecies reveals novel patterns of adaptation to SIV. Specifically, we observe evidence of positive selection in numerous steps of the biological pathway responsible for T-helper cell differentiation, including CD4 and multiple genes that SIV/HIV use to infect and control host cells. This pathway is active only in CD4+ cells which SIV/HIV infects, and it plays a crucial role in shaping the immune response so it can efficiently control the virus. Our results confirm the importance of SIV as a selective factor, identify specific genetic changes that may have allowed our closest living relatives to reduce SIV's pathogenicity, and demonstrate the potential of population genomics to reveal the evolutionary mechanisms used by naïve hosts to reduce the pathogenicity of zoonotic pathogens

Microtubule cross-linking triggers the directional motility of kinesin-5

Although assembly of the mitotic spindle is known to be a precisely controlled process, regulation of the key motor proteins involved remains poorly understood. In eukaryotes, homotetrameric kinesin-5 motors are required for bipolar spindle formation. Eg5, the vertebrate kinesin-5, has two modes of motion: an adenosine triphosphate (ATP)–dependent directional mode and a diffusive mode that does not require ATP hydrolysis. We use single-molecule experiments to examine how the switching between these modes is controlled. We find that Eg5 diffuses along individual microtubules without detectable directional bias at close to physiological ionic strength. Eg5's motility becomes directional when bound between two microtubules. Such activation through binding cargo, which, for Eg5, is a second microtubule, is analogous to known mechanisms for other kinesins. In the spindle, this might allow Eg5 to diffuse on single microtubules without hydrolyzing ATP until the motor is activated by binding to another microtubule. This mechanism would increase energy and filament cross-linking efficiency

β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts

β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts. β2-microglobulin amyloidosis (Aβ2m) is a serious complication for patients undergoing long-term dialysis. β2-microglobulin modified with advanced glycation end products (β2m-AGE) is a major component of the amyloid in Aβ2m. It is not completely understood whether β2m-AGE plays an active role in the pathogenesis of Aβ2m, or if its presence is a secondary event of the disease. β2-microglobulin amyloid is mainly located in tendon and osteo-articular structures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of collagen. Recent identification of AGE binding proteins on human fibroblasts lead to the hypothesis that the fibroblast may be a target for the biological action of β2m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen type I mRNA and type I collagen synthesis after exposure to β2m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor for AGE, attenuated this decrease in synthesis, indicating that the response was partially mediated by RAGE. In addition, antibody against epidermal growth factor (EGF) attenuated the decrease in type I procollagen mRNA and type I collagen induced by β2m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that β2m-AGE actively participates in connective tissue and bone remodeling via a pathway involving fibroblast RAGE, and at least one interposed mediator, the growth factor EGF

A High-Resolution Spectroscopic Search for the Remaining Donor for Tycho's Supernova

In this paper, we report on our analysis using Hubble Space Telescope astrometry and Keck-I HIRES spectroscopy of the central six stars of Tycho's supernova remnant (SN 1572). With these data, we measured the proper motions, radial velocities, rotational velocities, and chemical abundances of these objects. Regarding the chemical abundances, we do not confirm the unusu- ally high [Ni/Fe] ratio previously reported for Tycho-G. Rather, we find that for all metrics in all stars, none exhibit the characteristics expected from traditional SN Ia single-degenerate-scenario calculations. The only possible exception is Tycho-B, a rare, metal-poor A-type star; however, we are unable to find a suitable scenario for it. Thus, we suggest that SN 1572 cannot be explained by the standard single-degenerate model.Comment: 34 pages, 11 Figures, revised and resubmitted to Ap

Spectroscopic Discovery of the Broad-Lined Type Ic Supernova 2010bh Associated with the Low-Redshift GRB 100316D

We present the spectroscopic discovery of a broad-lined Type Ic supernova (SN 2010bh) associated with the nearby long-duration gamma-ray burst (GRB) 100316D. At z = 0.0593, this is the third-nearest GRB-SN. Nightly optical spectra obtained with the Magellan telescopes during the first week after explosion reveal the gradual emergence of very broad spectral features superposed on a blue continuum. The supernova features are typical of broad-lined SNe Ic and are generally consistent with previous supernovae associated with low-redshift GRBs. However, the inferred velocities of SN 2010bh at 21 days after explosion are a factor of ~2 times larger than those of the prototypical SN 1998bw at similar epochs, with v ~ 26,000 km/s, indicating a larger explosion energy or a different ejecta structure. A near-infrared spectrum taken 13.8 days after explosion shows no strong evidence for He I at 1.083 microns, implying that the progenitor was largely stripped of its helium envelope. The host galaxy is of low luminosity (M_R ~ -18.5 mag) and low metallicity (Z < 0.4 Z_solar), similar to the hosts of other low-redshift GRB-SNe.Comment: 6 pages, 4 figures, 1 table, submitted to ApJ Letter

Beyond the angle of repose: A review and synthesis of landslide processes in response to rapid uplift, Eel River, Northern California

In mountainous settings, increases in rock uplift are often followed by a commensurate uptick in denudation as rivers incise and steepen hillslopes, making them increasingly prone to landsliding as slope angles approach a limiting value. For decades, the threshold slope model has been invoked to account for landslide-driven increases in sediment flux that limit topographic relief, but the manner by which slope failures organize themselves spatially and temporally in order for erosion to keep pace with rock uplift has not been well documented. Here, we review past work and present new findings from remote sensing, cosmogenic radionuclides, suspended sediment records, and airborne lidar data, to decipher patterns of landslide activity and geomorphic processes related to rapid uplift along the northward-migrating Mendocino Triple Junction in Northern California. From historical air photos and airborne lidar, we estimated the velocity and sediment flux associated with active, slow-moving landslides (or earthflows) in the mélange- and argillite-dominated Eel River watershed using the downslope displacement of surface markers such as trees and shrubs. Although active landslides that directly convey sediment into the channel network account for only 7% of the landscape surface, their sediment flux amounts to more than 50% of the suspended load recorded at downstream sediment gaging stations. These active slides tend to exhibit seasonal variations in velocity as satellite-based interferometry has demonstrated that rapid acceleration commences within 1 to 2 months of the onset of autumn rainfall events before slower deceleration ensues in the spring and summer months. Curiously, this seasonal velocity pattern does not appear to vary with landslide size, suggesting that complex hydrologic–mechanical feedbacks (rather than 1-D pore pressure diffusion) may govern slide dynamics. A new analysis of 14 yrs of discharge and sediment concentration data for the Eel River indicates that the characteristic mid-winter timing of earthflow acceleration corresponds with increased suspended concentration values, suggesting that the seasonal onset of landslide motion each year may be reflected in the export of sediments to the continental margin. The vast majority of active slides exhibit gullied surfaces and the gully networks, which are also seasonally active, may facilitate sediment export although the proportion of material produced by this pathway is poorly known. Along Kekawaka Creek, a prominent tributary to the Eel River, new analyses of catchment-averaged erosion rates derived from cosmogenic radionuclides reveal rapid erosion (0.76 mm/yr) below a prominent knickpoint and slower erosion (0.29 mm/yr) upstream. Such knickpoints are frequently observed in Eel tributaries and are usually comprised of massive (> 10 m) interlocking resistant boulders that likely persist in the landscape for long periods of time (> 105 yr). Upstream of these knickpoints, active landslides tend to be less frequent and average slope angles are slightly gentler than in downstream areas, which indicates that landslide density and average slope angle appear to increase with erosion rate. Lastly, we synthesize evidence for the role of large, catastrophic landslides in regulating sediment flux and landscape form. The emergence of resistant blocks within the mélange bedrock has promoted large catastrophic slides that have dammed the Eel River and perhaps generated outburst events in the past. The frequency and impact of these landslide dams likely depend on the spatial and size distributions of resistant blocks relative to the width and drainage area of adjacent valley networks. Overall, our findings demonstrate that landslides within the Eel River catchment do not occur randomly, but instead exhibit spatial and temporal patterns related to baselevel lowering, climate forcing, and lithologic variations. Combined with recent landscape evolution models that incorporate landslides, these results provide predictive capability for estimating erosion rates and managing hazards in mountainous regions

High Harvest Yield, High Expansion, and Phenotype Stability of CD146 Mesenchymal Stromal Cells from Whole Primitive Human Umbilical Cord Tissue

Human umbilical cord blood is an excellent primitive source of noncontroversial stem cells for treatment of hematologic disorders; meanwhile, new stem cell candidates in the umbilical cord (UC) tissue could provide therapeutic cells for nonhematologic disorders. We show novel in situ characterization to identify and localize a panel of some markers expressed by mesenchymal stromal cells (MSCs; CD44, CD105, CD73, CD90) and CD146 in the UC. We describe enzymatic isolation and purification methods of different UC cell populations that do not require manual separation of the vessels and stroma of the coiled, helical-like UC tissue. Unique quantitation of in situ cell frequency and stromal cell counts upon harvest illustrate the potential to obtain high numerical yields with these methods. UC stromal cells can differentiate to the osteogenic and chondrogenic lineages and, under specific culturing conditions, they exhibit high expandability with unique long-term stability of their phenotype. The remarkable stability of the phenotype represents a novel finding for human MSCs, from any source, and supports the use of these cells as highly accessible stromal cells for both basic studies and potentially therapeutic applications such as allogeneic clinical use for musculoskeletal disorders