New Radiocarbon-Dated Vertebrate Fossils from Herschel Island: Implications for the Palaeoenvironments and Glacial Chronology of the Beaufort Sea Coastlands

Palaeontological research on Herschel Island, Yukon, has yielded a diverse collection of Quaternary marine and terrestrial vertebrate fossils. The terrestrial faunal remains, which have largely been collected as allochthonous beach debris at Pauline Cove, are dominated by Yukon horse (Equus sp.), with fewer specimens of steppe bison (Bison priscus), proboscideans (Mammuthus primigenius and a single Mammut americanum specimen), and other large and medium-sized mammals. This pattern of a horse-dominated Late Pleistocene fauna is consistent with those from the North Slope of Alaska and further demonstrates that conditions in northernmost Beringia were more arid than those in interior areas such as Fairbanks or the Klondike. This paper presents new AMS radiocarbon dates on terrestrial vertebrate fossils and peat from the island that span the range from greater than 53 000 to modern 14C yr BP. When considered with other data from the region, our new radiocarbon-dated fauna cannot adequately resolve whether the Herschel Island ice-thrust ridge was formed during the Early Wisconsinan or the Late Wisconsinan advance of the Laurentide Ice Sheet over the Yukon Coastal Plain.Des fouilles paléontologiques réalisées sur l’île Herschel, au Yukon, ont permis de prélever une collection variée de fossiles marins et de fossiles vertébrés terrestres du quaternaire. Les restes de faune terrestre, qui ont surtout été ramassés sous la forme de débris de plage allochtones à Pauline Cove, prennent la forme de restes de chevaux du Yukon en prédominance (Equus sp.), parsemés de quelques spécimens de bisons priscus (Bison priscus), de proboscidiens (Mammuthus primigenius et d’un seul spécimen de Mammut americanum), ainsi que d’autres mammifères de taille moyenne et de grande taille. La prédominance de faune du type cheval du Pléistocène tardif correspond à celle enregistrée sur le versant nord de l’Alaska et montre encore une fois que les conditions qui régnaient dans la partie la plus au nord de la Béringie étaient plus arides que les conditions qui prévalaient dans les régions de l’intérieur, comme à Fairbanks ou au Klondike. Dans ce document, nous présentons de nouvelles dates établies par le radiocarbone SMAquant aux fossiles de vertébrés terrestres et à la tourbe de l’île, dates allant de plus de 53 000 14C années BP à l’ère moderne. Lorsque ces données sont considérées à la lumière d’autres données de la région, la nouvelle faune datée par le radiocarbone ne nous permet pas de déterminer adéquatement si la dorsale découlant de la poussée des glaces de l’île Herschel a été formée pendant la progression du Wisconsinien précoce ou du Wisconsinien tardif de la nappe glaciaire laurentienne sur la plaine côtière du Yukon

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo– or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo–onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P = .018). The cumulative incidence of de novo– or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD

Biomarker Panel for Chronic Graft-Versus-Host Disease

PURPOSE: To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). RESULTS: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. CONCLUSION: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD

Alu insertion polymorphisms shared by Papio baboons and Theropithecus gelada reveal an intertwined common ancestry

© 2019 The Author(s). Background: Baboons (genus Papio) and geladas (Theropithecus gelada) are now generally recognized as close phylogenetic relatives, though morphologically quite distinct and generally classified in separate genera. Primate specific Alu retrotransposons are well-established genomic markers for the study of phylogenetic and population genetic relationships. We previously reported a computational reconstruction of Papio phylogeny using large-scale whole genome sequence (WGS) analysis of Alu insertion polymorphisms. Recently, high coverage WGS was generated for Theropithecus gelada. The objective of this study was to apply the high-Throughput poly-Detect method to computationally determine the number of Alu insertion polymorphisms shared by T. gelada and Papio, and vice versa, by each individual Papio species and T. gelada. Secondly, we performed locus-specific polymerase chain reaction (PCR) assays on a diverse DNA panel to complement the computational data. Results: We identified 27,700 Alu insertions from T. gelada WGS that were also present among six Papio species, with nearly half (12,956) remaining unfixed among 12 Papio individuals. Similarly, each of the six Papio species had species-indicative Alu insertions that were also present in T. gelada. In general, P. kindae shared more insertion polymorphisms with T. gelada than did any of the other five Papio species. PCR-based genotype data provided additional support for the computational findings. Conclusions: Our discovery that several thousand Alu insertion polymorphisms are shared by T. gelada and Papio baboons suggests a much more permeable reproductive barrier between the two genera then previously suspected. Their intertwined evolution likely involves a long history of admixture, gene flow and incomplete lineage sorting

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP. KEYWORDS: Craniopharyngioma; IL1-β; Inflammasome; MAPK/ERK pathway; Odontogenesis; Paracrine signalling; Trametini

In Silico Reconstitution of Actin-Based Symmetry Breaking and Motility

Computational modeling and experimentation in a model system for actin-based force generation explain how actin networks initiate and maintain directional movement

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies

The Atacama Cosmology Telescope: Combined kinematic and thermal Sunyaev-Zel'dovich measurements from BOSS CMASS and LOWZ halos

The scattering of cosmic microwave background (CMB) photons off the free-electron gas in galaxies and clusters leaves detectable imprints on high resolution CMB maps: the thermal and kinematic Sunyaev-Zel'dovich effects (tSZ and kSZ respectively). We use combined microwave maps from the Atacama Cosmology Telescope (ACT) DR5 and Planck in combination with the CMASS and LOWZ galaxy catalogs from the Baryon Oscillation Spectroscopic Survey (BOSS DR10 and DR12), to study the gas associated with these galaxy groups. Using individual reconstructed velocities, we perform a stacking analysis and reject the no-kSZ hypothesis at 6.5$\sigma$, the highest significance to date. This directly translates into a measurement of the electron number density profile, and thus of the gas density profile. Despite the limited signal to noise, the measurement shows at high significance that the gas density profile is more extended than the dark matter density profile, for any reasonable baryon abundance (formally $>90\sigma$ for the cosmic baryon abundance). We simultaneously measure the tSZ signal, i.e. the electron thermal pressure profile of the same CMASS objects, and reject the no-tSZ hypothesis at 10$\sigma$. We combine tSZ and kSZ measurements to estimate the electron temperature to 20% precision in several aperture bins, and find it comparable to the virial temperature. In a companion paper, we analyze these measurements to constrain the gas thermodynamics and the properties of feedback inside galaxy groups. We present the corresponding LOWZ measurements in this paper, ruling out a null kSZ (tSZ) signal at 2.9 (13.9)$\sigma$, and leave their interpretation to future work. Our stacking software ThumbStack is publicly available at https://github.com/EmmanuelSchaan/ThumbStack and directly applicable to future Simons Observatory and CMB-S4 data.Comment: Accepted in Physical Review D, Editors' Suggestio