Evolutionary history of saber-toothed cats based on ancient mitogenomics

Saber-toothed cats (Machairodontinae) are among the most widely recognized representatives of the now largely extinct Pleistocene megafauna. However, many aspects of their ecology, evolution, and extinction remain uncertain. Although ancient-DNA studies have led to huge advances in our knowledge of these aspects of many other megafauna species (e.g., mammoths and cave bears), relatively few ancient-DNA studies have focused on saber-toothed cats, and they have been restricted to short fragments of mitochondrial DNA. Here we investigate the evolutionary history of two lineages of saber-toothed cats (Smilodon and Homotherium) in relation to living carnivores and find that the Machairodontinae form a well-supported clade that is distinct from all living felids. We present partial mitochondrial genomes from one S. populator sample and three Homotherium sp. samples, including the only Late Pleistocene Homotherium sample from Eurasia. We confirm the identification of the unique Late Pleistocene European fossil through ancient-DNA analyses, thus strengthening the evidence that Homotherium occurred in Europe over 200,000 years later than previously believed. This in turn forces a re-evaluation of its demography and extinction dynamics. Within the Machairodontinae, we find a deep divergence between Smilodon and Homotherium ( 18 million years) but limited diversity between the American and European Homotherium specimens. The genetic data support the hypothesis that all Late Pleistocene (or post-Villafrancian) Homotherium should be considered a single species, H. latidens, which was previously proposed based on morphological data

The Prognostic Significance of Whole Blood Global and Specific DNA Methylation Levels in Gastric Adenocarcinoma

Epigenetics, particularly DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression. We investigated the clinical and prognostic importance of whole blood global and site-specific DNA methylation in GC. tests. Survival analyses were carried out using the Kaplan-Meier method and log rank test. A backward conditional Cox proportional hazards regression model was used to identify independent predictors of survival. = 0.02) respectively.Analysis of global and site-specific DNA methylation in peripheral blood by pyrosequencing provides quantitative DNA methylation values that may serve as important prognostic indicators

Nitrogen and Carbon Isotopic Dynamics of Subarctic Soils and Plants in Southern Yukon Territory and its Implications for Paleoecological and Paleodietary Studies

We examine here the carbon and nitrogen isotopic compositions of bulk soils (8 topsoil and 7 subsoils, including two soil profiles) and five different plant parts of 79 C3 plants from two main functional groups: herbs and shrubs/subshrubs, from 18 different locations in grasslands of southern Yukon Territory, Canada (eastern shoreline of Kluane Lake and Whitehorse area). The Kluane Lake region in particular has been identified previously as an analogue for Late Pleistocene eastern Beringia. All topsoils have higher average total nitrogen δ15N and organic carbon δ13C than plants from the same sites with a positive shift occurring with depth in two soil profiles analyzed. All plants analyzed have an average whole plant δ13C of −27.5 ± 1.2 ‰ and foliar δ13C of ±28.0 ± 1.3 ‰, and average whole plant δ15N of −0.3 ± 2.2 ‰ and foliar δ15N of ±0.6 ± 2.7 ‰. Plants analyzed here showed relatively smaller variability in δ13C than δ15N. Their average δ13C after suitable corrections for the Suess effect should be suitable as baseline for interpreting diets of Late Pleistocene herbivores that lived in eastern Beringia. Water availability, nitrogen availability, spacial differences and intra-plant variability are important controls on δ15N of herbaceous plants in the study area. The wider range of δ15N, the more numerous factors that affect nitrogen isotopic composition and their likely differences in the past, however, limit use of the modern N isotopic baseline for vegetation in paleodietary models for such ecosystems. That said, the positive correlation between foliar δ15N and N content shown for the modern plants could support use of plant δ15N as an index for plant N content and therefore forage quality. The modern N isotopic baseline cannot be applied directly to the past, but it is prerequisite to future efforts to detect shifts in N cycling and forage quality since the Late Pleistocene through comparison with fossil plants from the same region

Population dynamics and range shifts of moose (Alces alces) during the Late Quaternary

Aim: Late Quaternary climate oscillations had major impacts on species distributions and abundances across the northern Holarctic. While many large mammals in this region went extinct towards the end of the Quaternary, some species survived and flourished. Here, we examine population dynamics and range shifts of one of the most widely distributed of these, the moose (Alces alces). Location: Northern Holarctic. Taxon: Moose (A. alces). Methods: We collected samples of modern and ancient moose from across their present and former range. We assessed their phylogeographical relations using part of the mitochondrial DNA in conjunction with radiocarbon dating to investigate the history of A. alces during the last glacial. Results: This species has a relatively shallow history, with the most recent common ancestor estimated at ca. 150–50 kyr. Ancient samples corroborate that its region of greatest diversity is in east Asia, supporting proposals that this is the region of origin of all extant moose. Both eastern and western haplogroups occur in the Ural Mountains during the last glacial period, implying a broader contact zone than previously proposed. It seems that this species went extinct over much of its northern range during the last glacial maximum (LGM) and recolonized the region with climate warming beginning around 15,000 yr bp. The post-LGM expansion included a movement from northeast Siberia to North America via Beringia, although the northeast Siberian source population is not the one currently occupying that area. Main conclusions: Moose are a relatively recently evolved species but have had a dynamic history. As a large-bodied subarctic browsing species, they were seemingly confined to refugia during full-glacial periods and expanded their range northwards when the boreal forest returned after the LGM. The main modern phylogeographical division is ancient, though its boundary has not remained constant. Moose population expansion into America was roughly synchronous with human and red deer expansion. © 2020 The Authors. Journal of Biogeography published by John Wiley & Sons LtdWe warmly thank the following museums, curators and people for access to samples: the late Andrei Sher, Severtsov Institute, Moscow; Andy Currant, Natural History Museum, London; Alfred Gardner, Smithsonian, Washington DC; R. Dale Guthrie, University of Alaska, Fairbanks; John de Vos, National Museum of Natural History (Naturalis), Leiden; Eileen Westwig, American Museum of Natural History, NY; Fyodor Shidlovsky, Ice-Age Museum, Moscow; Tong Haowen, Institute of Vertebrate Palaeontology and Paleoanthropology, Beijing; Mammoth Museum, Yakutsk; Geological Museum, Yakutsk; Paleontological Institute, Moscow; Royal Alberta Museum, Edmonton; Zoological Institute, Saint Petersburg; Museum of the Institute of Plant and Animal Ecology, Ekaterinburg. We thank our Yukon First Nation research partners for their continued support for our work on the ice age fossils of Yukon Territory. We are grateful to the placer gold mining community and the Tr'ond?k Hw?ch'in First Nation for their continued support and partnership with our research in the Klondike goldfields region; and the Vuntut Gwitchin First Nation for their collaboration with research in the Old Crow region. We would also like to thank Shai Meiri for help in drawing the map and useful discussion, Tony Stuart for access to radiocarbon dates, and Iris van Pijlen for laboratory assistance. This research was funded by NERC grant NE/G00269X/1 through the European Union FP7 ERA-NET program BiodivERsA. Funding for AMS dating was provided through NERC/AHRC/ORAU Grant NF/2008/2/15

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Arctic ground squirrels of the mammoth-steppe: paleoecology of Late Pleistocene middens (similar to 24000-29450 C-14 yr BP), Yukon Territory, Canada

This paper presents paleoecological analyses of 48 fossil arctic ground squirrel (Spermophilus parryii) middens (nests and caches) recovered from ice-rich loess sediments in the Klondike region of west-central Yukon Territory. AMS radiocarbon dates and stratigraphic association of middens with Dawson tephra (similar to 25 300 C-14 yr BP), indicate these paleoecological data reflect the onset of glacial conditions of early Marine Isotope Stage (MIS) 2 and terminal MIS 3 (similar to 24000-29 450 14C yr BP). Plant macrofossils include at least 60 plant taxa, including diverse graminoids (Poa, Elymus trachycaulus, Kobresia myosuroides), steppe forbs (Penstemon gormanii, Anemone patens var. multifida, Plantago cf. canescens), tundra forbs (Draba spp., Bistorta vivipara), dwarf shrubs (Salix cf. arctica, S. cf. polaris), sage (Artemisia frigida) and rare trees (Picea mariana). Many of these taxa identified in the middens represent the first recorded fossils for these plants in Eastern Beringia and add to our knowledge of the floristic composition of Pleistocene vegetation and biogeography in this region. Fossil beetles include typical members of the Eastern Beringian steppe-tundra fauna (Lepidophorus lineaticollis and Connatichela artemisiae) and others suggesting predominantly dry, open habitats. Cache forage selection is suggested by some plant taxa which were particularly frequent and abundant in the middens (Bistorta vivipara, Kobresia myosuroides, Ranunculus spp., Potentilla, Erysimum cf. cheiranthoides, Poa, Carex and Draba). Factors such as proximity of vegetation to burrows and abundance of fruits and seeds per plant were probably important in cache selection. Glacial conditions enabled arctic ground squirrels to form widespread and dense populations in regions such as the Klondike in which they are rare or absent at present. This fossil midden record supports previous hypotheses that suggest arctic ground squirrels evolved in and are well-adapted to the open, steppe-tundra vegetation, loessal soils and glacial climates of the mammoth-steppe biome. (c) 2007 Elsevier Ltd. All rights reserved

Invoking adaptation to decipher the genetic legacy of past climate change

Persistence of natural populations during periods of climate change is likely to depend on migration (range shifts) or adaptation. These responses were traditionally considered discrete processes and conceptually divided into the realms of ecology and evolution. In a milestone paper, Davis and Shaw (2001) Science 292:673 argued that the interplay of adaptation and migration was central to biotic responses to Quaternary climate, but since then there has been no synthesis of efforts made to set up this research program. Here we review some of the salient findings from molecular genetic studies assessing ecological and evolutionary responses to Quaternary climate change. These studies have revolutionized our understanding of population processes associated with past species migration. However, knowledge remains limited about the role of natural selection for local adaptation of populations to Quaternary environmental fluctuations and associated range shifts, and for the footprints this might have left on extant populations. Next‐generation sequencing technologies, high‐resolution paleoclimate analyses, and advances in population genetic theory offer an unprecedented opportunity to test hypotheses about adaptation through time. Recent population genomics studies have greatly improved our understanding of the role of contemporary adaptation to local environments in shaping spatial patterns of genetic diversity across modern‐day landscapes. Advances in this burgeoning field provide important conceptual and methodological bases to decipher the historical role of natural selection and assess adaptation to past environmental variation. We suggest that a process called “temporal conditional neutrality” has taken place: some alleles favored in glacial environments become selectively neutral in modern‐day conditions, whereas some alleles that had been neutral during glacial periods become under selection in modern environments. Building on this view, we present a new integrative framework for addressing the interplay of demographic and adaptive evolutionary responses to Quaternary climate dynamics, the research agenda initially envisioned by Davis and Shaw (2001) Science 292:673