Did Beringian environments represent an ecological barrier to humans until less than 15 000 years ago or was access to the Americas controlled by the spatial–temporal distribution of North American ice sheets? Beringian environments varied with respect to climate and biota, especially in the two major areas of exposed continental shelf. The East Siberian Arctic Shelf (‘Great Arctic Plain’ (GAP)) supported a dry steppe-tundra biome inhabited by a diverse large-mammal community, while the southern Bering-Chukchi Platform (‘Bering Land Bridge’ (BLB)) supported mesic tundra and probably a lower large-mammal biomass. A human population with west Eurasian roots occupied the GAP before the Last Glacial Maximum (LGM) and may have accessed mid-latitude North America via an interior ice-free corridor. Re-opening of the corridor less than 14 000 years ago indicates that the primary ancestors of living First Peoples, who already had spread widely in the Americas at this time, probably dispersed from the NW Pacific coast. A genetic ‘arctic signal’ in non-arctic First Peoples suggests that their parent population inhabited the GAP during the LGM, before their split from the former. We infer a shift from GAP terrestrial to a subarctic maritime economy on the southern BLB coast before dispersal in the Americas from the NW Pacific coast.

The paper reviews history of studies and research areas on a frozen mummy of the woolly mammoth (Mammuthus primigenius) found in 2010 in Oyogoss Yar, about 30 km west of the Kondratyeva River mouth, northern Yakutia. Introduced to the scientific literature as the Yuka Mammoth, it became the first, partly preserved carcass of female woolly mammoth of adolescent age found in the world, which lived about 39 000 calendar years BP, during relatively warm period (MIS 3, Molotkovskian, or Leningrad Interstadials).The multidisciplinary study of Yuka by various approaches (anatomical-morphological, palynological, paleobotanical, microbiological, computer tomography, and radiocarbon dating methods) yielded fundamentally new data on this proboscidean species. The paper evaluates systematic studies of this unique specimen, from identification of its age and studies of skeletal morphology, ontogenetic development and environmental conditions to reporting the presence of viable bacteria in Yuka’s soft tissues. This paper also features the discovery of the preserved brain and analysis of its structure, as well as a revelation of unique morphology of the trunk, for the first time for this species. The paleobotanical data indicated predomination of open herbaceous landscapes during Yuka’s life. New features of the species morphology were revealed: delayed eruption of the permanent tusks (I) and different number of nail plates and phalanges on the forelegs. The presence of viable bacteria strains of Bacillus genus was recorded in Yuka’s tissues.

A widely accepted model for the peopling of the Americas postulates a source population in the Northeast Asian maritime region, which includes northern Japan. The model is based on similarities in stone artifacts (stemmed points) found in North American sites dating as early as 15,000 years ago and those of comparable age in Japan and neighboring regions of Northeast Asia. Here we show, on the basis of data and analyses in biological anthropology, that the people who made stemmed points in northern Japan (labeled “Incipient Jomon” in the archaeological literature) represent an unlikely source population for the indigenous peoples of the Western Hemisphere.

The central lowland of Beringia (aka the Bering land bridge) has been viewed alternately as a barrier or a refugium to the Native American founder population during the Last Glacial Maximum (LGM). Here we suggest that an equally - if not more - likely LGM home for the founder population is the arctic zone of Beringia. People were drawn to eastern arctic Beringia during the post-LGM Younger Dryas (YD) cold period and occupied western arctic Beringia during the cold interval preceding the LGM (GS5/HE3). Arctic Beringia probably contained adequate resources for an LGM human population, especially across the exposed East Siberian Arctic Shelf ("Northwest Beringian Plain"), which supported an extensive steppe-tundra habitat populated by mammoth and other large mammals before and during the LGM. An arctic Beringian refugium would explain a growing body of evidence that indicates an early (or pre-) LGM divergence of the Native American founder population from its Asian source.

Reverse transcriptase (RT) enzymes are indispensable tools for interrogating diverse aspects of RNA metabolism and transcriptome composition. Due to the growing interest in sequence and structural complexity of long RNA molecules, processive RT enzymes are now required for preserving linkage and information content in mixed populations of transcripts, and the low-processivity RT enzymes that are commercially available cannot meet this need. MarathonRT is encoded within a eubacterial group II intron, and it has been shown to efficiently copy highly structured long RNA molecules in a single pass. In this work, we systematically characterize MarathonRT as a tool enzyme and optimize its performance in a variety of applications that include single-cycle reverse transcription of long RNAs, dimethyl sulfate mutational profiling (DMS-MaP), selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), using ultra-long amplicons and the detection of natural RNA base modifications. By diversifying MarathonRT reaction protocols, we provide an upgraded suite of tools for cutting-edge RNA research and clinical application.

The RIG-I receptor plays a key role in the vertebrate innate immune system, where it functions as a sensor for detecting infection by RNA viruses. Although agonists of RIG-I show great potential as antitumor and antimicrobial therapies, antagonists of RIG-I remain undeveloped, despite the role of RIG-I hyperstimulation in a range of diseases, including COPD and autoimmune disorders. There is now a wealth of information on RIG-I structure, enzymatic function, and signaling mechanism that can drive new drug design strategies. Here, we used the enzymatic activity of RIG-I to develop assays for high-throughput screening, SAR, and downstream optimization of RIG-I antagonists. Using this approach, we have developed potent RIG-I antagonists that interact directly with the receptor and which inhibit RIG-I signaling and interferon response in living cells.

Ancient DNA has significantly improved our understanding of the evolution and population history of extinct megafauna. However, few studies have used complete ancient genomes to examine species responses to climate change prior to extinction. The woolly rhinoceros (Coelodonta antiquitatis) was a cold-adapted megaherbivore widely distributed across northern Eurasia during the Late Pleistocene and became extinct approximately 14 thousand years before present (ka BP). While humans and climate change have been proposed as potential causes of extinction [1-3], knowledge is limited on how the woolly rhinoceros was impacted by human arrival and climatic fluctuations [2]. Here, we use one complete nuclear genome and 14 mitogenomes to investigate the demographic history of woolly rhinoceros leading up to its extinction. Unlike other northern megafauna, the effective population size of woolly rhinoceros likely increased at 29.7 ka BP and subsequently remained stable until close to the species' extinction. Analysis of the nuclear genome from a similar to 18.5-ka-old specimen did not indicate any increased inbreeding or reduced genetic diversity, suggesting that the population size remained steady for more than 13 ka following the arrival of humans [4]. The population contraction leading to extinction of the woolly rhinoceros may have thus been sudden and mostly driven by rapid warming in the Bolling-Allerod interstadial. Furthermore, we identify woolly rhinoceros-specific adaptations to arctic climate, similar to those of the woolly mammoth. This study highlights how species respond differently to climatic fluctuations and further illustrates the potential of palaeogenomics to study the evolutionary history of extinct species.

Recent efforts to identify new highly potent arginase inhibitors have resulted in the discovery of a novel family of (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid analogues with up to a 1000-fold increase in potency relative to the current standards, 2-amino-6-boronohexanoic acid (ABH) and N-hydroxy-nor-l-arginine (nor-NOHA). The lead candidate, with an N-2-amino-3-phenylpropyl substituent (NED-3238), example 43, inhibits arginase I and II with IC50 values of 1.3 and 8.1 nM, respectively. Herein, we report the design, synthesis, and structure-activity relationships for this novel series of inhibitors, along with X-ray crystallographic data for selected examples bound to human arginase II.

Majority of tumors consist of two populations of cancer cells: actively proliferating and those in the reversible dormant or quiescent state, which contribute to the resistance of human tumors to chemotherapies. Conventional chemotherapeutic agents have limited efficacy in ovarian adenocarcinoma patients: while the appropriate chemotherapeutic agent kills proliferating cancer cells, dormant cancer cells survive the treatments and result in recurrent disease. The presence of dormant cancer cells is not revealed by standard H&E staining and morphological tumor analysis. CDK inhibitor p27 is known to be a marker of the dormant state. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with survival of many types of cancers and was shown to play a key role in maintaining the cancer cells in quiescent state by stabilizing p27 and by inducing the breakdown of cyclin D isoforms. In this study, we investigated the functional and therapeutic relevance of DYRK1B in ovarian carcinomas. We have conducted an immunohistochemical study of 70 human ovarian tumors (35 primary/treatment-naive and 35 recurrent/standard chemotherapy resistant ones) and 20+ cases of normal and benign ovarian tissues for expression of DYRK1B, p27 and Ki-67. All FFPE tissue samples have been obtained from the consented patients and under the IRB-approved protocols clinical network, groups have been normalized for age and the disease type/stage. High levels of DYRK1B and p27 proteins expression in malignant treatment-naïve tumors and their significant correlation indicates the presence of dormant cancer cells mixed up with the proliferating ones within patient’s tumors. This effect was detected regardless of the tumor histological subtype (endometrial, serous, mucinous, etc.) and/or stage. While all advanced stage tumors (Stage IIIC and IV) overexpress both markers of dormancy; the early stage tumors (Stage I-II) also presented a higher number of cases with greatly positive scores. Tissue microarray and immunohistochemistry analysis in the literature showed that higher expression levels of DYRK1B correlated with a worse prognosis. We suggest that specific immunostaining of DYRK1B in tumor and endothelial cells can be explored as a predictive risk factor of time to progression/death in patients with primary ovarian tumors. Inhibition of DYRK1B kinase activity with FX9847, specific and selective DYRK1B inhibitor, inhibited ovarian cancer cell growth and induced apoptosis. Moreover, combination of FX9847 with chemotherapeutic agents such as taxanes or vinca alkaloids demonstrated an increased anti-cancer effect on ovarian cancer cells. Together, these findings suggest that DYRK1B is critically involved in the survival of ovarian carcinoma providing a new rationale for their treatment with the kinase inhibitors. Citation Format: Alexandra Kuznetsova, Arianna Damiani, Lita De Leon, Michael Frid, Menelik Duey, Jason Law, Olga Potapova, Maria Vilenchik. Implication of DYRK1B Kinase in ovarian cancers and utilization of DYRK1B Inhibitors as a novel therapeutic strategy for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3038.

e14670 Background: A major determinant of cancer resistance and recurrence is the presence of quiescent cancer cells. It has long been known that quiescent cancers are resistant to a wide variety of anti-cancer therapeutics relative to actively proliferating cells. However, the presence and relative size of the quiescent compartment is not revealed by standard H&E staining and morphological tumor analysis and, therefore, the data demonstrating its importance and prevalence by tumor type are lacking. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with growth and survival of many types of cancer cells and was shown to play a key role in maintaining the cancer cells in reversible quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Methods: We conducted an immunohistochemical study of 80 human glioblastoma (GBM) tumors (primary / treatment-naive, Grade IV) and 10 cases of normal postmortem brain tissues for expression of DYRK1B, and quiescence and proliferation markers p27 and Ki-67, respectively. For subsection of these tissues, high levels of DYRK1B and p27 expression were observed. Results: In this study, we investigated the functional and therapeutic relevance of DYRK1B expression in glioblastomas, the most common brain cancer in adults. It is an aggressive, highly resistant to treatment tumor type with median survival time of less than 16 months following surgery and treatment. Conclusions: There was a statistically significant correlation between immunostaining of DYRK1B and p27, indicating the presence of dormant cancer cells mixed with the proliferating cancer cells within the patients' tumors. We suggest that DYRK1B inhibitors in combination with chemotherapeutics agents have a potential to improve patient treatment outcome and prolong survival.

The paper presents a description of a rare finding of the partial frozen corpse of the Yukagir horse. Discovered from thawing deposits in northern East Siberia (Yakutia, Russia), its age is confirmed to be Mid-Holocene (about 4600 BP). The mummy had a preserved head with the neck and the back of the torso with the legs and tail. The Yukagir horse was relatively short, with short ears and tail. Compared to the modern breeds, including the Yakutian domestic horse, wild Przewalski’s horse, and extinct Lena horse, Equus lenensis, the Yukagir horse was closest to the latter, which was also confirmed by studies of the hair microstructure. The pollen and plant remains from the horse’s intestines indicated a preference to grasses. The late geological age of the Yukagir horse is an indication that this species survived the Pleistocene–Holocene crisis and lived through the Mid-Holocene in northern Eastern Siberia.

We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated stem-loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNA sequencing, we provide the first in vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, polyinosinic: polycytidylic acid [poly(I:C)], which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10 to 14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system.

RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a 'proof-reading' mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.

This paper reports the results of an in-depth analysis of the frozen remains of a woolly mammoth (Mammuthus primigenius) named Zhenya, which has been dated to 48,000 cal BP. The carcass, found near the mouth of the Yenisey River in eastern Siberia, was a juvenile male whose ontogenetic age at death was 8-10 AEY. Its reconstructed live height at the shoulders (pSH 227.4 cm) was the equal of some adult female woolly mammoths and extant elephants. The large stature and a flaked off tusk tip that matches breaks on tusks of male African elephants are indirect indications that this mammoth most likely had reached sexual maturity, had been expelled from its maternal herd, and had been in at least one fight with another male. The mammoth's bones were relatively healthy, although some had minor lesions. Rudimentary upper second molars (M2/m2) were present, but no lower second molars were found in the alveoli, and the left tusk had never developed. Despite the abnormal development of the upper and lower second molars, the cheek teeth which were in wear (Dp4/dp4 and M1/m1) showed normal function without any indications of developmental delay. The completed growth of the light-colored dentin bands on the tusk strongly suggests the Fall of the year was the season of death. This season is also supported by accumulated fat in the upper parts of the torso, indicative of physiological preparation for the winter ahead. The few minor traces of carnivore scavenging, the little disturbed condition of the carcass, and the absence of bone modifications made by human actions, along with the social status of this young male animal, are interpreted here as highly probable evidence that the Zhenya Mammoth died from unrecoverable injuries inflicted during a bull-to-bull fight. The mineralogical analysis of site sediments revealed that the mammoth's burial in situ took place in the Yenisey River valley seasonally inundated by the river, which together with Fall's freezing temperatures protected the carcass from scavengers. An analysis of ancient DNA provides strong support for Zhenya's mitochondrial lineage within the deeply diverging clade III haplogroup B. (C) 2017 Elsevier Ltd and INQUA. All rights reserved.

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Global warming is predicted to cause substantial habitat rearrangements, with the most severe effects expected to occur in high-latitude biomes. However, one major uncertainty is whether species will be able to shift their ranges to keep pace with climate-driven environmental changes. Many recent studies on mammals have shown that past range contractions have been associated with local extinctions rather than survival by habitat tracking. Here, we have used an interdisciplinary approach that combines ancient DNA techniques, coalescent simulations and species distribution modelling, to investigate how two common cold-adapted bird species, willow and rock ptarmigan (Lagopus lagopus and Lagopus muta), respond to long-term climate warming. Contrary to previous findings in mammals, we demonstrate a genetic continuity in Europe over the last 20 millennia. Results from back-casted species distribution models suggest that this continuity may have been facilitated by uninterrupted habitat availability and potentially also the greater dispersal ability of birds. However, our predictions show that in the near future, some isolated regions will have little suitable habitat left, implying a future decrease in local populations at a scale unprecedented since the last glacial maximum.

The paper presents the first morphological description of the internal organs of a frozen corpse of the steppe bison Bison priscus (Bojanus, 1827) from the Holocene of northern Yakutia. Necropsy revealed that most of the internal organs, including the brain, heart with the main vessels, and reproductive system were well preserved. It demonstrated that the anatomy of this bison was close to that of the genera Bos and Bison. Trauma or pathological changes in the organs were not detected. The cause of death of the bison remains unknown.