Ancient Pbx-Hox signatures define hundreds of vertebrate developmental enhancers

Background: Gene regulation through cis-regulatory elements plays a crucial role in development and disease. A major aim of the post-genomic era is to be able to read the function of cis-regulatory elements through scrutiny of their DNA sequence. Whilst comparative genomics approaches have identified thousands of putative regulatory elements, our knowledge of their mechanism of action is poor and very little progress has been made in systematically de-coding them. Results: Here, we identify ancient functional signatures within vertebrate conserved non-coding elements (CNEs) through a combination of phylogenetic footprinting and functional assay, using genomic sequence from the sea lamprey as a reference. We uncover a striking enrichment within vertebrate CNEs for conserved binding-site motifs of the Pbx-Hox hetero-dimer. We further show that these predict reporter gene expression in a segment specific manner in the hindbrain and pharyngeal arches during zebrafish development. Conclusions: These findings evoke an evolutionary scenario in which many CNEs evolved early in the vertebrate lineage to co-ordinate Hox-dependent gene-regulatory interactions that pattern the vertebrate head. In a broader context, our evolutionary analyses reveal that CNEs are composed of tightly linked transcription-factor binding-sites (TFBSs), which can be systematically identified through phylogenetic footprinting approaches. By placing a large number of ancient vertebrate CNEs into a developmental context, our findings promise to have a significant impact on efforts toward de-coding gene-regulatory elements that underlie vertebrate development, and will facilitate building general models of regulatory element evolution

Search for the Galactic accelerators of Cosmic-Rays up to the Knee with the Pevatron Test Statistic

The Pevatron Test Statistic (PTS) is applied to data from $\gamma$-ray observatories to test for the origin of Cosmic Rays (CRs) at energies around the knee of the CR spectrum. Several sources are analyzed within hadronic emission models. Previously derived results for RX J1713.7$-$3946, Vela Jr., and HESS J1745$-$290 are confirmed to demonstrate the concept, reliability, and advantages of the PTS. It is excluded with a significance more than $5\sigma$ that the sources RX J1713.7$-$3946 and Vela Jr. are Pevatrons, while strong indications exceeding $4\sigma$ are found for excluding HESS J1745$-$290 as a Pevatron. The importance to resolve source confusion with high angular resolution observations for Pevatrons searches is demonstrated using PTS for the region containing the SNR G106.3+2.7 and the Boomerang nebula. No statistically significant conclusion with respect to Pevatron associations could be drawn from this region, for the diffuse $\gamma$-ray emission around the Galactic Center, and the unidentified $\gamma$-ray sources LHAASO J2108$+$5157, HESS J1702$-$420A and MGRO J1908$+$06. Assuming the entire $\gamma$-ray emission from MGRO J1908+06 and the tail region of SNR G106.3+2.7 is hadronic, a statistical indication exceeding $3\sigma$ is found for the underlying proton spectrum to extend beyond 350$-$400 TeV as a power-law. This result can indicate that these sources are proton and helium Pevatrons, in which the accelerated particles contribute to the knee of proton and helium spectra observed at Earth.Comment: Accepted for publication in MNRAS. 16 pages, 9 figure

A Sox10 enhancer element common to the otic placode and neural crest is activated by tissue-specific paralogs

The otic placode, a specialized region of ectoderm, gives rise to components of the inner ear and shares many characteristics with the neural crest, including expression of the key transcription factor Sox10. Here, we show that in avian embryos, a highly conserved cranial neural crest enhancer, Sox10E2, also controls the onset of Sox10 expression in the otic placode. Interestingly, we show that different combinations of paralogous transcription factors (Sox8, Pea3 and cMyb versus Sox9, Ets1 and cMyb) are required to mediate Sox10E2 activity in the ear and neural crest, respectively. Mutating their binding motifs within Sox10E2 greatly reduces enhancer activity in the ear. Moreover, simultaneous knockdown of Sox8, Pea3 and cMyb eliminates not only the enhancer-driven reporter expression, but also the onset of endogenous Sox10 expression in the ear. Rescue experiments confirm that the specific combination of Myb together with Sox8 and Pea3 is responsible for the onset of Sox10 expression in the otic placode, as opposed to Myb plus Sox9 and Ets1 for neural crest Sox10 expression. Whereas SUMOylation of Sox8 is not required for the initial onset of Sox10 expression, it is necessary for later otic vesicle formation. This new role of Sox8, Pea3 and cMyb in controlling Sox10 expression via a common otic/neural crest enhancer suggests an evolutionarily conserved function for the combination of paralogous transcription factors in these tissues of distinct embryological origin

Introduction to the Special Issue: "Introduction and intensification of agriculture in Central Eurasia and adjacent regions"

For well over a century, scholars from across the social and biological sciences have been trying to understand the origins and spread of agriculture. This debate is often intertwined with discussions of climate change and human environmental impact. Over the past decade, this debate has spread into Central Eurasia, from western China to Ukraine and southern Russia to Turkmenistan, a part of the world often thought to have been largely dominated by pastoralists. A growing interest in the prehistory of Central Eurasia has spurred a new chapter in the origins of agriculture debate; archaeobotanical research is showing how important farming practices in this region were in regard to the spread of crops across the Old World. While early people living in Central Eurasia played an influential role in shaping human history, there is still limited understanding of the trajectories of social evolution among these populations. In March 2015, 30 leading scholars from around the globe came together in Berlin, Germany, to discuss the introduction and intensification of agriculture in Central Eurasia and adjacent regions. At the German Archaeological Institute in Berlin (Deutsches Archäologisches Institut, DAI), these scholars presented novel data on topics covering East, South, and Central Asia, spanning a wide realm of methodological approaches. The present special edition volume deals with a selection of the papers given at this conference, and it marks a significant step toward recognizing the contribution of Central Eurasian populations in the spread and development of agricultural systems over the course of the Holocene

Vemurafenib‐induced granulomatous hepatitis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135991/1/hep28692_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135991/2/hep28692.pd

Detection and Deterrence in the Economics of Corruption: a Game Theoretic Analysis and some Experimental Evidence

This thesis contributes to our understanding of corruption deterrence for a specific class of game-theoretic corruption models, in which we assume that inspection of corrupt be- haviour happens through randomisation. Three models are explored theoretically and one experimentally. All models are three-player variations of the inspection game, and their typically unusual insights result from mixed-strategy equilibrium solutions. The first model examines an inspection game between an inspector and two potentially col- laborating offenders (a corrupt client and an official). Strikingly, its comparative statics suggest that higher penalties on corrupt clients increase the probability of corruption in the mixed equilibrium. The second model compares two states of the world, one where corrupt officials merely reject bribes (if they do not accept them), and one where corrupt officials report bribes (the latter leading to definite punishment of clients). The surprising result here is that, when officials prefer to report bribes (instead of merely rejecting them), the probability of corruption is again higher in equilibrium. The third model takes into account three different types of officials, a reporting type, a rejecting type, and a corruptible type. Its results show that e.g. an increase in the proportion of the reporting type increases the probability of corruption. To compare our theoretical results with data, we test a simple version of this game in the laboratory. Results of this pilot experiment were mixed, suggesting that three-player mixed-equilibrium behaviour is only in part and only qualitatively true on the aggregate, but not quantitatively or for individual play. An epilogue describes developments of a new, much improved experimental design and software, intended for future experiments

Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution

Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ~500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms

DNA methyltransferase3A as a molecular switch mediating the neural tube-to-neural crest fate transition

Here, we explore whether silencing via promoter DNA methylation plays a role in neural versus neural crest cell lineage decisions. We show that DNA methyltransferase3A (DNMT3A) promotes neural crest specification by directly mediating repression of neural genes like Sox2 and Sox3. DNMT3A is expressed in the neural plate border, and its knockdown causes ectopic Sox2 and Sox3 expression at the expense of neural crest markers. In vivo chromatin immunoprecipitation of neural folds demonstrates that DNMT3A specifically associates with CpG islands in the Sox2 and Sox3 promoter regions, resulting in their repression by methylation. Thus, DNMT3A functions as a molecular switch, repressing neural to favor neural crest cell fate

Expression and function of transcription factor cMyb during cranial neural crest development

The transcription factor cMyb has well known functions in vertebrate hematopoiesis, but little was known about its distribution or function at early developmental stages. Here, we show that cMyb transcripts are present at the neural plate during gastrulation in chick embryos. cMyb expression then resolves to the cranial neural folds and is maintained in early migrating cranial neural crest cells during and after neurulation. Morpholino-mediated knock-down of cMyb reduces expression of Pax7 and Twist at the neural plate border, as well as reducing expression of neural crest specifier genes Snail2 and Sox10 and completely eliminating expression of Ets1. On the other hand, its loss results in abnormal maintenance of Zic1, but little or no effect on other neural crest specifier genes like FoxD3 or Sox9. These results place cMyb in a critical hierarchical position within the cranial neural crest cell gene regulatory network, likely directly inhibiting Zic1 and upstream of Ets1 and some, but not all, neural crest specifier genes