The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Liberals claim that globalization has led to fragmentation and decentralized networks of power relations. This does not explain how states increasingly “weaponize interdependence” by leveraging glo...

Weaponized Interdependence: How Global Economic Networks Shape State Coercion

List of figures Preface Acknowledgements List of abbreviations 1. Introduction 2. Explaining asymmetric conflict outcomes 3. Russia in the Caucasus: the Murid War, 1830-59 4. Britain in Orange Free State and Transvaal: the South African War, 1899-1902 5. Italy in Ethiopia: the Italo-Ethiopian War, 1935-40 6. The United States in Vietnam: the Vietnam War, 1965-73 7. The USSR in Afghanistan: the Afghan Civil War, 1979-89 8. Conclusion Appendix References Index.

How the Weak Win Wars: A Theory of Asymmetric Conflict

The U.S. commercial space launch industry has changed considerably since the enactment of the Commercial Space Launch Amendments Act of 2004. FAA is required to license or permit commercial space launches, but to allow the space tourism industry to develop, the act prohibited FAA from regulating crew and spaceflight participant safety before 2012—a moratorium that was later extended but will now expire on September 30, 2015. Since October 2014, there have been three mishaps involving FAA licensed or permitted launches.

美聯邦航空廳(Federal Aviation Administration)의 航空機 製作檢査 制度의 現況

FACTS An officer in Midvale, Utah was doing some paperwork in his patrol car when he was approached by man, later identified as Nitokalisi Fonua (hereinafter, “Nick”). Nick “looked suspicious,” mainly because he was “jittery, looking around and appeared to be very nervous.” Nick’s suspicion rating jumped dramatically when, for no apparent reason, he informed the officer he had stolen a white GMC Blazer, which he had parked nearby. Naturally, the officer asked Nick if he would show him the Blazer, and Nick said sure. When they located the Blazer, the officer walked over and looked inside. The first thing he saw was a sawed-off shotgun on the back seat. Then he noticed some markings on the shotgun, “markings that looked gang-related.” Nick told the officer that the key to the Blazer was inside his motel room at the Days Inn. Also in the room, he said, were his “cousins,” meaning “people he knows from the streets.” The officer asked Nick “if we could obtain the keys to the vehicle so we could turn those back over to the owner.” Nick said the keys “were in the room somewhere” and that he “didn’t care” if the officer went in and retrieved them. Nick also gave the officer his key to the room. When backup arrived at the motel, officers knocked on the door which was opened by a man named Vake. There were two other occupants: a woman and Kimoana, the defendant. By this time, the officers were aware that Kimoana—not Nick—had rented the room. The first thing the officers saw as the door opened was the woman pointing “an unidentified black object” at the wall. Concerned for their safety, they ordered the occupants to “show their hands.” Then they pat searched them. Finding no weapons (the “unidentified black object” was a television remote control), they holstered their guns. Although the officers already had Nick’s consent to search the room, they sought and obtained consent from Vake. During the search, they found a “long-barreled revolver” under a mattress. As the result, Kimoana was convicted of being a felon in possession of a firearm.

United States V. _____

Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.

The National Security Agency’s bulk collection of telephony metadata runs contrary to Congress’s intent in enacting the 1978 Foreign Intelligence Surveillance Act. The program also violates the statute in three ways: the requirement that records sought be “relevant to an authorized investigation;” the requirement that information could be obtained via subpoena duces mecum; and the steps required for use of pen registers and trap and trace devices. Additionally, the program gives rise to serious constitutional concerns. Efforts by the government to save the program on grounds of third party doctrine are unpersuasive in light of the unique circumstances of Smith v. Maryland, the privacy invasions resulting from the universal use of pen registers and trap and trace devices, and the advent of new technologies. Over the past decade, tension has emerged between the view that new technologies should be considered from the perspective of trespass doctrine and the view that Katz’s reasonable expectation of privacy test should apply. Cases involving, for instance, GPS chips, thermal scanners, and highly-trained dogs divide along these lines. Regardless of which approach one adopts, however, similar results mark the application of these doctrines. Under trespass doctrine, the primary order for the telephony metadata program amounts to a general warrant — the elimination of which was the aim of the Fourth Amendment. Under Katz, in turn, citizens do not expect that their telephony metadata will be collected and analyzed. Most Americans do not even realize what can be learned from such data, making invalid any claim that they reasonably expect the government to have access to such information. FISA reform is necessary to enable the government to take advantage of new technologies, to empower the intelligence agencies to respond to national security threats, and to bring surveillance operations within the bounds of statutory and constitutional law. Inserting adversarial counsel into the FISA process, creating a repository of technological expertise for FISC and FISCR, restoring prior targeting, heightening protections for U.S. persons, further delimiting relevant data, narrowing the definition of “foreign intelligence” to exclude “foreign affairs,” and requiring the government to demonstrate past effectiveness prior to obtaining renewal orders offer some possibilities for the future of foreign intelligence gathering in the United States.

/pdf/bulk-metadata-collection-statutory-and-constitutional-vsacjztrfv.pdf

Bulk Metadata Collection: Statutory and Constitutional Considerations

Counterterrorist arguments that justify the erosion of individual rights frequently depend on the claim a balance can—and should—be struck between security and freedom. But this analogy, under both consequentialist and rights-based analysis, is at best misleading and at worst structurally wrong. Calculations from utility resting on the immediate dangers posed by terrorism do not give appropriate weight to (a) the long-term effects of inroads into individual rights, (such as individual harm, blocked political, social, and legal mechanisms), and (b) precedent-setting in a tightly-interwoven structure of individual rights and state power. Constitutive rules further delimit the types of measures that can be introduced, regardless of the “tradeoffs” considered in balancing security and freedom. In the rights-based realm, arguments related to expanded state powers, distributive justice, and practical effect undermine the analogy.

Security and Freedom on the Fulcrum

Quantitative criteria to identify proteins as RNA-binding proteins (RBPs) are presently lacking, as are criteria to define RBP target RNAs. Here, we develop an ultraviolet (UV) cross-linking immunoprecipitation (CLIP)-sequencing method, easyCLIP. easyCLIP provides absolute cross-link rates, as well as increased simplicity, efficiency, and capacity to visualize RNA libraries during sequencing library preparation. Measurement of >200 independent cross-link experiments across >35 proteins identifies an RNA cross-link rate threshold that distinguishes RBPs from non-RBPs and defines target RNAs as those with a complex frequency unlikely for a random protein. We apply easyCLIP to the 33 most recurrent cancer mutations across 28 RBPs, finding increased RNA binding per RBP molecule for KHDRBS2 R168C, A1CF E34K and PCBP1 L100P/Q cancer mutations. Quantitating RBP-RNA interactions can thus nominate proteins as RBPs and define the impact of specific disease-associated RBP mutations on RNA association.

/pdf/easyclip-analysis-of-rna-protein-interactions-incorporating-4wxy9397eb.pdf

easyCLIP analysis of RNA-protein interactions incorporating absolute quantification.

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Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.

Bulk Metadata Collection: Statutory and Constitutional Considerations

Security and Freedom on the Fulcrum

easyCLIP analysis of RNA-protein interactions incorporating absolute quantification.