Fiat: Deductive Synthesis of Abstract Data Types in a Proof Assistant

We present Fiat, a library for the Coq proof assistant supporting refinement of declarative specifications into efficient functional programs with a high degree of automation. Each refinement process leaves a proof trail, checkable by the normal Coq kernel, justifying its soundness. We focus on the synthesis of abstract data types that package methods with private data. We demonstrate the utility of our framework by applying it to the synthesis of query structures--abstract data types with SQL-like query and insert operations. Fiat includes a library for writing specifications of query structures in SQL-inspired notation, expressing operations over relations (tables) in terms of mathematical sets. This library includes a suite of tactics for automating the refinement of specifications into efficient, correct- by-construction OCaml code. Using these tactics, a programmer can generate such an implementation completely automatically by only specifying the equivalent of SQL indexes, data structures capturing useful views of the abstract data. Throughout we speculate on the new programming modularity possibilities enabled by an automated refinement system with proved-correct rules. “Every block of stone has a statue inside it and it is the task of the sculptor to discover it.”--MichelangeloNational Science Foundation (U.S.) (NSF grant CCF-1253229)United States. Defense Advanced Research Projects Agency (DARPA, agreement number FA8750-12-2- 0293

A continuum model of gas flows with localized density variations

We discuss the kinetic representation of gases and the derivation of macroscopic equations governing the thermomechanical behavior of a dilute gas viewed at the macroscopic level as a continuous medium. We introduce an approach to kinetic theory where spatial distributions of the molecules are incorporated through a mean-free-volume argument. The new kinetic equation derived contains an extra term involving the evolution of this volume, which we attribute to changes in the thermodynamic properties of the medium. Our kinetic equation leads to a macroscopic set of continuum equations in which the gradients of thermodynamic properties, in particular density gradients, impact on diffusive fluxes. New transport terms bearing both convective and diffusive natures arise and are interpreted as purely macroscopic expansion or compression. Our new model is useful for describing gas flows that display non-local-thermodynamic-equilibrium (rarefied gas flows), flows with relatively large variations of macroscopic properties, and/or highly compressible fluid flows

Genetic Mapping and Functional Studies of a Natural Inhibitor of the Insulin Receptor Tyrosine Kinase: The Mouse Ortholog of Human α2-HS Glycoprotein

Fetuin/α2-HS glycoprotein (α2-HSG) homologs have been identified in several species including rat, sheep, pig, rabbit, guinea pig, cattle, mouse and human. Multiple physiological roles for these homologs have been suggested, including ability to bind to hydroxyapatite crystals and to specifically inhibit the tyrosine kinase (TK) activity of the insulin receptor (IR). In this study we report the identification, cloning, and characterization of the mouse Ahsg gene and its function as an IR-TK inhibitor. Genomic clones derived from a mouse Svj 129 genomic library were sequenced in order to characterize the intron–exon organization of the mouse Ahsg gene, including an 875 bp subclone containing 154 bp upstream from the transcription start site, the first exon, and part of the first intron. A second genomic subclone harboring a 3.45 kb Bgl II fragment contained exons 2, 3 and 4 in addition to two adjacent elements within the first intron-a repetitive element of the B1 family (92 bp) and a 271 bp tract of (T,C)n * (A,G)n. We have mapped mouse Ahsg at 16 cM adjacent to the Diacylglycerol kinase 3 (Dagk3) gene on chromosome 16 by genotyping interspecific backcross panels between C57BL/6J and Mus spretus. The position is syntenic with human chromosome 3q27, where the human AHSG gene resides. Using recombinant mouse α2-HSG expressed from a recombinant baculovirus, we demonstrate that mouse α2-HSG inhibits insulin–stimulated IR autophosphorylation and IR-TKA in vitro. In addition, mouse α2-HSG (25μg/ml) completely abolishes insulin-induced DNA synthesis in H-35 rat hepatoma cells. Based on the sequence data and functional analysis, we conclude that the mouse Ahsg gene is the true ortholog of the human AHSG gene

Development of structural correlations and synchronization from adaptive rewiring in networks of Kuramoto oscillators

L.P. acknowledges support from the National Science Foundation Graduate Research Fellowship Program. J.K. acknowledges support from the National Science Foundation Graduate Research Fellowship Program and NIH T32-EB020087, PD: Felix W. Wehrli. D.S.B. also acknowledges support from the John D. and Catherine T. MacArthur Foundation, the Alfred P. Sloan Foundation, and the National Science Foundation (BCS-1441502, CAREER PHY-1554488, BCS-1631550, and CNS-1626008). We also thank two anonymous reviewers whose comments greatly improved the quality of this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies.Peer reviewedPublisher PD

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

HIV-infected individuals are living longer on antiretro-viral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First,we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across \u3e80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA).We find that decreased HLA methylation is predictive of lower CD4/CD8T cell ratio, linking molecular aging, epigenetic regulation, and disease progression

Return of the EMC Effect: Finite Nuclei

A light front formalism for deep inelastic lepton scattering from finite nuclei is developed. In particular, the nucleon plus momentum distribution and a finite system analog of the Hugenholtz-van Hove theorem are presented. Using a relativistic mean field model, numerical results for the plus momentum distribution and ratio of bound to free nucleon structure functions for Oxygen, Calcium and Lead are given. We show that we can incorporate light front physics with excellent accuracy while using easily computed equal time wavefunctions. Assuming nucleon structure is not modified in-medium we find that the calculations are not consistent with the binding effect apparent in the data not only in the magnitude of the effect, but in the dependence on the number of nucleons.Comment: 11 pages, 6 figure

Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network.

We have mapped a global network of virus-host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV- but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.Significance: In this study, we created a protein-protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474-89. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333