Hammering towards QED

This paper surveys the emerging methods to automate reasoning over large libraries developed with formal proof assistants. We call these methods hammers. They give the authors of formal proofs a strong “one-stroke” tool for discharging difficult lemmas without the need for careful and detailed manual programming of proof search. The main ingredients underlying this approach are efficient automatic theorem provers that can cope with hundreds of axioms, suitable translations of the proof assistant’s logic to the logic of the automatic provers, heuristic and learning methods that select relevant facts from large libraries, and methods that reconstruct the automatically found proofs inside the proof assistants. We outline the history of these methods, explain the main issues and techniques, and show their strength on several large benchmarks. We also discuss the relation of this technology to the QED Manifesto and consider its implications for QED-like efforts.Blanchette’s Sledgehammer research was supported by the Deutsche Forschungs- gemeinschaft projects Quis Custodiet (grants NI 491/11-1 and NI 491/11-2) and Hardening the Hammer (grant NI 491/14-1). Kaliszyk is supported by the Austrian Science Fund (FWF) grant P26201. Sledgehammer was originally supported by the UK’s Engineering and Physical Sciences Research Council (grant GR/S57198/01). Urban’s work was supported by the Marie-Curie Outgoing International Fellowship project AUTOKNOMATH (grant MOIF-CT-2005-21875) and by the Netherlands Organisation for Scientific Research (NWO) project Knowledge-based Automated Reasoning (grant 612.001.208).This is the final published version. It first appeared at http://jfr.unibo.it/article/view/4593/5730?acceptCookies=1

Mammalian adaptation of influenza A(H7N9) virus is limited by a narrow genetic bottleneck

Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry. The factors that allow interspecies transmission but limit human-to-human transmission are unknown. Here we show that A/Anhui/1/2013(H7N9) influenza virus infection of chickens (natural hosts) is asymptomatic and that it generates a high genetic diversity. In contrast, diversity is tightly restricted in infected ferrets, limiting further adaptation to a fully transmissible form. Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity. Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost. Our results reveal that a tight genetic bottleneck during avian-to-mammalian transmission is a limiting factor in A(H7N9) influenza virus adaptation to mammals. This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.published_or_final_versio

Recent advances in real geometric reasoning

In the 1930s Tarski showed that real quantifier elimination was possible, and in 1975 Collins gave a remotely practicable method, albeit with doubly-exponential complexity, which was later shown to be inherent. We discuss some of the recent major advances in Collins method: such as an alternative approach based on passing via the complexes, and advances which come closer to "solving the question asked" rather than "solving all problems to do with these polynomials"

Friends with benefits: implementing corecursion in foundational proof assistants

We introduce AmiCo, a tool that extends a proof assistant, Isabelle/HOL, with flexible function definitions well beyond primitive corecursion. All definitions are certified by the assistant’s inference kernel to guard against inconsistencies. A central notion is that of friends: functions that preserve the productivity of their arguments and that are allowed in corecursive call contexts. As new friends are registered, corecursion benefits by becoming more expressive. We describe this process and its implementation, from the user’s specification to the synthesis of a higher-order definition to the registration of a friend. We show some substantial case studies where our approach makes a difference

Glycans as receptors for influenza pathogenesis

Influenza A viruses, members of the Orthomyxoviridae family, are responsible for annual seasonal influenza epidemics and occasional global pandemics. The binding of viral coat glycoprotein hemagglutinin (HA) to sialylated glycan receptors on host epithelial cells is the critical initial step in the infection and transmission of these viruses. Scientists believe that a switch in the binding specificity of HA from Neu5Acα2-3Gal linked (α2-3) to Neu5Acα2-6Gal linked (α2-6) glycans is essential for the crossover of the viruses from avian to human hosts. However, studies have shown that the classification of glycan binding preference of HA based on sialic acid linkage alone is insufficient to establish a correlation between receptor specificity of HA and the efficient transmission of influenza A viruses. A recent study reported extensive diversity in the structure and composition of α2-6 glycans (which goes beyond the sialic acid linkage) in human upper respiratory epithelia and identified different glycan structural topologies. Biochemical examination of the multivalent HA binding to these diverse sialylated glycan structures also demonstrated that high affinity binding of HA to α2-6 glycans with a characteristic umbrella-like structural topology is critical for efficient human adaptation and human-human transmission of influenza A viruses. This review summarizes studies which suggest a new paradigm for understanding the role of the structure of sialylated glycan receptors in influenza virus pathogenesis.National Institute of General Medical Sciences (U.S.) (Glue Grant U54 GM62116)National Institutes of Health (U.S.) (Grant GM57073)Singapore-MIT Alliance for Research and Technolog

Inhibition of sialidase activity and cellular invasion by the bacterial vaginosis pathogen Gardnerella vaginalis

Bacterial vaginosis is a genital tract infection, thought to be caused by transformation of a lactobacillus-rich flora to a dysbiotic microbiota enriched in mixed anaerobes. The most prominent of these is Gardnerella vaginalis (GV), an anaerobic pathogen that produces sialidase enzyme to cleave terminal sialic acid residues from human glycans. Notably, high sialidase activity is associated with preterm birth and low birthweight. We explored the potential of the sialidase inhibitor Zanamavir against GV whole cell sialidase activity using methyl-umbelliferyl neuraminic acid (MU-NANA) cleavage assays, with Zanamavir causing a 30% reduction in whole cell GV sialidase activity (p < 0.05). Furthermore, cellular invasion assays using HeLa cervical epithelial cells, infected with GV, demonstrated that Zanamivir elicited a 50% reduction in cell association and invasion (p < 0.05). Our data thus highlight that pharmacological sialidase inhibitors are able to modify BV-associated sialidase activity and influence host-pathogen interactions and may represent novel therapeutic adjuncts

Glyco-engineered MDCK cells display preferred receptors of H3N2 influenza absent in eggs used for vaccines

Evolution of human H3N2 influenza viruses driven by immune selection has narrowed the receptor specificity of the hemagglutinin (HA) to a restricted subset of human-type (Neu5Acα2-6 Gal) glycan receptors that have extended poly-LacNAc (Galβ1-4GlcNAc) repeats. This altered specificity has presented challenges for hemagglutination assays, growth in laboratory hosts, and vaccine production in eggs. To assess the impact of extended glycan receptors on virus binding, infection, and growth, we have engineered N-glycan extended (NExt) cell lines by overexpressing β3-Ν-acetylglucosaminyltransferase 2 in MDCK, SIAT, and hCK cell lines. Of these, SIAT-NExt cells exhibit markedly increased binding of H3 HAs and susceptibility to infection by recent H3N2 virus strains, but without impacting final virus titers. Glycome analysis of these cell lines and allantoic and amniotic egg membranes provide insights into the importance of extended glycan receptors for growth of recent H3N2 viruses and relevance to their production for cell- and egg-based vaccines

Introduction to Milestones in Interactive Theorem Proving

On March 8, 2018, Tobias Nipkow celebrated his sixtieth birthday. In anticipation of the occasion, in January 2016, two of his former students, Gerwin Klein and Jasmin Blanchette, and one of his former postdocs, Andrei Popescu, approached the editorial board of the Journal of Automated Reasoning with a proposal to publish a surprise Festschrift issue in his honor. The e-mail was sent to twenty-six members of the board, leaving out one, for reasons that will become clear in a moment. It is a sign of the love and respect that Tobias commands from his colleagues that within two days every recipient of the e-mail had responded favorably and enthusiastically to the proposal

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio