Focusing on Refinement Typing

We present a logically principled foundation for systematizing, in a way that works with any computational effect and evaluation order, SMT constraint generation seen in refinement type systems for functional programming languages. By carefully combining a focalized variant of call-by-push-value, bidirectional typing, and our novel technique of value-determined indexes, our system generates solvable SMT constraints without existential (unification) variables. We design a polarized subtyping relation allowing us to prove our logically focused typing algorithm is sound, complete, and decidable. We prove type soundness of our declarative system with respect to an elementary domain-theoretic denotational semantics. Type soundness implies, relatively simply, the total correctness and logical consistency of our system. The relative ease with which we obtain both algorithmic and semantic results ultimately stems from the proof-theoretic technique of focalization.Comment: 61 pages + appendix with proofs, Just Accepted version of paper (with new title) at ACM Transactions on Programming Languages and System

An Analysis of the Corporate Cash Holding Decision

We investigate the tradeoff theory as an explanation for how managers allocate cash to post-spin-off parent and subsidiary firms. Spin-offs provide an opportunity to examine the determinants of cash holdings free from the confounding effects of the pecking order theory. Our results indicate that difference in asset size, sales growth, research and development expenses, net working capital, and leverage significantly affect the difference in cash holdings of post-spin-off entities. These results suggest that cash holdings are decreasing in the ease of raising cash and availability of cash from internal sources, and are increasing in growth opportunities, asymmetric information levels, and financial distress costs

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599

<SUP>187</SUP>Re-<SUP>187</SUP>Os in Lesser Himalayan sediments: measurement techniques and preliminary results

The applications of the 187Re-187Os isotope pair as a petrogenetic and geologic tracer are increasing in recent years due to several advances in the chemical extraction and purification of Re and Os, occurring at ppb levels in environmental samples, and in the precise determination of the Os isotope composition. We have established in our laboratory; based on available methods, chemical procedures and Negative Thermal Ionisation Mass Spectrometric techniques for the measurement of Re-Os concentrations in environmental samples and the Os isotope composition in them. Using these techniques, we are able to determine187Os/186Os ratios with a precision of ~1% (&#177;2&#963;&#956;; twice the standard error of the mean) in several tens of picogram of Os. Preliminary analysis of black shales from the Lower Tal section of the Maldeota phosphorite mine yields a mean187Re-187Os model age of 597 &#177; 30 Ma. The 187Os/186Os and Os concentration in black shales of the Lesser Himalaya range from 8 to 96 and 0.02 to 13 ng g-1 respectively. The mean 187Os/186Os in these samples is ~ 25, significantly higher than the crustal value of ~ 10.5, suggesting that these black shales could be an important source of radiogenic Os to the rivers draining the Himalaya and to the steady increase in 187Os/186Os of the oceans through the Cenozoic

MID3: Mission Impossible or Model-Informed Drug Discovery and Development? Point-Counterpoint Discussions on Key Challenges

MID3: Mission Impossible, or Model‐Informed, Drug Discovery and Development? At the 2019 American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meeting, point‐counterpoint discussions were held on key challenges that limit, and future directions that enhance the adoption of model‐informed drug discovery and development (MID3) across the drug discovery, development, regulatory, and utilization continuum. We envision that the opportunities discussed and lessons learned from having contrasting perspectives on issues that lack consensus may aid our discipline in more effectively implementing MID3 principles

Uranium isotopes and radium in the Bhagirathi Alaknanda river system - evidence for high uranium mobilization in the Himalaya

Extensive measurements of dissolved 238U and 226Ra concentrations and 234U/238U activity ratio have been made on samples collected from the Bhagirathi, Alaknanda and their tributaries-the source waters of the Ganga. The objectives of this study are to determine (i) the sources of U and Ra to the Ganga river; (ii) the weathering rate of uranium in the Himalaya, and (iii) the role of Himalayan-Tibetan rivers on the marine budget of uranium. The dissolved 238U and 226Ra concentrations in the Ganga source waters are typically ~ 2-μgl-1 and ~ 0.2 dpml-1 respectively. The low 226Ra concentrations relative to 238U in these waters indicate that Ra is far less mobile. The Bhagirathi and Alaknanda weather uranium from their drainage basins at a rate of ~2 kgkm-2yr-1 comparable to that of the other Himalayan rivers like the Yamuna, Gandak and Ghaghara, but orders of magnitude higher than that derived for some of the world's major rivers (Amazon and Congo). These results suggest that large-scale mobilization of uranium in the Himalaya by rivers is ubiquitous. In the global context, the rivers draining the Himalayan-Tibetan region could be a major source of uranium to the oceans and that its supply via these rivers may have considerably influenced the marine budget of uranium

Practical API Protocol Checking with Access Permissions

Reusable APIs often define usage protocols. We previously developed a sound modular type system that checks compliance with typestate-based protocols while affording a great deal of aliasing flexibility. We also developed Plural, a prototype tool that embodies our approach as an automated static analysis and includes several extensions we found useful in practice. This paper evaluates our approach along the following dimensions: (1) We report on experience in specifying relevant usage rules for a large Java standard API with our approach. We also specify several other Java APIs and identify recurring patterns. (2) We summarize two case studies in verifying third-party open-source code bases with few false positives using our tool. We discuss how tool shortcomings can be addressed either with code refactorings or extensions to the tool itself. These results indicate that our approach can be used to specify and enforce real API protocols in practice