Dependent Types In Haskell: Theory And Practice

Haskell, as implemented in the Glasgow Haskell Compiler (GHC), has been adding new type-level programming features for some time. Many of these features---generalized algebraic datatypes (GADTs), type families, kind polymorphism, and promoted datatypes---have brought Haskell to the doorstep of dependent types. Many dependently typed programs can even currently be encoded, but often the constructions are painful. In this dissertation, I describe Dependent Haskell, which supports full dependent types via a backward-compatible extension to today\u27s Haskell. An important contribution of this work is an implementation, in GHC, of a portion of Dependent Haskell, with the rest to follow. The features I have implemented are already released, in GHC 8.0. This dissertation contains several practical examples of Dependent Haskell code, a full description of the differences between Dependent Haskell and today\u27s Haskell, a novel dependently typed lambda-calculus (called Pico) suitable for use as an intermediate language for compiling Dependent Haskell, and a type inference and elaboration algorithm, Bake, that translates Dependent Haskell to type-correct Pico. Full proofs of type safety of Pico and the soundness of Bake are included in the appendix

Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Platinum(II) polypyridyl complexes for visible light-driven hydrogen production from water

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2009.This thesis employs Pt(II) terpyridyl and cyclometalated complexes as the chromophores to construct photoactive systems for hydrogen production from water. Several catalysts, including Pt nanoparticles, Pt(II) bi- and terpyridyl chloro complexes, and cobalt dimethylglyoximate complexes, were investigated to catalyze the hydrogen production reactions. Chapter 1, as an introduction part, describes the recent progress in photoinduced hydrogen production from water, including heterogeneous multiple-component systems, homogeneous multiple-component systems and an integrated approach to artificial photosynthesis for photoinduced hydrogen production. Chapter 2 studies a multiple-component system containing a platinum(II) terpyridyl acetylide chromophore, a sacrificial donor (TEOA), an electron relay (MV2+ and diquats) and colloidal platinum catalyst for photocatalytic generation of hydrogen from water. Hydrogen efficiency varies by using different Pt(II) photosensitizers and electron relays, as well as the different concentrations of each species. Chapter 3 discusses the real role of [Pt(ttpy)Cl]+ and Pt(dcbpy)Cl2 as the hydrogen production catalysts. TEM, EDAX and mecury tests show the Pt(II) chloro complexes are only the precursors to form colloidal platinum, which is the real catalyst for hydrogen generation. Chapter 4 and chapter 5 study a novel homogeneous system for photochemical hydrogen production using a cobalt(III) dimethylglyoximate complex as the hydrogen production catalyst and a Pt(II) terpyridyl acetylide complex as the photosensitizer. Cobalt(III) dimethylglyoximate has been used for hydrogen generation by electrochemical method. But very few examples have been reported in photochemical way. The variation of the photosensitizers and cobaloximes are also discussed, as well as the reaction mechanism. Chapter 6 discusses a novel terpyridyl cationic complex [Pt(TPPPB)Cl]Cl, containing a bulky terpyridyl ligand (1-terpyridyl-2,3,4,5,6-pentaphenyl-benzene (TPPPB)). The complex exhibits reversible vapochromic behavior upon exposure to methylene chloride vapors, changing color from red to green. The shift to higher energy in the emission maximum from 654 nm to 514 nm is the largest vapochromic shift (140 nm) yet reported. The [Pt(TPPPB)Cl]Cl complex exhibits high selectivity for certain volatile organic compounds (VOCs) including only methylene chloride, ethanol, ethyl acetate and acetonitrile. The crystal structures of both the green and red forms have been determined by single crystal X-ray diffraction. Chapter 7 describes the perspectives and future directions in this project. More potential efficient and stable cobalt complexes are designed and discussed. The platinum-cobalt supramolecular assemblies towards photochemical molecular devices show interesting properties for hydrogen production