The Theory and Practice of Constitutionalism in Pre-Revolutionary Massachusetts Bay: James Otis on the Writs of Assistance, 1761

The subject of constitutionalism is of considerable topical importance in Canada today, and it is hoped that this essay in historical jurisprudence will be of value to Canadian scholars attempting to discover a usable past in the eighteenth century constitution of Empire. To plunge twentieth century scholars into the eighteenth century legal world, however, may have a tortious quality to it. Recently, an American scholar commented rather grimly that much modern scholarship on the subject shares a sense of the strangeness of the eighteenthcentury world, its pervasive differentness from the legal world we know and have internalized. We cannot, he concluded, with any expectation of success pretend to be a judge in a court in provincial America.... I We can, perhaps, pretend to be a student or practitioner in provincial America, for the texts from which provincial American lawyers learned the law are well known and accessible, and their minutes of cases are often also available. The published Diary and Autobiography of John Adams reveals his own attempts to master the subject in the following recitation of sources

The Emergence of the European Integration Dimension in National Party Systems, 1945-2010

We investigate whether and, if so, when and where a new European integration dimension emerges in national party competition that complements the traditional left/right-dimension in Europe. We develop a Bayesian Finite Mixture Factor Analysis to estimate the probability for the latent one-dimensional traditional left/right and two-dimensional inverted U-shaped configuration with anti-European parties at the peripheries. Our empirical analysis combines expert and transformed manifesto data, covering the period since World War II. The estimation reveals that the probability for a one-dimensional configuration becomes on average less likely than the probability for a two-dimensional configuration since the late 1980s. We provide evidence that the increasing transfer of competences to the EU as manifested by EU membership plays a key role for the emergence of the European integration dimension. Our findings are supported by a series of validity tests and have implications for a many political phenomena

Introduction: Celebrating the Mound City Bar Association Centennial: Looking Back, Leading Forward

In 2022, the Mound City Bar Association in St. Louis, one of the first Black bar associations in the country, celebrates its 100th anniversary. In this volume of the Washington University Journal of Law & Policy, distinguished authors look back at a century of contributions of Mound City Bar Association lawyers, judges, and allies, documenting their efforts to eliminate racial discrimination and break down barriers to equal justice. The volume is a testament to the work of countless individuals in the fight for civil rights since the beginning of the association in 1922. The authors also anticipate and examine the challenges ahead and the work yet to be done to achieve equal justice for all in our city, the region, and the country in the years to come

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3–tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively

Systematic Approaches towards the Development of Host-Directed Antiviral Therapeutics

Since the onset of antiviral therapy, viral resistance has compromised the clinical value of small-molecule drugs targeting pathogen components. As intracellular parasites, viruses complete their life cycle by hijacking a multitude of host-factors. Aiming at the latter rather than the pathogen directly, host-directed antiviral therapy has emerged as a concept to counteract evolution of viral resistance and develop broad-spectrum drug classes. This approach is propelled by bioinformatics analysis of genome-wide screens that greatly enhance insights into the complex network of host-pathogen interactions and generate a shortlist of potential gene targets from a multitude of candidates, thus setting the stage for a new era of rational identification of drug targets for host-directed antiviral therapies. With particular emphasis on human immunodeficiency virus and influenza virus, two major human pathogens, we review screens employed to elucidate host-pathogen interactions and discuss the state of database ontology approaches applicable to defining a therapeutic endpoint. The value of this strategy for drug discovery is evaluated, and perspectives for bioinformatics-driven hit identification are outlined

An RNA-based transcription activator derived from an inhibitory aptamer

According to the recruitment model of transcriptional activation, an activator helps initiate transcription by bringing the RNA polymerase to a specific location on the DNA through interaction with components of the transcriptional machinery. However, it is difficult to isolate and define the activities of specific activator–target pairs experimentally through rearranging existing protein parts. Here we designed and constructed an RNA-based transcriptional activator to study specificity from both sides of the activator–target interface. Utilizing a well-characterized site-specific RNA aptamer for TFIIB, we were able to delineate some key features of this process. By rationally converting an inhibitory aptamer into the activation domain of the activator, we also introduced a new source of submolecular building blocks to synthetic biology

Identifying Rare Variants from Exome Scans: The GAW17 Experience

Genetic Analysis Workshop 17 (GAW17) provided a platform for evaluating existing statistical genetic methods and for developing novel methods to analyze rare variants that modulate complex traits. In this article, we present an overview of the 1000 Genomes Project exome data and simulated phenotype data that were distributed to GAW17 participants for analyses, the different issues addressed by the participants, and the process of preparation of manuscripts resulting from the discussions during the worksho