Quinolone-resistant gyrase mutants demonstrate decreased susceptibility to triclosan

Objectives: Cross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance. Methods: WT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined. Results: All gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance. Conclusions: Our data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials

Presidential Commission on the Supreme Court of the United States Final Report

On April 9, 2021, President Joseph R. Biden, Jr. issued Executive Order 14023 establishing this Commission, to consist of “individuals having experience with and knowledge of the Federal judiciary and the Supreme Court of the United States.” The Order charged the Commission with producing a report for the President that addresses three sets of questions. First, the Report should include “[a]n account of the contemporary commentary and debate about the role and operation of the Supreme Court in our constitutional system and about the functioning of the constitutional process by which the President nominates and, by and with the advice and consent of the Senate, appoints Justices to the Supreme Court.” Second, the Report should consider the “historical background of other periods in the Nation’s history when the Supreme Court’s role and the nominations and advice-and-consent process were subject to critical assessment and prompted proposals for reform.” Third, the Report should provide an analysis of the principal arguments for and against particular proposals to reform the Supreme Court, “including an appraisal of [their] merits and legality,” and should be informed by “a broad spectrum of ideas.” The Report begins by explaining the genesis of today’s Court reform debate, including by identifying developments that gave rise to President Biden’s decision to issue the April 2021 Executive Order, particularly the debates surrounding the most recent nominations. This Introduction emphasizes that the Court’s composition and jurisprudence long have been subjects of public controversy and debate in the nation’s civic life: The Court serves as a crucial guardian of the rule of law and also plays a central role in major social and political conflicts. Its decisions have profound effects on the life of the nation. Though conflict surrounding the processes by which the President nominates and the Senate confirms Justices is not new, it has become more intensely partisan in recent years. The Introduction also articulates three common and interrelated ideas frequently invoked in reform debates and throughout the Chapters of the Report: the importance of protecting or enhancing the Court’s legitimacy; the role of judicial independence in our system of government; and the value of democracy and its relationship to the Supreme Court’s decisionmaking. These important ideas can mean different things to different people. The Introduction discusses the range of meanings ascribed to these terms, with the aim of clarifying how they are deployed in arguments for and against reform

Booknote: Sara Ahmed Complaint! - New Formations

I read Sara Ahmed’s Complaint! at a time where I had become exhausted and deflated with the sheer weight of what it means to be a first-generation Black woman researcher in academia. I came to Complaint! at a time when I didn’t have anything left in me to say. This, as Sara Ahmed explains, ‘can be a sign of how much you have to complain about’ (p153). The pure exhaustion of complaint had rendered me silent. There was so much to be said that if I started to complain, I didn’t know whether I could stop. Ahmed’s Complaint! reminded me however, that I didn’t even need to say anything to be registered as complaining, all I needed to do was turn up. Turning up was enough. Turning up became exhausting. Being the only Black woman in a white space, registers as complaint. Writing a literature review and discovering that next to nothing has been written in your area and then simply stating that discovery registers as complaint. I discovered that even confusion can register as a complaint when it comes to unwarranted advances made by external male academics. I wondered about the entanglement of complaint, the entanglement of complaint with my joy for academic exploration, with the considered support available to me at my home institution, and with the stimulating discussions which I delight in and get to take part in. This book came at this time

When Saving Means Losing: Weighing the Benefits of College-Savings Plans

Since the early 1980s, college tuitions have soared, and state and federal governments have sought new ways to help students and families meet the costs of attendance. Annual state and federal appropriations to traditional student aid programs have more than doubled in the past two decades. In addition, the federal government created the Hope Scholarship and Lifetime Learning tax credit programs, and state governments created prepaid tuition plans and college-savings plans. These state savings plans, called "529 plans," are used by many families to help pay for college. However, because of the way funds invested in the different plans are treated by traditional financial aid programs, participation in them can affect eligibility for scholarships, grants and loans. Depending on the details, an increase in savings in a 529 plan may result in a dollar-for-dollar decrease in eligibility for need-based grant aid or it may result in no decrease at all. This paper describes the ways in which this might happen for different groups of students at different types of institutions

A step towards refining and translating B control annotations to Handel-C

The design and implementation of critical controllers benefit from development in a formal method such as the B-Method. However, B does not support direct specification of executions, but this is a requirement in controller design. The aim here is to develop a set of annotations so that they can be used by a B design engineer to capture execution requirements while creating the B model. The annotations, once shown to be consistent with the B machine, can be used independently to assess the correctness of the proposed CSP controllers. CSP parallel to B is an alternative formal method integration that can be used to develop critical controllers with both state and event behaviour. The advantage of using annotations is that the execution requirements can be captured and shown to be consistent with the state during operation development, and that a control loop invariant to establish correctness does not have to be independently developed. Handel-C is used on route to hardware synthesis as it supports the implementation of concurrency and the manipulation of state. Annotations are again used to guide the translation of the B and control annotations into Handel-C. This work has three main aims. First, we introduce a set of annotations to describe control directives to permit controller development in B. The annotations capture execution requirements. They give rise to proof obligations that when discharged prove that the annotations are consistent with the machine they are written in, and therefore will not cause the machine to diverge. Second, we prove that CSP controllers that are consistent with the annotations will preserve the non-divergence property established between the machine and the annotations. Third, we show how annotation refinement is possible, and show a range of mappings from annotated B and consistent controllers to Handel-C. The development of mappings demonstrates the feasibility of automatic translation of annotated B to Handel-C. Copyright (C) 2010 John Wiley & Sons, Ltd

A step towards refining and translating B control annotations to Handel-C

The design and implementation of critical controllers benefit from development in a formal method such as the B-Method. However, B does not support direct specification of executions, but this is a requirement in controller design. The aim here is to develop a set of annotations so that they can be used by a B design engineer to capture execution requirements while creating the B model. The annotations, once shown to be consistent with the B machine, can be used independently to assess the correctness of the proposed CSP controllers. CSP parallel to B is an alternative formal method integration that can be used to develop critical controllers with both state and event behaviour. The advantage of using annotations is that the execution requirements can be captured and shown to be consistent with the state during operation development, and that a control loop invariant to establish correctness does not have to be independently developed. Handel-C is used on route to hardware synthesis as it supports the implementation of concurrency and the manipulation of state. Annotations are again used to guide the translation of the B and control annotations into Handel-C. This work has three main aims. First, we introduce a set of annotations to describe control directives to permit controller development in B. The annotations capture execution requirements. They give rise to proof obligations that when discharged prove that the annotations are consistent with the machine they are written in, and therefore will not cause the machine to diverge. Second, we prove that CSP controllers that are consistent with the annotations will preserve the non-divergence property established between the machine and the annotations. Third, we show how annotation refinement is possible, and show a range of mappings from annotated B and consistent controllers to Handel-C. The development of mappings demonstrates the feasibility of automatic translation of annotated B to Handel-C. Copyright (C) 2010 John Wiley & Sons, Ltd

cis-acting elements required for RNA polymerase II and III transcription in the human U2 and U6 snRNA promoters.

Although the human U2 and U6 snRNA genes are transcribed by RNA polymerases II and III respectively, their promoters are remarkably similar in structure. Both promoters contain a proximal element and an enhancer region with an octamer motif. The U6 promoter contains in addition an A/T rich region that defines it as an RNA polymerase III promoter. We have examined in further detail the contributions of sequences in the human U2 and U6 promoter regions to transcription by RNA polymerase II and III. We find that although the sequences surrounding the U2 cap site favor RNA polymerase II transcription, their presence cannot suppress a shift to RNA polymerase III specificity upon insertion of the U6 A/T box. In the U6 promoter, the 3' part of the proximal element homology is essential for efficient transcription and is also involved in localizing the start site of transcription. A region downstream of the proximal element homology is required for RNA polymerase II (but not for RNA polymerase III) transcription, both in the U2 promoter and in the U6 promoter. This element may be recognized by an RNA polymerase II transcription factor or by RNA polymerase II itself. The presence of this element in the U6 promoter raises the possibility that the human U6 gene is, under certain circumstances, transcribed by RNA polymerase II

Experiments in Translating CSP||B to Handel-C

This paper considers the issues involved in translating specifications described in the CSP||B formal method into Handel-C. There have previously been approaches to translating CSP descriptions to Handel-C, and the work presented ill this paper is part of a programme of work to extend it to include the B component of a CSP parallel to B description. Handel-C is a suitable target language because of its capability of programming communication and state. and its compilation route to hardware. The paper presents two case studies that investigate aspects of the translation: a buffer case study, and all abstract arbiter case Study. These investigations have exposed a number of issues relating to the translation of the B component, and have identified a range of options available, informing more recent work oil the development of a style for CSP parallel to B specifications particularly appropriate to translation to Handel-C

A Step towards Merging xUML and CSP||B

Much research work has been done on linking UML, and formal methods but few have focused on using formal methods to check the integrity of the UML models so that the models can be verified. In this paper we focus on executable UML and on the issues related to concurrent state machines. We show that one integrated formal methods approach, CSP parallel to B, has the potential to be tailored to support reasoning about concurrent state machines and in turn expose any weaknesses in the UML model. We identify future avenues of research so that a system methodology based on executable UML can be enhanced by formal reasoning