Formal design specification of a Processor Interface Unit

This report describes work to formally specify the requirements and design of a processor interface unit (PIU), a single-chip subsystem providing memory-interface bus-interface, and additional support services for a commercial microprocessor within a fault-tolerant computer system. This system, the Fault-Tolerant Embedded Processor (FTEP), is targeted towards applications in avionics and space requiring extremely high levels of mission reliability, extended maintenance-free operation, or both. The need for high-quality design assurance in such applications is an undisputed fact, given the disastrous consequences that even a single design flaw can produce. Thus, the further development and application of formal methods to fault-tolerant systems is of critical importance as these systems see increasing use in modern society

Interpreter composition issues in the formal verification of a processor-memory module

This report describes interpreter composition techniques suitable for the formal specification and verification of a processor-memory module using the HOL theorem proving system. The processor-memory module is a multichip subsystem within a fault-tolerant embedded system under development within the Boeing Defense and Space Group. Modeling and verification methods were developed that permit provably secure composition at the transaction-level of specification, significantly reducing the complexity of the hierarchical verification of the system

Towards the formal specification of the requirements and design of a processor interface unit

Work to formally specify the requirements and design of a Processor Interface Unit (PIU), a single-chip subsystem providing memory interface, bus interface, and additional support services for a commercial microprocessor within a fault-tolerant computer system, is described. This system, the Fault-Tolerant Embedded Processor (FTEP), is targeted towards applications in avionics and space requiring extremely high levels of mission reliability, extended maintenance free operation, or both. The approaches that were developed for modeling the PIU requirements and for composition of the PIU subcomponents at high levels of abstraction are described. These approaches were used to specify and verify a nontrivial subset of the PIU behavior. The PIU specification in Higher Order Logic (HOL) is documented in a companion NASA contractor report entitled 'Towards the Formal Specification of the Requirements and Design of a Processor Interfacs Unit - HOL Listings.' The subsequent verification approach and HOL listings are documented in NASA contractor report entitled 'Towards the Formal Verification of the Requirements and Design of a Processor Interface Unit' and NASA contractor report entitled 'Towards the Formal Verification of the Requirements and Design of a Processor Interface Unit - HOL Listings.

Towards the formal verification of the requirements and design of a processor interface unit: HOL listings

This technical report contains the Higher-Order Logic (HOL) listings of the partial verification of the requirements and design for a commercially developed processor interface unit (PIU). The PIU is an interface chip performing memory interface, bus interface, and additional support services for a commercial microprocessor within a fault tolerant computer system. This system, the Fault Tolerant Embedded Processor (FTEP), is targeted towards applications in avionics and space requiring extremely high levels of mission reliability, extended maintenance-free operation, or both. This report contains the actual HOL listings of the PIU verification as it currently exists. Section two of this report contains general-purpose HOL theories and definitions that support the PIU verification. These include arithmetic theories dealing with inequalities and associativity, and a collection of tactics used in the PIU proofs. Section three contains the HOL listings for the completed PIU design verification. Section 4 contains the HOL listings for the partial requirements verification of the P-Port

Towards the formal verification of the requirements and design of a processor interface unit

The formal verification of the design and partial requirements for a Processor Interface Unit (PIU) using the Higher Order Logic (HOL) theorem-proving system is described. The processor interface unit is a single-chip subsystem within a fault-tolerant embedded system under development within the Boeing Defense and Space Group. It provides the opportunity to investigate the specification and verification of a real-world subsystem within a commercially-developed fault-tolerant computer. An overview of the PIU verification effort is given. The actual HOL listing from the verification effort are documented in a companion NASA contractor report entitled 'Towards the Formal Verification of the Requirements and Design of a Processor Interface Unit - HOL Listings' including the general-purpose HOL theories and definitions that support the PIU verification as well as tactics used in the proofs

Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study

Background Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate. Methods This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study was conducted across 14 countries and 79 clinical sites. We recruited people aged 18 years or older with a documented diagnosis of rheumatoid arthritis at least 16 weeks before screening with an inadequate response to methotrexate with or without inadequate response to up to two tumour necrosis factor inhibitors. Participants were randomly assigned (1:1:1:1) to oral BMS-986142 (100 mg, 200 mg, or 350 mg) or placebo once daily for 12 weeks. Randomisation was done using an interactive voice response system and stratified by prior treatment status and geographical region. All participants, care providers, investigators, and outcome assessors were masked to treatment allocation. Co-primary endpoints were 20% and 70% improvement in American College of Rheumatology criteria (ACR20 and ACR70) at week 12. Primary endpoints were assessed in the efficacy analysis population (all randomised patients who received at least one dose of the study drug and did not discontinue the study). Safety endpoints were analysed in the as-treated analysis population, which included all patients who received at least one dose of the study drug (patients were grouped according to the treatment they actually received vs the treatment to which they were randomised). This trial was registered with ClinicalTrials.gov, number NCT02638948. Findings Between Feb 24, 2016 and May 3, 2018, 248 patients were randomised (73 in the BMS-986142 100 mg group, 73 in the 200 mg group, 26 in the 350 mg group, and 75 in the placebo group; one post-randomisation exclusion); mean age was 56·7 years (SD 12·7); 214 (87%) of 247 were women, 33 (13%) were men, and 188 (76%) were White. Pre-specified interim analysis resulted in discontinuation of the 350 mg BMS-986142 dose due to elevated liver enzymes and absence of benefit versus placebo. Co-primary endpoints were not met. Response rates for ACR20 (placebo: 23 [31%] of 75; 100 mg: 26 [36%] of 73; 200 mg: 31 [42%] of 73) and ACR70 (placebo: three [4%] of 75; 100 mg: three [4%] of 73; 200 mg: seven [10%] of 73) were not significantly different to placebo; estimate of difference versus placebo for ACR20 was 4·9 (95% CI –10·2 to 20·1; p=0·52) for 100 mg and 11·8 (–3·6 to 27·2; p=0·14) for 200 mg, and for ACR70 the estimate of difference was 0·1 (–16·0 to 16·5; nominal p=1·00) for 100 mg and 5·6 (–10·5 to 21·9; nominal p=0·21) for 200 mg. Six patients experienced serious adverse events (four in the placebo group [mouth ulceration, open globe injury, rheumatoid arthritis flare, and endometrial adenocarcinoma] and two in the BMS-986142 100 mg group [angina pectoris and intestinal obstruction]); there were no deaths. Interpretation Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis

Customs Law

This article summarizes important developments in 2014 in customs law, including U.S. judicial decisions, trade, legislative, administrative, and executive developments, as well as Canadian and European legal developments

Fluorescent D-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorous predation

Modification of essential bacterial peptidoglycan (PG) containing cell walls can lead to antibiotic resistance, for example β-lactam resistance by L,D-transpeptidase activities. Predatory Bdellovibrio bacteriovorus are naturally antibacterial and combat infections by traversing, modifying and finally destroying walls of Gram-negative prey bacteria, modifying their own PG as they grow inside prey. Historically, these multi-enzymatic processes on two similar PG walls have proved challenging to elucidate. Here, with a PG labelling approach utilizing timed pulses of multiple fluorescent D-amino acids (FDAAs), we illuminate dynamic changes that predator and prey walls go through during the different phases of bacteria:bacteria invasion. We show formation of a reinforced circular port-hole in the prey wall; L,D-transpeptidaseBd mediated D-amino acid modifications strengthening prey PG during Bdellovibrio invasion and a zonal mode of predator-elongation. This process is followed by unconventional, multi-point and synchronous septation of the intracellular Bdellovibrio, accommodating odd- and even-numbered progeny formation by non-binary division