The genome of the emerging barley pathogen Ramularia collo-cygni

Background Ramularia collo-cygni is a newly important, foliar fungal pathogen of barley that causes the disease Ramularia leaf spot. The fungus exhibits a prolonged endophytic growth stage before switching life habit to become an aggressive, necrotrophic pathogen that causes significant losses to green leaf area and hence grain yield and quality. Results The R. collo-cygni genome was sequenced using a combination of Illumina and Roche 454 technologies. The draft assembly of 30.3 Mb contained 11,617 predicted gene models. Our phylogenomic analysis confirmed the classification of this ascomycete fungus within the family Mycosphaerellaceae, order Capnodiales of the class Dothideomycetes. A predicted secretome comprising 1053 proteins included redox-related enzymes and carbohydrate-modifying enzymes and proteases. The relative paucity of plant cell wall degrading enzyme genes may be associated with the stealth pathogenesis characteristic of plant pathogens from the Mycosphaerellaceae. A large number of genes associated with secondary metabolite production, including homologs of toxin biosynthesis genes found in other Dothideomycete plant pathogens, were identified. Conclusions The genome sequence of R. collo-cygni provides a framework for understanding the genetic basis of pathogenesis in this important emerging pathogen. The reduced complement of carbohydrate-degrading enzyme genes is likely to reflect a strategy to avoid detection by host defences during its prolonged asymptomatic growth. Of particular interest will be the analysis of R. collo-cygni gene expression during interactions with the host barley, to understand what triggers this fungus to switch from being a benign endophyte to an aggressive necrotroph

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Pricing in telecommunications networks offering multiple services and quality of service guarantees

In this dissertation, we consider approaches for pricing multiple services offered over a single telecommunications network. Each service has quality of service (QoS) requirements that are guaranteed to users. Service classes may be defined by the type of service, such as voice, video or data, as well as the origin and destination of the connection provided to the user. We formulate our problems to address two issues, flow control and efficient allocation of resources. We proceed by first considering the ability to estimate demand quantities and the demand function on-line. We identify this problem as a critical issue in the design of pricing schemes, where the calculated price depends on a real-time estimate of demand. On-line estimation of demand, under a pricing policy that uses the estimated functions, is found to be prone to bias in the estimates. This serves to motivate the design of a novel flow control scheme for connection requests. We limit the number of connection requests by offering discounts in exchange for delayed use of connections. This allows us to regulate the proportion of blocked requests. Furthermore, the scheme can be implemented under uncertainty, since all the problem parameters can be estimated on-line. In the latter part of the dissertation, we address efficient allocation of resources. We formulate and solve problems that calculate optimal prices by service class. We simultaneously solve for the resource allocations necessary to provide connections with guaranteed QoS, to serve the demand resulting from the prices. We first consider single switch problems and study the impact of service class parameters on the optimal solutions. We derive optimality conditions and a solution method for this class of problems. We extend both the formulation and solution method for network problems. The optimality properties derived earlier still apply, in addition to properties dependent on the routing of traffic within the network

Pricing in telecommunications networks offering multiple services and quality of service guarantees

In this dissertation, we consider approaches for pricing multiple services offered over a single telecommunications network. Each service has quality of service (QoS) requirements that are guaranteed to users. Service classes may be defined by the type of service, such as voice, video or data, as well as the origin and destination of the connection provided to the user. We formulate our problems to address two issues, flow control and efficient allocation of resources. We proceed by first considering the ability to estimate demand quantities and the demand function on-line. We identify this problem as a critical issue in the design of pricing schemes, where the calculated price depends on a real-time estimate of demand. On-line estimation of demand, under a pricing policy that uses the estimated functions, is found to be prone to bias in the estimates. This serves to motivate the design of a novel flow control scheme for connection requests. We limit the number of connection requests by offering discounts in exchange for delayed use of connections. This allows us to regulate the proportion of blocked requests. Furthermore, the scheme can be implemented under uncertainty, since all the problem parameters can be estimated on-line. In the latter part of the dissertation, we address efficient allocation of resources. We formulate and solve problems that calculate optimal prices by service class. We simultaneously solve for the resource allocations necessary to provide connections with guaranteed QoS, to serve the demand resulting from the prices. We first consider single switch problems and study the impact of service class parameters on the optimal solutions. We derive optimality conditions and a solution method for this class of problems. We extend both the formulation and solution method for network problems. The optimality properties derived earlier still apply, in addition to properties dependent on the routing of traffic within the network

Pricing in telecommunications networks offering multiple services and quality of service guarantees

In this dissertation, we consider approaches for pricing multiple services offered over a single telecommunications network. Each service has quality of service (QoS) requirements that are guaranteed to users. Service classes may be defined by the type of service, such as voice, video or data, as well as the origin and destination of the connection provided to the user. We formulate our problems to address two issues, flow control and efficient allocation of resources. We proceed by first considering the ability to estimate demand quantities and the demand function on-line. We identify this problem as a critical issue in the design of pricing schemes, where the calculated price depends on a real-time estimate of demand. On-line estimation of demand, under a pricing policy that uses the estimated functions, is found to be prone to bias in the estimates. This serves to motivate the design of a novel flow control scheme for connection requests. We limit the number of connection requests by offering discounts in exchange for delayed use of connections. This allows us to regulate the proportion of blocked requests. Furthermore, the scheme can be implemented under uncertainty, since all the problem parameters can be estimated on-line. In the latter part of the dissertation, we address efficient allocation of resources. We formulate and solve problems that calculate optimal prices by service class. We simultaneously solve for the resource allocations necessary to provide connections with guaranteed QoS, to serve the demand resulting from the prices. We first consider single switch problems and study the impact of service class parameters on the optimal solutions. We derive optimality conditions and a solution method for this class of problems. We extend both the formulation and solution method for network problems. The optimality properties derived earlier still apply, in addition to properties dependent on the routing of traffic within the network

Optimal Pricing for Multiple Services in Telecommunications Networks Offering Quality of Service Guarantees

Abstract — We consider pricing for multiple services offered over a single telecommunications network. Each service has quality of service (QoS) requirements that are guaranteed to users. Service classes may be defined by the type of service, such as voice, video or data, as well as the origin and destination of the connection provided to the user. We formulate the optimal pricing problem as a nonlinear integer expected revenue optimization problem. We simultaneously solve for prices and the resource allocations necessary to provide connections with guaranteed QoS. We derive optimality conditions and a solution method for this class of problems, and apply to a realistic model of a multi-service communications network

The Market for Video on Demand

Video on demand, Efficient bandwidth, Cournot competition, Market equilibrium,