Scheduling a multi class queue with many exponential servers: asymptotic optimality in heavy traffic

We consider the problem of scheduling a queueing system in which many statistically identical servers cater to several classes of impatient customers. Service times and impatience clocks are exponential while arrival processes are renewal. Our cost is an expected cumulative discounted function, linear or nonlinear, of appropriately normalized performance measures. As a special case, the cost per unit time can be a function of the number of customers waiting to be served in each class, the number actually being served, the abandonment rate, the delay experienced by customers, the number of idling servers, as well as certain combinations thereof. We study the system in an asymptotic heavy-traffic regime where the number of servers n and the offered load r are simultaneously scaled up and carefully balanced: n\approx r+\beta \sqrtr for some scalar \beta. This yields an operation that enjoys the benefits of both heavy traffic (high server utilization) and light traffic (high service levels.

Strong "quantum" chaos in the global ballooning mode spectrum of three-dimensional plasmas

The spectrum of ideal magnetohydrodynamic (MHD) pressure-driven (ballooning) modes in strongly nonaxisymmetric toroidal systems is difficult to analyze numerically owing to the singular nature of ideal MHD caused by lack of an inherent scale length. In this paper, ideal MHD is regularized by using a $k$-space cutoff, making the ray tracing for the WKB ballooning formalism a chaotic Hamiltonian billiard problem. The minimum width of the toroidal Fourier spectrum needed for resolving toroidally localized ballooning modes with a global eigenvalue code is estimated from the Weyl formula. This phase-space-volume estimation method is applied to two stellarator cases.Comment: 4 pages typeset, including 2 figures. Paper accepted for publication in Phys. Rev. Letter

Chemically attenuated blood-stage Plasmodium yoelii parasites induce long-lived and strain-transcending protection

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccinehas not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuatedwhole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17Xand demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection againstblood-stage infection persisted for at least 9 months. Activation of both CD4+ and CD8+ T cells was shown after vaccination;however, in vivo studies demonstrated a pivotal role for both CD4+ T cells and B cells since the absence of either cell type led toloss of vaccine-induced protection. In spite of significant activation of circulating CD8+ T cells, liver-stage immunity was notevident. Neither did vaccine-induced CD8+ T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis,since all vaccinated mice depleted of both CD4+ and CD8+ T cells survived a challenge infection. This study providescritical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans

Chemically attenuated blood-stage Plasmodium yoelii parasites induce long-lived and strain-transcending protection

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+ and CD8+ T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4+ T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+ T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+ T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+ and CD8+ T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans

Singularities of bi-Hamiltonian systems

We study the relationship between singularities of bi-Hamiltonian systems and algebraic properties of compatible Poisson brackets. As the main tool, we introduce the notion of linearization of a Poisson pencil. From the algebraic viewpoint, a linearized Poisson pencil can be understood as a Lie algebra with a fixed 2-cocycle. In terms of such linearizations, we give a criterion for non-degeneracy of singular points of bi-Hamiltonian systems and describe their types

The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go–no-go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention

Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study

Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline