Evolutionary History and Attenuation of Myxoma Virus on Two Continents

The attenuation of myxoma virus (MYXV) following its introduction as a biological control into the European rabbit populations of Australia and Europe is the canonical study of the evolution of virulence. However, the evolutionary genetics of this profound change in host-pathogen relationship is unknown. We describe the genome-scale evolution of MYXV covering a range of virulence grades sampled over 49 years from the parallel Australian and European epidemics, including the high-virulence progenitor strains released in the early 1950s. MYXV evolved rapidly over the sampling period, exhibiting one of the highest nucleotide substitution rates ever reported for a double-stranded DNA virus, and indicative of a relatively high mutation rate and/or a continually changing selective environment. Our comparative sequence data reveal that changes in virulence involved multiple genes, likely losses of gene function due to insertion-deletion events, and no mutations common to specific virulence grades. Hence, despite the similarity in selection pressures there are multiple genetic routes to attain either highly virulent or attenuated phenotypes in MYXV, resulting in convergence for phenotype but not genotype. © 2012 Kerr et al

Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease

Hypothesis/introduction. The risks and benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with end-stage renal disease (ESRD) after cardiac events are unknown. We sought to determine the independent effect of ACE inhibitors (ACE-I) on long-term mortality in ESRD patients after cardiac events. Materials and methods. We analysed a prospective coronary care unit registry and identified 527 ESRD patients, 368 with complete data on medications prescribed, over eight years at a single, tertiary centre. Results. The overall mean age was 64.4±13.8 years with 54.9% men, and 59.2% African-American. A total of 143/386 (37.0%) were prescribed ACE-I during the hospital stay for cardiac reasons, including congestive heart failure (CHF) 52.8% and acute coronary syndromes (ACS) 47.2%. There were no significant differences in the rates of hypotension or arrhythmias in those who were treated with ACE-I versus those who were not. Survival analysis over three years, adjusted for known confounders, demonstrated a 37% reduction in all-cause mortality in those who received ACE-I, (p=0.0145). Conclusions. In the setting of coronary care unit admission for CHF and ACS, ESRD patients selected for ACE-I, did not have increased rates of adverse haemodynamic or arrhythmic complications. The use of ACE-I conferred an independent mortality reduction over long-term follow-up

Directed differentiation of pluripotent cells to neural lineages: homogeneous formation and differentiation of a neurectoderm population

During embryogenesis the central and peripheral nervous systems arise from a neural precursor population, neurectoderm, formed during gastrulation. We demonstrate the differentiation of mouse embryonic stem cells to neurectoderm in culture, in a manner which recapitulates embryogenesis, with the sequential and homogeneous formation of primitive ectoderm, neural plate and neural tube. Formation of neurectoderm occurs in the absence of extraembryonic endoderm or mesoderm and results in a stratified epithelium of cells with morphology, gene expression and differentiation potential consistent with positionally unspecified neural tube. Differentiation of this population to homogeneous populations of neural crest or glia was also achieved. Neurectoderm formation in culture allows elucidation of signals involved in neural specification and generation of implantable cell populations for therapeutic use

Prospects for the cavity-assisted laser cooling of molecules

Cooling of molecules via free-space dissipative scattering of photons is thought not to be practicable due to the inherently large number of Raman loss channels available to molecules and the prohibitive expense of building multiple repumping laser systems. The use of an optical cavity to enhance coherent Rayleigh scattering into a decaying cavity mode has been suggested as a potential method to mitigate Raman loss, thereby enabling the laser cooling of molecules to ultracold temperatures. We discuss the possibility of cavity-assisted laser cooling particles without closed transitions, identify conditions necessary to achieve efficient cooling, and suggest solutions given experimental constraints. Specifically, it is shown that cooperativities much greater than unity are required for cooling without loss, and that this could be achieved via the superradiant scattering associated with intracavity self-localization of the molecules. Particular emphasis is given to the polar hydroxyl radical (OH), cold samples of which are readily obtained from Stark deceleration.Comment: 18 pages, 10 figure

Legislative strengthening meets party support in international assistance: a closer relationship?

Recent reports recommend that international efforts to help strengthen legislatures in emerging democracies should work more closely with support for building stronger political parties and competitive party systems. This article locates the recommendations within international assistance more generally and reviews the arguments. It explores problems that must be addressed if the recommendations are to be implemented effectively. The article argues that an alternative, issue-based approach to strengthening legislatures and closer links with civil society could gain more traction. However, that is directed more centrally at promoting good governance for the purpose of furthering development than at democratisation goals sought by party aid and legislative strengtheners in the democracy assistance industry

Disease Introduction Is Associated With a Phase Transition in Bighorn Sheep Demographics

Ecological theory suggests that pathogens are capable of regulating or limiting host population dynamics, and this relationship has been empirically established in several settings. However, although studies of childhood diseases were integral to the development of disease ecology, few studies show population limitation by a disease affecting juveniles. Here, we present empirical evidence that disease in lambs constrains population growth in bighorn sheep (Ovis canadensis) based on 45 years of population‐level and 18 years of individual‐level monitoring across 12 populations. While populations generally increased (λ = 1.11) prior to disease introduction, most of these same populations experienced an abrupt change in trajectory at the time of disease invasion, usually followed by stagnant‐to‐declining growth rates (λ = 0.98) over the next 20 years. Disease‐induced juvenile mortality imposed strong constraints on population growth that were not observed prior to disease introduction, even as adult survival returned to pre‐invasion levels. Simulations suggested that models including persistent disease‐induced mortality in juveniles qualitatively matched observed population trajectories, whereas models that only incorporated all‐age disease events did not. We use these results to argue that pathogen persistence may pose a lasting, but under‐recognized, threat to host populations, particularly in cases where clinical disease manifests primarily in juveniles

Contact Networks and Mortality Patterns Suggest Pneumonia-Causing Pathogens may Persist in Wild Bighorn Sheep

Efficacy of disease control efforts is often contingent on whether the disease persists locally in the host population or is repeatedly introduced from an alternative host species. Local persistence is partially determined by the interaction between host contact structure and disease transmission rates: relatively isolated host groups facilitate pathogen persistence by slowing the rate at which highly transmissible pathogens access new susceptibles; alternatively, isolated host groups impede persistence for pathogens with low transmission rates by limiting the number of available hosts and forcing premature fade-out. Here, we use long-term data from the Hells Canyon region to investigate whether variable host contact patterns are associated with survival outcomes for 46 cohorts of bighorn sheep (Ovis canadensis) lambs subject to recurrent pneumonia outbreaks. We build social contact networks for each lamb cohort, and quantify variation in lamb mortality attributable to populations, years, and groups. We then refine estimates of chronic carriage rates in ewes, and disease-induced mortality rates in lambs, by finding parameters for the disease process that produce lamb morality rates similar to those observed when simulated on the observed host contact networks. Our results suggest that summer lamb hazards are spatially structured at the subpopulation level: 92.5 percent of the variation in lamb hazards during pneumonia outbreak years was attributable to sub-population-level groups, whereas 1.7 percent and 5.6 percent were attributable to year and population, respectively.  Additionally, the posterior distribution generated by our disease transmission model suggests that pneumonia-causing pathogens may persist locally in bighorn sheep populations, even during apparently healthy years

The independent association of renal dysfunction and arrhythmias in critically ill patients

Study objectives: The purpose of this study was to quantify the impact of baseline renal dysfunction on incidence and occurrence of cardiac arrhythmias in the coronary ICU. Background: Renal dysfunction is an established predictor of all-cause mortality in the ICU setting. We set out to evaluate the independent contributory effect of renal dysfunction to arrhythmias and mortality in this population. Design and setting: We analyzed a prospective coronary care unit registry of 12, 648 admissions by 9, 557 patients over 8 years at a single, tertiary center. An admission serum creatinine level was available for 9, 544 patients. Those patients not receiving long-term dialysis were classified into quartiles of corrected creatinine clearance with cutpoints of 46.2 mL/min/72 kg (group 1), 63.1 mL/min/72 kg, and 81.5 mL/min/72 kg. Dialysis patients (n = 527) were considered as a fifth comparison group (group 5). Measurements and results: Baseline characteristics including older age, African-American race, diabetes, hypertension, history of previous coronary disease, and heart failure were incrementally more common with increasing renal dysfunction strata. There were graded, independent increased risks for accelerated idioventricular rhythm (relative risk [RR], 2.43; 95% confidence interval [CI], 1.40 to 4.20; p = 0.002), sustained ventricular tachycardia (RR, 2.07; 95% CI, 1.02 to 4.22; p = 0.04), ventricular fibrillation (RR, 2.42; 95% CI, 1.13 to 5.15; p = 0.02), and complete heart block (RR, 3.64; 95% CI, 1.77 to 7.48; p = 0.0004, group 5 vs group 1). Conclusions: We conclude that baseline renal function is a powerful, independent predictor of cardiac arrhythmias in the coronary ICU population