Within-host demographic fluctuations and correlations in early retroviral infection.

In this paper we analyze the demographic fluctuations and correlations present in within-host populations of viruses and their target cells during the early stages of infection. In particular, we present an exact treatment of a discrete-population, stochastic, continuous-time master equation description of HIV or similar retroviral infection dynamics, employing Monte Carlo simulations. The results of calculations employing Gillespie's direct method clearly demonstrate the importance of considering the microscopic details of the interactions which constitute the macroscopic dynamics. We then employ the τ-leaping approach to study the statistical characteristics of infections involving realistic absolute numbers of within-host viral and cellular populations, before going on to investigate the effect that initial viral population size plays on these characteristics. Our main conclusion is that cross-correlations between infected cell and virion populations alter dramatically over the course of the infection. We suggest that these statistical correlations offer a novel and robust signature for the acute phase of retroviral infection.

Epidemic dynamics revealed in dengue evolution.

Dengue is an emerging tropical disease infecting tens of millions of people annually. A febrile illness with potentially severe hemorrhagic manifestations, dengue is caused by mosquito-borne viruses (DENV-1 to -4) that are maintained in endemic transmission in large urban centers of the tropics with periodic epidemic cycles at 3- to 5-year intervals. Puerto Rico (PR), a major population center in the Caribbean, has experienced increasingly severe epidemics since multiple dengue serotypes were introduced beginning in the late 1970s. We document the phylodynamics of DENV-4 between 1981 and 1998, a period of dramatic ecological expansion during which evolutionary change also occurs. The timescale of viral evolution is sufficiently short that viral transmission dynamics can be elucidated from genetic diversity data. Specifically, by combining virus sequence data with confirmed case counts in PR over these two decades, we show that the pattern of cyclic epidemics is strongly correlated with coalescent estimates of effective population size that have been estimated from sampled virus sequences using Bayesian Markov Chain Monte Carlo methods. Thus, we show that the observed epidemiologic dynamics are correlated with similar fluctuations in diversity, including severe interepidemic reductions in genetic diversity compatible with population bottlenecks that may greatly impact DENV evolutionary dynamics. Mean effective population sizes based on genetic data appear to increase prior to isolation counts, suggesting a potential bias in the latter and justifying more active surveillance of DENV activity. Our analysis explicitly integrates epidemiologic and sequence data in a joint model that could be used to further explore transmission models of infectious disease.

Language phylogenies reveal expansion pulses and pauses in Pacific settlement.

Debates about human prehistory often center on the role that population expansions play in shaping biological and cultural diversity. Hypotheses on the origin of the Austronesian settlers of the Pacific are divided between a recent "pulse-pause" expansion from Taiwan and an older "slow-boat" diffusion from Wallacea. We used lexical data and Bayesian phylogenetic methods to construct a phylogeny of 400 languages. In agreement with the pulse-pause scenario, the language trees place the Austronesian origin in Taiwan approximately 5230 years ago and reveal a series of settlement pauses and expansion pulses linked to technological and social innovations. These results are robust to assumptions about the rooting and calibration of the trees and demonstrate the combined power of linguistic scholarship, database technologies, and computational phylogenetic methods for resolving questions about human prehistory.

The evolutionary genetics of viral emergence.

Despite the wealth of data describing the ecological factors that underpin viral emergence, little is known about the evolutionary processes that allow viruses to jump species barriers and establish productive infections in new hosts. Understanding the evolutionary basis to virus emergence is therefore a key research goal and many of the debates in this area can be considered within the rigorous theoretical framework established by evolutionary genetics. In particular, the respective roles played by natural selection and genetic drift in shaping genetic diversity are also of fundamental importance for understanding the nature of viral emergence. Herein, we discuss whether there are evolutionary rules to viral emergence, and especially whether certain types of virus, or those that infect a particular type of host species, are more likely to emerge than others. We stress the complex interplay between rates of viral evolution and the ability to recognize cell receptors from phylogenetically divergent host species. We also emphasize the current lack of convincing data as to whether viral emergence requires adaptation to the new host species during the early stages of infection, or whether it is largely a chance process involving the transmission of a viral strain with the necessary genetic characteristics.

Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low-frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation.

Bayesian coalescent inference of past population dynamics from molecular sequences.

We introduce the Bayesian skyline plot, a new method for estimating past population dynamics through time from a sample of molecular sequences without dependence on a prespecified parametric model of demographic history. We describe a Markov chain Monte Carlo sampling procedure that efficiently samples a variant of the generalized skyline plot, given sequence data, and combines these plots to generate a posterior distribution of effective population size through time. We apply the Bayesian skyline plot to simulated data sets and show that it correctly reconstructs demographic history under canonical scenarios. Finally, we compare the Bayesian skyline plot model to previous coalescent approaches by analyzing two real data sets (hepatitis C virus in Egypt and mitochondrial DNA of Beringian bison) that have been previously investigated using alternative coalescent methods. In the bison analysis, we detect a severe but previously unrecognized bottleneck, estimated to have occurred 10,000 radiocarbon years ago, which coincides with both the earliest undisputed record of large numbers of humans in Alaska and the megafaunal extinctions in North America at the beginning of the Holocene.

The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescent approach.

Hepatitis C virus (HCV) is a leading cause of liver cancer and cirrhosis, and Egypt has possibly the highest HCV prevalence worldwide. In this article we use a newly developed Bayesian inference framework to estimate the transmission dynamics of HCV in Egypt from sampled viral gene sequences, and to predict the public health impact of the virus. Our results indicate that the effective number of HCV infections in Egypt underwent rapid exponential growth between 1930 and 1955. The timing and speed of this spread provides quantitative genetic evidence that the Egyptian HCV epidemic was initiated and propagated by extensive antischistosomiasis injection campaigns. Although our results show that HCV transmission has since decreased, we conclude that HCV is likely to remain prevalent in Egypt for several decades. Our combined population genetic and epidemiological analysis provides detailed estimates of historical changes in Egyptian HCV prevalence. Because our results are consistent with a demographic scenario specified a priori, they also provide an objective test of inference methods based on the coalescent process.

Rates of evolution in ancient DNA from Adélie penguins.

Well-preserved subfossil bones of Adélie penguins, Pygoscelis adeliae, underlie existing and abandoned nesting colonies in Antarctica. These bones, dating back to more than 7000 years before the present, harbor some of the best-preserved ancient DNA yet discovered. From 96 radiocarbon-aged bones, we report large numbers of mitochondrial haplotypes, some of which appear to be extinct, given the 380 living birds sampled. We demonstrate DNA sequence evolution through time and estimate the rate of evolution of the hypervariable region I using a Markov chain Monte Carlo integration and a least-squares regression analysis. Our calculated rates of evolution are approximately two to seven times higher than previous indirect phylogenetic estimates.

A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome.

A simple multiple system organ failure (MSOF) score may predict mortality of patients who have sepsis syndrome. Using an MSOF scoring system, we prospectively determined the presence or absence of respiratory, cardiovascular, renal, hepatic, gastrointestinal, hematologic, and neurologic organ failure on day 1 of sepsis syndrome in 154 consecutive patients who had sepsis syndrome in the ICU of a tertiary care, teaching hospital. We used 30-day hospital mortality as the primary outcome variable. Overall 30-day mortality was 34 percent. There was a strong linear association between number of organ system failures and 30-day mortality (p < 0.0001). Mortality was 20 percent in patients who had less than 3 organ system failures (n = 111) and 70 percent in patients who had 3 or more organ system failures (n = 43). Survival was assessed using the Cox proportional hazards model and was found to be significantly different (p < 0.01) between the two groups defined by the aforementioned dichotomy after adjustment for age and sex using time to death as the primary outcome. The increase in relative risk of death associated with 3 or more organ system failures was 2.77 (95 percent confidence interval, 2.74 to 2.83). Using logistic regression, the adjusted odds ratios (OR) for covariates most predictive of mortality were hematologic (OR = 6.2), neurologic (OR = 4.4), hepatic (OR = 3.4), cardiovascular (OR = 2.6), and age (1.05 per year). The logistic model using the seven organ system failures and age as covariates accurately predicted outcome 75 percent of the time with a sensitivity of 51 percent and specificity of 87 percent. In conclusion, a simple scoring system tabulating the number of organ system failures present on day 1 of sepsis syndrome predicts the mortality of patients who have sepsis syndrome with reasonable accuracy.

Nimbus-6 earth radiation budget experiment.

This paper describes the Nimbus-6 earth radiation budget experiment including its prelaunch calibration and in-flight performance. A preliminary assessment of the data shows the ERB measurement of the solar constant to be 1392 W/m(2) which is 1.6% higher than the expected value of 1370 W/m(2). Both values are traceable to the cavity radiometer scale. There is a disagreement between the fixed wide-angle and scanning narrow-angle measurements of planetary outgoing longwave radiation flux. Since the scanning channels are calibrated in-flight and show good agreement with previous observations of the Nimbus-3 satellite, the discrepancy is believed to be due to erroneous wide-angle flux estimates. The erroneous estimates may be caused by the misinterpretation of the transfer function for the wide-angle-earth-flux sensing thermopile detectors when viewing the earth which, unlike the prelaunch calibration source, does not fill the field of view of the detector and is not an isotropic radiation source. A field of view factor for the wide-angle channels is determined using an in-flight calibration procedure using the night-time scanning channel longwave radiation flux measurements as the absolute standard. The planetary global albedoes, longwave radiation fluxes, and net radiation are about 30%, 240 W/m(2), and -4 W/m(2) for the months of July and August 1975, which is in good agreement with previous Nimbus-3 estimates.

Some Measurements of the Attenuation of Solar Radiation During BOMEX.

Measurements of the upward and downward flux of solar radiation in two broad wavelength bands defined by glass filters were made at height between about 300 m and 12,000 m in the neighborhood of Barbados during the BOMEX experiment in the summer of 1969. These were examined on selected occasions, apparently cloudless, to determine the attenuation-absorption and upward scattering-that could not be attributed to atmospheric gases and must be considered to be caused by particles. Total particle absorption between the lowest and highest flight levels was found to be of order 5%, and upward scatter of order 1% of the incident radiation. Unexplained attenuation above the highest level was of order 2%. The attenuation attributed to particles was of approximately the same magnitude as the geometrical cross section deduced by direct particle sampling on the same flights. Unexplained attenuation above the highest flight level was not found in a series of similar flights in northern temperate latitudes. It is attributed to cirrus cloud in the high tropical troposphere not otherwise observed.

Derivation of the photometric flux of daylight from filtered measurements of global (sun and sky) radiant energy.

The study reported on here is a continuation of an earlier investigation by the same authors into the relationship between natural illumination and shortwave solar radiation. Whereas the initial approach treated the illumination of sunlight as derived from the corresponding filtered direct radiation component, the results now given extend this work to parallel determination of the (more generally applicable) illumination of integral daylight on the basis of similarly filtered global (sun and sky) radiation. Characteristics are outlined of the instrumentation employed in the investigation undertaken at different locations, viz., Newport, Jerusalem (Israel), and Mauna Loa (Hawaii), as compared with the basic work that utilized data assembled at Pretoria (South Africa). Included is an extension to recent solar radiation measurements obtained on high-altitude aircraft. In general, it is established that it is possible to derive such estimates of natural illumination from radiometric measurements with an accuracy comparable with that obtainable in the best direct photometric efforts.

Solar constant: first direct measurements.

The solar constant was directly measured from an altitude of about 82 kilometers-apparently the first such determination. The total solar intensity was 136.1 milliwatts per square centimeter, or 1.952 calories per square centimeter, per minute-about 2.5 percent less than Johnson's derived value. Energy in the ultraviolet and visible regions (for lambda less than 607 nanometers) was 7.0 percent less than that obtained by integration over Johnson'Scurve; for integral flux of lambda greater than 607 nanometers there was almost perfect agreement. Seven supporting series of measurements from lower altitudes agreed extremely well with these results after correction for atmospheric extinction.