Evolutionary Entropy Determines Invasion Success in Emergent Epidemics

Background: Standard epidemiological theory claims that in structured populations competition between multiple pathogen strains is a deterministic process which is mediated by the basic reproduction number (R0) of the individual strains. A new theory based on analysis, simulation and empirical study challenges this predictor of success. Principal Findings: We show that the quantity R0 is a valid predictor in structured populations only when size is infinite. In this article we show that when population size is finite the dynamics of infection by multi-strain pathogens is a stochastic process whose outcome can be predicted by evolutionary entropy, S, an information theoretic measure which describes the uncertainty in the infectious age of an infected parent of a randomly chosen new infective. Evolutionary entropy characterises the demographic stability or robustness of the population of infectives. This statistical parameter determines the duration of infection and thus provides a quantitative index of the pathogenicity of a strain. Standard epidemiological theory based on R0 as a measure of selective advantage is the limit as the population size tends to infinity of the entropic selection theory. The standard model is an approximation to the entropic selection theory whose validity increases with population size. Conclusion: An epidemiological analysis based on entropy is shown to explain empirical observations regarding the emergence of less pathogenic strains of human influenza during the antigenic drift phase. Furthermore, we exploit th

Using Technical Performance Measures

All programs have requirements. For these requirements to be met, there must be a means of measurement. A Technical Performance Measure (TPM) is defined to produce a measured quantity that can be compared to the requirement. In practice, the TPM is often expressed as a maximum or minimum and a goal. Example TPMs for a rocket program are: vacuum or sea level specific impulse (lsp), weight, reliability (often expressed as a failure rate), schedule, operability (turn-around time), design and development cost, production cost, and operating cost. Program status is evaluated by comparing the TPMs against specified values of the requirements. During the program many design decisions are made and most of them affect some or all of the TPMs. Often, the same design decision changes some TPMs favorably while affecting other TPMs unfavorably. The problem then becomes how to compare the effects of a design decision on different TPMs. How much failure rate is one second of specific impulse worth? How many days of schedule is one pound of weight worth? In other words, how to compare dissimilar quantities in order to trade and manage the TPMs to meet all requirements. One method that has been used successfully and has a mathematical basis is Utility Analysis. Utility Analysis enables quantitative comparison among dissimilar attributes. It uses a mathematical model that maps decision maker preferences over the tradeable range of each attribute. It is capable of modeling both independent and dependent attributes. Utility Analysis is well supported in the literature on Decision Theory. It has been used at Pratt & Whitney Rocketdyne for internal programs and for contracted work such as the J-2X rocket engine program. This paper describes the construction of TPMs and describes Utility Analysis. It then discusses the use of TPMs in design trades and to manage margin during a program using Utility Analysis

Direct Autocrine Action of Insulin on β-Cells: Does It Make Physiological Sense?

In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1–3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for β-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled

The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion.

Glucose-stimulated insulin secretion (GSIS) is mediated in part by glucose metabolism-driven increases in ATP/ADP ratio, but by-products of mitochondrial glucose metabolism also play an important role. Here we investigate the role of the mitochondrial citrate/isocitrate carrier (CIC) in regulation of GSIS. Inhibition of CIC activity in INS-1-derived 832/13 cells or primary rat islets by the substrate analogue 1,2,3-benzenetricarboxylate (BTC) resulted in potent inhibition of GSIS, involving both first and second phase secretion. A recombinant adenovirus containing a CIC-specific siRNA (Ad-siCIC) dose-dependently reduced CIC expression in 832/13 cells and caused parallel inhibitory effects on citrate accumulation in the cytosol. Ad-siCIC treatment did not affect glucose utilization, glucose oxidation, or ATP/ADP ratio but did inhibit glucose incorporation into fatty acids and glucose-induced increases in NADPH/NADP+ ratio relative to cells treated with a control siRNA virus (Ad-siControl). Ad-siCIC also inhibited GSIS in 832/13 cells, whereas overexpression of CIC enhanced GSIS and raised cytosolic citrate levels. In normal rat islets, Ad-siCIC treatment also suppressed CIC mRNA levels and inhibited GSIS. We conclude that export of citrate and/or isocitrate from the mitochondria to the cytosol is an important step in control of GSIS

Habitat diversity and structure regulate British bird richness: implications of non-linear relationships for conservation

Spatial environmental heterogeneity (EH) is an important factor determining species richness among many taxa across spatial scales. Increased EH may support higher diversity mainly by providing a higher number of ecological niches. However, the shapes of the EH-diversity relationships and their influence on diversity measures at landscape scales are poorly understood. We used random forests regression models to assess the relationships between different components of EH and bird species richness across Great Britain. Bird data were obtained using BTO/JNCC/RSPB Breeding Bird Survey methods across 335 UK Countryside Survey (CS) 1-km squares in 2000. Data on components of EH, including; vegetation, habitat diversity, and habitat structure were collected in associated field surveys. Using the results of our EH component-bird richness models, we applied the case of the likely decline of the ash tree, a species of conservation concern and a key component of British landscape complexity, to create predictive scenarios of future bird richness. We found that EH components had a strong positive effect on bird richness and identified six key components that explained over 70% of variance in bird richness. Bird richness responses were strongly dependent on the specific EH components and were generally non-linear, especially for habitat structural variables, such as lines of trees and hedges. Our predictive scenarios showed a decrease in bird species richness only for simulated ash tree decreases within the habitat structural variables of over 90%, and only for areas where this tree species was a particularly abundant component of the landscape. Our findings, showing that bird richness responses differ for EH components, and that non-linear responses are common, could help the ‘design’ of landscapes that enhance bird diversity. In particular, our study indicates that, in some cases, increasing the occurrence of key structural components of habitat (such as ensuring a minimum of 700 m of managed hedges or a minimum of 70 individual trees per km square), could have disproportionally positive impacts on bird richness

Severely Photosensitive Psoriasis: A Phenotypically Defined Patient Subset

A subset of patients with chronic plaque psoriasis exhibits severely photosensitive psoriasis (PP) with a pronounced seasonal pattern, but the pathomechanism is not understood. We performed two related studies; first, a detailed clinical characterization of PP, and second, a controlled investigation exploring the underlying pathomechanisms through the assessment of disease onset after photoprovocation. Patients with PP (n=20) showed striking female predominance (19F:1M), very low mean age of psoriasis onset (11 years, range 2–24), family history of psoriasis (13/20), a strong HLA–Cw*0602 association (16/17), and a rapid abnormal clinical response to broadband UVA, comprising erythema±scaling plaques (17/20). Subsequently, patients with PP (n=10), non-PP (n=9), and healthy volunteers (n=11) were challenged with low-dose broadband UVA on 3 consecutive days, and serial biopsies were taken after 6hours to 7 days and from unchallenged skin. Histological changes consistent with early psoriasis occurred in 4 of 10 PP patients, but in neither of the control groups, with significant dermal infiltration by neutrophils, CD4+, CD8+, and CD45RO+ cells at 24h, accompanied by acanthosis. Thus, a phenotypically distinct subset of psoriasis has been characterized. In contrast with earlier assumptions, UV can provoke psoriasiform features rapidly de novo; a role for memory effector T cells is supported in the early phase

Expansion of the Knockdown Resistance Frequency Map for Human Head Lice (Phthiraptera: Pediculidae) in the United States Using Quantitative Sequencing

Pediculosis is a prevalent parasitic infestation of humans, which is increasing due, in part, to the selection of lice resistant to either the pyrethrins or pyrethroid insecticides by the knockdown resistance (kdr) mechanism. To determine the extent and magnitude of thekdr-type mutations responsible for this resistance, lice were collected from 138 collection sites in 48 U.S. states from 22 July 2013 to 11 May 2015 and analyzed by quantitative sequencing. Previously published data were used for comparisons of the changes in the frequency of thekdr-type mutations over time. Mean percent resistance allele frequency (mean % RAF) values across the three mutation loci were determined from each collection site. The overall mean % RAF (+/-SD) for all analyzed lice was 98.3 +/- 10%. 132/138 sites (95.6%) had a mean % RAF of 100%, five sites (3.7%) had intermediate values, and only a single site had no mutations (0.0%). Forty-two states (88%) had a mean % RAF of 100%. The frequencies ofkdr-type mutations did not differ regardless of the human population size that the lice were collected from, indicating a uniformly high level of resistant alleles. The loss of efficacy of the Nix formulation (Prestige Brand, Tarrytown, NY) from 1998 to 2013 was correlated to the increase inkdr-type mutations. These data provide a plausible reason for the decrease in the effectiveness of permethrin in the Nix formulation, which is the parallel increase ofkdr-type mutations in lice over time

Mycobacterial infections in striped bass (Morone saxatilis) from Delaware Bay

Much of what is known of mycobacteriosis in wild striped bass from the mid-Atlantic region of the United States is based on our observations from Chesapeake Bay and its tributaries, where high infection prevalence and lesioned fish are frequently observed. Comparatively, the occurrence and severity of mycobacteriosis in striped bass from watersheds adjacent to Chesapeake Bay are relatively unknown. This study represents the first report on mycobacterial infection in striped bass harvested from two sites in Delaware Bay.https://scholarworks.wm.edu/vimsbooks/1082/thumbnail.jp