Noise driven evolutionary waves

Adaptation in spatially extended populations entails the propagation of evolutionary novelties across habitat ranges. Driven by natural selection, beneficial mutations sweep through the population in a "wave of advance". The standard model for these traveling waves, due to R. Fisher and A. Kolmogorov, plays an important role in many scientific areas besides evolution, such as ecology, epidemiology, chemical kinetics, and recently even in particle physics. Here, we extend the Fisher-Kolmogorov model to account for mutations that confer an increase in the density of the population, for instance as a result of an improved metabolic efficiency. We show that these mutations invade by the action of random genetic drift, even if the mutations are slightly deleterious. The ensuing class of noise-driven waves are characterized by a wave speed that decreases with increasing population sizes, contrary to conventional Fisher-Kolmogorov waves. When a trade-off exists between density and growth rate, an evolutionary optimal population density can be predicted. Our simulations and analytical results show that genetic drift in conjunction with spatial structure promotes the economical use of limited resources. The simplicity of our model, which lacks any complex interactions between individuals, suggests that noise-induced pattern formation may arise in many complex biological systems including evolution.     

Mechanisms behind the portion size effect: visibility and bite size

Increases in portion size lead to increases in energy intake, yet the mechanisms behind this "portion size effect" are unclear. This study tested possible mechanisms of the portion size effect, i.e., bite size and visual cues. A 2 × 2 repeated measures, within-subject design was used to test the effects of portion size (410 g vs. 820 g of a pasta dish) and visual cues (blindfolded vs. visible) on energy intake in 30 individuals (15 men, 15 women). At each meal participants were exposed to one of four experimental conditions (small portion/visible; small portion/blindfold; large portion/visible; large portion/blindfold). Participant characteristics, food intake, number of bites, meal duration, palatability measures and hunger and fullness were assessed. In response to a doubling of the portion presented, entrée energy intake increased 26% (220 kcal; P < 0.001) and mean bite size increased 2.4 g/bite (P < 0.05). Overweight (OW) individuals consumed 40% (334 kcal) more of the entrée in response to the large portion condition (P < 0.05), while lean individuals' intakes did not differ (P < 0.56). A 12% (122 kcal) decrease in entrée intake was observed in the blindfolded condition (P < 0.01), but no portion by visual cue interaction was found; indicating that blindfolding did not significantly attenuate the portion size effect. These data suggest that the portion size effect is not impacted by removing the visual cue of food and that this effect occurs via changes in bite size in adults.     

The leukemia-specific fusion gene ETV6/RUNX1 perturbs distinct key biological functions primarily by gene repression

Background

ETV6/RUNX1 (E/R) (also known as TEL/AML1) is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL) and also most likely the crucial factor for disease initiation; its role in leukemia propagation and maintenance, however, remains largely elusive. To address this issue we performed a shRNA-mediated knock-down (KD) of the E/R fusion gene and investigated the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions in two E/R-positive leukemic cell lines.

Findings

Microarray analyses identified 777 genes whose expression was substantially altered. Although approximately equal proportions were either up- (KD-UP) or down-regulated (KD-DOWN), the effects on biological processes and pathways differed considerably. The E/R KD-UP set was significantly enriched for genes included in the “cell activation”, “immune response”, “apoptosis”, “signal transduction” and “development and differentiation” categories, whereas in the E/R KD-DOWN set only the “PI3K/AKT/mTOR signaling” and “hematopoietic stem cells” categories became evident. Comparable expression signatures obtained from primary E/R-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories “stem cell properties”, “B-cell differentiation”, “immune response”, “cell adhesion” and “DNA damage” with RT-qPCR.

Conclusion

Our analyses provide the first preliminary evidence that the continuous expression of the E/R fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets.     

8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.     

Communicable diseases prioritized for surveillance and epidemiological research: results of a standardized prioritization procedure in Germany, 2011

Introduction

To establish strategic priorities for the German national public health institute (RKI) and guide the institute''s mid-term strategic decisions, we prioritized infectious pathogens in accordance with their importance for national surveillance and epidemiological research.

Methods

We used the Delphi process with internal (RKI) and external experts and a metric-consensus approach to score pathogens according to ten three-tiered criteria. Additional experts were invited to weight each criterion, leading to the calculation of a median weight by which each score was multiplied. We ranked the pathogens according to the total weighted score and divided them into four priority groups.

Results

127 pathogens were scored. Eighty-six experts participated in the weighting; “Case fatality rate” was rated as the most important criterion. Twenty-six pathogens were ranked in the highest priority group; among those were pathogens with internationally recognised importance (e.g., Human Immunodeficiency Virus, Mycobacterium tuberculosis, Influenza virus, Hepatitis C virus, Neisseria meningitides), pathogens frequently causing large outbreaks (e.g., Campylobacter spp.), and nosocomial pathogens associated with antimicrobial resistance. Other pathogens in the highest priority group included Helicobacter pylori, Respiratory Syncytial Virus, Varicella zoster virus and Hantavirus.

Discussion

While several pathogens from the highest priority group already have a high profile in national and international health policy documents, high scores for other pathogens (e.g., Helicobacter pylori, Respiratory syncytial virus or Hantavirus) indicate a possible under-recognised importance within the current German public health framework. A process to strengthen respective surveillance systems and research has been started. The prioritization methodology has worked well; its modular structure makes it potentially useful for other settings.     

Maize and the Origin of Highland Chavín Civilization: An Isotopic Perspective

Scholars frequently posit maize as the staple food of Chavín civilization and some even argue that this crop provided the critical stimulus for its development. Stable carbon isotope analysis permits an evaluation of these hypotheses because maize, the only C₄ cultigen consumed in pre-Hispanic Peru, leaves an unambiguous imprint on the bone chemistry of its consumers that allows the calculation of its relative importance in the diet. Analysis of osteological samples from Chavín de Huántar and Huaricoto indicates that although maize was eaten, C₃ foods like potatoes and quinoa constituted the bulk of the dietary intake during the development and climax of highland Chavín civilization (ca. 850-200 B.C.). The authors briefly explore possible reasons for the secondary importance of maize in the Initial Period/Early Horizon subsistence systems of this region, a pattern already established by the late Preceramic period (ca. 2000 B.C.).