The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a β-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention.

Influenza A (H6N6) virus isolated from chickens replicate in mice and human lungs without prior adaptation

H6H6 subtype avian influenza virus (AIV) is currently prevalent in wild birds and poultry. Its host range has gradually expanded to the mammals, such as swine. Some strains of H6N6 AIV have even acquired the ability to bind to human-like receptors SA-α2, 6Gal, thus increasing the risk of animal-human transmission. To investigate whether H6N6 AIV can cross interspecies barriers from poultry to mammals and even humans, we assessed the molecular characteristics, receptor-binding preference, replication in mice, and the human lung of three chicken-originated H6N6 strains. Among the three chicken-originated H6N6 strains, A/CK/ZZ/346/2014 (ZZ346) virus with P186T, H156R, S263G mutation of hemagglutinin (HA) showed the ability to bind to avian-like SAα-2,3Gal and human-like SAα-2,6Gal receptors. Moreover, H6N6 viruses, especially the ZZ346 strain, could replicate and infect mice and human lungs. Our study detected the H6N6 virus favorable to bind to both avian-like SAα-2,3Gal and human-like SAα-2,6Gal receptors, verified its ability to cross the species barrier to infect mice, and verified to infect human lungs without prior adaptation. This study emphasizes the importance of continuous and intense monitoring of the evolution of the H6N6 virus in the terrestrial bird.

How the footprint of history shapes the evolution of digital organisms

Gould’s thought experiment of “replaying life’s tape” provides a conceptual framework for experiments that quantify the contributions of adaptation, chance, and history to evolutionary outcomes. For example, we can empirically measure how varying the depth of history in one environment influences subsequent evolution in a new environment. Can this “footprint of history”—the genomic legacy of prior adaptation—grow too deep to overcome? Can it constrain adaptation, even with intense selection in the new environment? We investigated these questions using digital organisms. Specifically, we evolved ten populations from one ancestor under identical conditions. We then replayed evolution from three time points in each population’s history (corresponding to shallow, intermediate, and deep history) in two new environments (one similar and one dissimilar to the prior environment). We measured the contributions of adaptation, chance, and history to the among-lineage variation in fitness and genome length in both new environments. In both environments, variation in genome length depended largely on history and chance, not adaptation, indicating weak selection. By contrast, adaptation, chance, and history all contributed to variation in fitness. Crucially, whether the depth of history affected adaptation depended on the environment. When the ancestral and new environments overlapped, history was as important as adaptation to the fitness achieved in the new environment for the populations with the deepest history. However, when the ancestral and novel environments favored different traits, adaptation overwhelmed even deep history. This experimental design for assessing the influence of the depth of history is promising for both biological and digital systems.

Non-Mouse-Adapted H1N1pdm09 Virus as a Model for Influenza Research

The number of lung-adapted influenza viruses is limited. Most of them are not antigenically related to current circulating viruses. Viruses similar to recent strains are required for screening modern antiviral compounds and studying new vaccine candidates against novel influenza viruses. The process by which an influenza virus adapts to a new host is rather difficult. The aim of this study was to select a non-adapted current virus whose major biological properties correspond to those of classical lab-adapted viruses. Mice were inoculated intranasally with non-lung-adapted influenza viruses of subtype H1N1pdm09. They were monitored closely for body weight loss, mortality outcomes and gross pathology for 14 days following inoculation, as well as viral replication in lung tissue. Lung-adapted PR8 virus was used as a control. The tested viruses multiplied equally well in the lower respiratory tract of mice without prior adaptation but dramatically differed in lethality; the differences in their toxicity and pathogenicity in mice were established. A/South Africa/3626/2013 (H1N1)pdm09 virus was found to be an appropriate candidate to replace PR8 as a model virus for influenza research. No prior adaptation to the animal model is needed to reach the pathogenicity level of the classical mouse-adapted PR8 virus.

Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus

Ebola virus (EBOV) is a zoonotic pathogen that poses a significant threat to public health, causing sporadic yet devastating outbreaks that have the potential to spread worldwide, as demonstrated during the 2013–2016 West African outbreak. Mouse models of infection are important tools for the development of therapeutics and vaccines. Exposure of immunocompetent mice to clinical isolates of EBOV is nonlethal; consequently, EBOV requires prior adaptation in mice to cause lethal disease. Until now, the only immunocompetent EBOV mouse model was based on the Mayinga variant, which was isolated in 1976. Here, we generated a novel mouse-adapted (MA)-EBOV based on the 2014 Makona isolate by inserting EBOV/Mayinga-MA mutations into the EBOV/Makona genome, followed by serial passaging of the rescued virus in suckling mice. The resulting EBOV/Makona-MA causes lethal disease in adult immunocompetent mice within 6 to 9 days and has a lethal dose (LD50) of 0.004 plaque forming units (PFU). Two additional mutations emerged after mouse-adaptation in the viral nucleoprotein (NP) and membrane-associated protein VP24. Using reverse genetics, we found the VP24 mutation to be critical for EBOV/Makona-MA virulence. EBOV/Makona-MA infected mice that presented with viremia, high viral burden in organs, increased release of pro-inflammatory cytokines/chemokines, and lymphopenia. Our mouse model will help advance pre-clinical development of countermeasures against contemporary EBOV variants.

Blur Adaptation and Induction

The image on the retina is always blurred because of optical aberrations of the eye. Yet typically the world does not “look” blurred, and although the acuity of the eye varies dramatically from the center of gaze to the periphery, the outside world generally “feels” focused throughout the visual field. This perception of focus is one of many illusions where the brain appears unaware of its own imperfections. The perceived focus of an image can be strongly biased by prior adaptation to a blurred or sharpened image or by simultaneous contrast from a blurred or sharpened surround. Adaptation to blur can selectively adjust to the patterns of blur introduced by different optical aberrations and may reflect adjustments that help compensate spatial perception for the optical and neural sensitivity limits of the visual system.