Mutagenesis by microbe: The role of the microbiota in shaping the cancer genome

Cancers arise through the process of somatic evolution fueled by the inception of somatic mutations. We lack a complete understanding of the sources of these somatic mutations. Humans host a vast repertoire of microbes collectively known as the microbiota. The microbiota plays a role in altering the tumor microenvironment and proliferation. In addition, microbes have been shown to elicit DNA damage which provides the driver for somatic mutations. An understanding of microbiota-driven mutational mechanisms would contribute to a more complete understanding of the origins of the cancer genome. Here, we review the modes by which microbes stimulate DNA damage and the effect of these phenomena upon the cancer genomic architecture, specifically in the form of mutational spectra and mutational signatures

National Forest Timber Management Over the Past Decade

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75177/1/j.1541-0072.1995.tb01742.x.pd

The signature of fine scale local adaptation in Atlantic salmon revealed from common garden experiments in nature

Understanding the extent, scale and genetic basis of local adaptation (LA) is important for conservation and management. Its relevance in salmonids at microgeographic scales, where dispersal (and hence potential gene flow) can be substantial, has however been questioned. Here, we compare the fitness of communally reared offspring of local and foreign Atlantic salmon Salmo salar from adjacent Irish rivers and reciprocal F-1 hybrid crosses between them, in the wild home' environment of the local population. Experimental groups did not differ in wild smolt output but a catastrophic flood event may have limited our ability to detect freshwater performance differences, which were evident in a previous study. Foreign parr exhibited higher, and hybrids intermediate, emigration rates from the natal stream relative to local parr, consistent with genetically based behavioural differences. Adult return rates were lower for the foreign compared to the local group. Overall lifetime success of foreigners and hybrids relative to locals was estimated at 31% and 40% (mean of both hybrid groups), respectively. The results imply a genetic basis to fitness differences among populations separated by only 50km, driven largely by variation in smolt to adult return rates. Hence even if supplementary stocking programs obtain broodstock from neighbouring rivers, the risk of extrinsic outbreeding depression may be high

BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis

BACKGROUND BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal/ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. METHODS 2636 participants' data across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinico-pathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were two-sided. RESULTS 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, HR = 1.01, 95% CI = 0.87-1.16, P=0.98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87-1.18, P=0.96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2 intact (BRCA1/2 wild type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific PCR and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66-0.97, P=0.02; OS: HR = 0.80, 95% CI = 0.63-1.00, P=0.05) on mixed-effects modelling. CONCLUSION BRCA1-methylated OC displays similar clinico-pathological features to BRCA1-mutated OC, but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes

Ants in a Labyrinth: A Statistical Mechanics Approach to the Division of Labour

Division of labour (DoL) is a fundamental organisational principle in human societies, within virtual and robotic swarms and at all levels of biological organisation. DoL reaches a pinnacle in the insect societies where the most widely used model is based on variation in response thresholds among individuals, and the assumption that individuals and stimuli are well-mixed. Here, we present a spatially explicit model of DoL. Our model is inspired by Pierre de Gennes' 'Ant in a Labyrinth' which laid the foundations of an entire new field in statistical mechanics. We demonstrate the emergence, even in a simplified one-dimensional model, of a spatial patterning of individuals and a right-skewed activity distribution, both of which are characteristics of division of labour in animal societies. We then show using a two-dimensional model that the work done by an individual within an activity bout is a sigmoidal function of its response threshold. Furthermore, there is an inverse relationship between the overall stimulus level and the skewness of the activity distribution. Therefore, the difference in the amount of work done by two individuals with different thresholds increases as the overall stimulus level decreases. Indeed, spatial fluctuations of task stimuli are minimised at these low stimulus levels. Hence, the more unequally labour is divided amongst individuals, the greater the ability of the colony to maintain homeostasis. Finally, we show that the non-random spatial distribution of individuals within biological and social systems could be caused by indirect (stigmergic) interactions, rather than direct agent-to-agent interactions. Our model links the principle of DoL with principles in the statistical mechanics and provides testable hypotheses for future experiments

Task-Specific Codes for Face Recognition: How they Shape the Neural Representation of Features for Detection and Individuation

The variety of ways in which faces are categorized makes face recognition challenging for both synthetic and biological vision systems. Here we focus on two face processing tasks, detection and individuation, and explore whether differences in task demands lead to differences both in the features most effective for automatic recognition and in the featural codes recruited by neural processing.Our study appeals to a computational framework characterizing the features representing object categories as sets of overlapping image fragments. Within this framework, we assess the extent to which task-relevant information differs across image fragments. Based on objective differences we find among task-specific representations, we test the sensitivity of the human visual system to these different face descriptions independently of one another. Both behavior and functional magnetic resonance imaging reveal effects elicited by objective task-specific levels of information. Behaviorally, recognition performance with image fragments improves with increasing task-specific information carried by different face fragments. Neurally, this sensitivity to the two tasks manifests as differential localization of neural responses across the ventral visual pathway. Fragments diagnostic for detection evoke larger neural responses than non-diagnostic ones in the right posterior fusiform gyrus and bilaterally in the inferior occipital gyrus. In contrast, fragments diagnostic for individuation evoke larger responses than non-diagnostic ones in the anterior inferior temporal gyrus. Finally, for individuation only, pattern analysis reveals sensitivity to task-specific information within the right "fusiform face area".OUR RESULTS DEMONSTRATE: 1) information diagnostic for face detection and individuation is roughly separable; 2) the human visual system is independently sensitive to both types of information; 3) neural responses differ according to the type of task-relevant information considered. More generally, these findings provide evidence for the computational utility and the neural validity of fragment-based visual representation and recognition

Real-Time High Resolution 3D Imaging of the Lyme Disease Spirochete Adhering to and Escaping from the Vasculature of a Living Host

Pathogenic spirochetes are bacteria that cause a number of emerging and re-emerging diseases worldwide, including syphilis, leptospirosis, relapsing fever, and Lyme borreliosis. They navigate efficiently through dense extracellular matrix and cross the blood–brain barrier by unknown mechanisms. Due to their slender morphology, spirochetes are difficult to visualize by standard light microscopy, impeding studies of their behavior in situ. We engineered a fluorescent infectious strain of Borrelia burgdorferi, the Lyme disease pathogen, which expressed green fluorescent protein (GFP). Real-time 3D and 4D quantitative analysis of fluorescent spirochete dissemination from the microvasculature of living mice at high resolution revealed that dissemination was a multi-stage process that included transient tethering-type associations, short-term dragging interactions, and stationary adhesion. Stationary adhesions and extravasating spirochetes were most commonly observed at endothelial junctions, and translational motility of spirochetes appeared to play an integral role in transendothelial migration. To our knowledge, this is the first report of high resolution 3D and 4D visualization of dissemination of a bacterial pathogen in a living mammalian host, and provides the first direct insight into spirochete dissemination in vivo

Fructooligosacharides Reduce Pseudomonas aeruginosa PAO1 Pathogenicity through Distinct Mechanisms

Pseudomonas aeruginosa is ubiquitously present in the environment and acts as an opportunistic pathogen on humans, animals and plants. We report here the effects of the prebiotic polysaccharide inulin and its hydrolysed form FOS on this bacterium. FOS was found to inhibit bacterial growth of strain PAO1, while inulin did not affect growth rate or yield in a significant manner. Inulin stimulated biofilm formation, whereas a dramatic reduction of the biofilm formation was observed in the presence of FOS. Similar opposing effects were observed for bacterial motility, where FOS inhibited the swarming and twitching behaviour whereas inulin caused its stimulation. In co-cultures with eukaryotic cells (macrophages) FOS and, to a lesser extent, inulin reduced the secretion of the inflammatory cytokines IL-6, IL-10 and TNF- a . Western blot experiments indicated that the effects mediated by FOS in macrophages are associated with a decreased activation of the NF- k B pathway. Since FOS and inulin stimulate pathway activation in the absence of bacteria, the FOS mediated effect is likely to be of indirect nature, such as via a reduction of bacterial virulence. Further, this modulatory effect is observed also with the highly virulent ptxS mutated strain. Co-culture experiments of P. aeruginosa with IEC18 eukaryotic cells showed that FOS reduces the concentration of the major virulence factor, exotoxin A, suggesting that this is a possible mechanism for the reduction of pathogenicity. The potential of these compounds as components of antibacterial and anti-inflammatory cocktails is discussed.The authors acknowledge financial support from FEDER funds and Fondo Social Europeo through grants from the Spanish Ministry of Economy and Competitiveness (grants SAF2011-22922, SAF2011-22812) the Andalusian regional government Junta de Andalucía (grant CVI-7335) and the Centre of Networked Biomedical Research on Hepatic and Digestive Diseases (CIBERehd) which is funded by the Carlos III Health Institute and the Ramón Areces Foundation, Spain