Modeling the evolution space of breakage fusion bridge cycles with a stochastic folding process

Breakage-Fusion-Bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then 'unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. The process has parallels with paper folding sequences that arise when a piece of paper is folded several times and then unfolded. Here we adapt such methods to study the breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are 2^(n(n-1)/2) qualitatively distinct evolutions involving n breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the fold positions, to determine evolution likelihoods, and also describe how amplicons become localised. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples

Consistent histories of systems and measurements in spacetime

Traditional interpretations of quantum theory in terms of wave function collapse are particularly unappealing when considering the universe as a whole, where there is no clean separation between classical observer and quantum system and where the description is inherently relativistic. As an alternative, the consistent histories approach provides an attractive "no collapse" interpretation of quantum physics. Consistent histories can also be linked to path-integral formulations that may be readily generalized to the relativistic case. A previous paper described how, in such a relativistic spacetime path formalism, the quantum history of the universe could be considered to be an eignestate of the measurements made within it. However, two important topics were not addressed in detail there: a model of measurement processes in the context of quantum histories in spacetime and a justification for why the probabilities for each possible cosmological eigenstate should follow Born's rule. The present paper addresses these topics by showing how Zurek's concepts of einselection and envariance can be applied in the context of relativistic spacetime and quantum histories. The result is a model of systems and subsystems within the universe and their interaction with each other and their environment.Comment: RevTeX 4; 37 pages; v2 is a revision in response to reviewer comments, connecting the discussion in the paper more closely to consistent history concepts; v3 has minor editorial corrections; accepted for publication in Foundations of Physics; v4 has a couple minor typographical correction

Learning to Eat Vegetables in Early Life: The Role of Timing, Age and Individual Eating Traits

Vegetable intake is generally low among children, who appear to be especially fussy during the pre-school years. Repeated exposure is known to enhance intake of a novel vegetable in early life but individual differences in response to familiarisation have emerged from recent studies. In order to understand the factors which predict different responses to repeated exposure, data from the same experiment conducted in three groups of children from three countries (n = 332) aged 4–38 m (18.9±9.9 m) were combined and modelled. During the intervention period each child was given between 5 and 10 exposures to a novel vegetable (artichoke puree) in one of three versions (basic, sweet or added energy). Intake of basic artichoke puree was measured both before and after the exposure period. Overall, younger children consumed more artichoke than older children. Four distinct patterns of eating behaviour during the exposure period were defined. Most children were “learners” (40%) who increased intake over time. 21% consumed more than 75% of what was offered each time and were labelled “plate-clearers”. 16% were considered “non-eaters” eating less than 10 g by the 5th exposure and the remainder were classified as “others” (23%) since their pattern was highly variable. Age was a significant predictor of eating pattern, with older pre-school children more likely to be non-eaters. Plate-clearers had higher enjoyment of food and lower satiety responsiveness than non-eaters who scored highest on food fussiness. Children in the added energy condition showed the smallest change in intake over time, compared to those in the basic or sweetened artichoke condition. Clearly whilst repeated exposure familiarises children with a novel food, alternative strategies that focus on encouraging initial tastes of the target food might be needed for the fussier and older pre-school children

Proapoptotic genes BAX and CD40L are predictors of survival in transitional cell carcinoma of the bladder

The purpose of the study was to investigate the effects of expression of a range of genes involved in apoptosis on outcome in bladder cancer. Immunohistochemistry was used to examine expression of BCL2, BAX, P53, CD40 and CD40L in archival tissues of patients included in various treatment trials for transitional cell carcinoma (TCC) of the bladder. Data were collected on 94 patients who first presented with either invasive or superficial bladder cancer. Median follow-up for alive patients was 83 months (m) (range 12-195 m). Median survival was 80 m (95% CI=56-128 m). Median survivals for the various markers were as follows: BAX-positive patients 110 m vs BAX-negative patients 18 m (P=0.0002); CD40L-positive patients 95 m vs CD40L-negative patients 45 m (P=0.04); BCL2-positive patients 44 m and BCL2-negative patients 74 m, (P=0.64); CD40-positive patients 110 m and CD40 negative patients 45 m (P=0.12); and P53 positive patients 80 m and P53 negative patients 45 m (P=0.58). In conclusion, it was seen that overexpressions of BAX and CD40L are prognostic of better survival in TCC of the bladder. Our results also raise the possibility of the future development of CD40- and CD40 ligand-based immunotherapy for bladder cancer. This study links proapoptotic and antiapoptotic markers to overall survival

Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness

Decomposition cross-correlation for analysis of collagen matrix deformation by single smooth muscle cells

Microvascular remodeling is known to depend on cellular interactions with matrix tissue. However, it is difficult to study the role of specific cells or matrix elements in an in vivo setting. The aim of this study is to develop an automated technique that can be employed to obtain and analyze local collagen matrix remodeling by single smooth muscle cells. We combined a motorized microscopic setup and time-lapse video microscopy with a new cross-correlation based image analysis algorithm to enable automated recording of cell-induced matrix reorganization. This method rendered 60–90 single cell studies per experiment, for which collagen deformation over time could be automatically derived. Thus, the current setup offers a tool to systematically study different components active in matrix remodeling

Biomarkers of acute lung injury: worth their salt?

The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI) and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy

An Experimental Field Study of Delayed Density Dependence in Natural Populations of Aedes albopictus

Aedes albopictus, a species known to transmit dengue and chikungunya viruses, is primarily a container-inhabiting mosquito. The potential for pathogen transmission by Ae. albopictus has increased our need to understand its ecology and population dynamics. Two parameters that we know little about are the impact of direct density-dependence and delayed density-dependence in the larval stage. The present study uses a manipulative experimental design, under field conditions, to understand the impact of delayed density dependence in a natural population of Ae. albopictus in Raleigh, North Carolina. Twenty liter buckets, divided in half prior to experimentation, placed in the field accumulated rainwater and detritus, providing oviposition and larval production sites for natural populations of Ae. albopictus. Two treatments, a larvae present and larvae absent treatment, were produced in each bucket. After five weeks all larvae were removed from both treatments and the buckets were covered with fine mesh cloth. Equal numbers of first instars were added to both treatments in every bucket. Pupae were collected daily and adults were frozen as they emerged. We found a significant impact of delayed density-dependence on larval survival, development time and adult body size in containers with high larval densities. Our results indicate that delayed density-dependence will have negative impacts on the mosquito population when larval densities are high enough to deplete accessible nutrients faster than the rate of natural food accumulation