Minimal models of evolution: germline fitness effects of cancer mutations and stochastic tunneling under strong recombination

In a time where data on the genetic make-up of organisms is available in abundance, the theory of evolution is of immediate importance to answer key questions of biology: How can one explain the variation seen in the DNA of different organisms and species? What are the effects of changes in the DNA on the function of cells? What are the driving mechanisms of diseases with a genetic component such as cancer? Minimal mathematical models of evolution provide a basis for the interpretation of DNA data. The explanations they offer are concrete and testable, their assumptions and limitations explicit. The application and further development of minimal evolution models is the main theme of this work. In the first part, the functional effects of mutations found in cancer cells are analyzed from the perspective of germline evolution. This is the process that produced the DNA of organisms as we see it today. Mutations have an effect on the fitness of healthy cells. This impact can be estimated from the variation seen in the sequences of protein domains. It is found that this evolutionarily informed conservation score has utility to identify cancer driver genes, especially if they are tumor suppressor genes. The relevance of this fitness scale for cancer mutations is demonstrated on a data set of mutations in protein kinase genes. This analysis is followed by an application of Hidden Markov Models (HMM) to the detection of signals of positive selection in cancer mutation data. Cancer as an evolutionary process of cells is markedly different from the process of germline evolution. Cancer-specific selection can be seen in genes, whose activity or lack thereof is essential for the progress of cancer. These cancer genes exhibit an increased rate of amino acid changing mutations, beyond the level expected by chance. The identification of these genes is a statistical task for which HMM are shown to be most suitable. Finally, an extended mathematical model of evolution is analyzed which describes the adaptation of a sexually reproducing population to a global fitness maximum via compensatory mutations. In a two-locus/two-allele model, the compound effects of mutation, selection, genetic drift, recombination and sign epistasis lead to the interesting situation of adaption via the crossing of a fitness valley in genotype space. This bottleneck can be overcome by rare large fluctuations in the allele frequencies overcoming the effect of recombinatorial reshuffling. The relevant time scales are derived for a parameter regime that includes large recombination

Rare events in population genetics: Stochastic tunneling in a two-locus model with recombination

We study the evolution of a population in a two-locus genotype space, in which the negative effects of two single mutations are overcompensated in a high fitness double mutant. We discuss how the interplay of finite population size, $N$, and sexual recombination at rate $r$ affects the escape times $t_\mathrm{esc}$ to the double mutant. For small populations demographic noise generates massive fluctuations in $t_\mathrm{esc}$. The mean escape time varies non-monotonically with $r$, and grows exponentially as $\ln t_{\mathrm{esc}} \sim N(r - r^\ast)^{3/2}$ beyond a critical value $r^\ast$.Comment: 4 pages, 3 figure

Performance Score (T2D)-A New Perspective in the Assessment of Six-Minute Walking Tests in Pulmonary Rehabilitation

Because absolute changes in outcomes are difficult to interpret and the minimal clinically important difference (MCID) is not suitable to address this challenge, a novel method of classifying outcomes by relating changes to baseline values is warranted. We used the "performance score" (T2D), which reflects individual performance, enabling us to consider the functional status at the beginning of rehabilitation without dealing with the problems of mathematical coupling or regression effects, as encountered in ANCOVA. To illustrate the T2D, we retrospectively analyzed changes in the six-minute walking test (6MWT) in COPD patients undergoing outpatient pulmonary rehabilitation and compared the results with absolute differences related to a predetermined MCID. We evaluated a total of 575 COPD patients with a mean age of 61.4 ± 9.2 years. 6MWT improved significantly, with a mean change of 32.3 ± 71.2. A total of 105/311 participants who had reached the MCID were still classified as "below average" by the T2D. Conversely, 76/264 patients who had not reached the MCID were classified as "above average". This new performance measure accounts for the patient's current status and for changes over time, potentially representing a simple and user-friendly tool that can be used to quantify a patient's performance and response to rehabilitation

Kepler Eclipsing Binary Stars. VI. Identification of Eclipsing Binaries in the K2 Campaign 0 Data-set

The original {\it Kepler} mission observed and characterized over 2400 eclipsing binaries in addition to its prolific exoplanet detections. Despite the mechanical malfunction and subsequent non-recovery of two reaction wheels used to stabilize the instrument, the {\it Kepler} satellite continues collecting data in its repurposed {\it K2} mission surveying a series of fields along the ecliptic plane. Here we present an analysis of the first full baseline {\it K2} data release: the Campaign 0 data-set. In the 7761 light curves, we have identified a total of 207 eclipsing binaries. Of these, 97 are new discoveries that were not previously identified. Our pixel-level analysis of these objects has also resulted in identification of several false positives (observed targets contaminated by neighboring eclipsing binaries), as well as the serendipitous discovery of two short period exoplanet candidates. We provide catalog cross-matched source identifications, orbital periods, morphologies and ephemerides for these eclipsing systems. We also describe the incorporation of the K2 sample into the Kepler Eclipsing Binary Catalog\footnote{\url{keplerebs.villanova.edu/k2}}, present spectroscopic follow-up observations for a limited selection of nine systems, and discuss prospects for upcoming {\it K2} campaigns.Comment: Accepted for publication in MNRAS. 51 pages [20 figures, 8 tables]. Results available online in the Kepler Eclipsing Binary Star Catalog http://keplerebs.villanova.edu/k

First Experience With The GoBack-Catheter For Successful Crossing of Complex Chronic Total Occlusions in Lower Limb Arteries

Purpose: To evaluate the use of the GoBack-catheter (Upstream Peripheral Technologies) in complex revascularizations in lower limb arteries. Materials and Methods: In this retrospective single-center study, the results of the first 100 consecutive patients including 101 limb-revascularizations, performed between May 2018 and July 2020 with the study device, were analyzed. In all cases, guidewire-crossing failed, and all lesions were chronic total occlusions (CTO), either de novo, reocclusions, or in-stent reocclusions. Successful crossing was defined as passing the CTO using the study device. Patency at discharge and after 30 days was defined as less than 50% restenosis on duplex sonography, without target lesion revascularization. Results: Median lesion length was 24 cm and 38 patients (37.6%) had a calcium grading according to the peripheral arterial calcium scoring system (PACSS) of 4 or 5. In 20.8% of patients, an occluded stent was treated. CTOs involved the femoropopliteal segment in 91.1%, iliac arteries in 5.9%, and tibial arteries in 7.9%. The GoBackcatheter was employed for entering into or crossing through parts or the full length of a CTO or an occluded stent as well as for re-entering into the true lumen after subintimal crossing. The device was used via contralateral and ipsilateral antegrade as well as retrograde access with an overall technical success rate of 92.1%. In 3 patients minor bleeding occurred at the crossing or re-entry site, which were managed conservatively. Thirty-day adverse limb events comprised minor amputations in 4 patients (4.0%), 1 major amputation (1.0%), and reocclusions in 7 limbs (6.9%). Conclusion: The new GoBack-catheter offers versatile endovascular applicability for complex CTO recanalization in a broad range of peripheral vascular interventions with a high technical success and low complication rate

Adenoma development in familial adenomatous polyposis andMUTYH-associated polyposis: somatic landscape and driver genes

Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Nuclear data for fusion technology – the European approach

The European approach for the development of nuclear data for fusion technology applications is presented. Related R&D activities are conducted by the Consortium on Nuclear Data Development and Analysis for Fusion to satisfy the nuclear data needs of the major projects including ITER, the Early Neutron Source (ENS) and DEMO. Recent achievements are presented in the area of nuclear data evaluations, benchmarking and validation, nuclear model improvements, and uncertainty assessments

Living off the land : Terrestrial-based diet and dairying in the farming communities of the Neolithic Balkans

The application of biomolecular techniques to archaeological materials from the Balkans is providing valuable new information on the prehistory of the region. This is especially relevant for the study of the neolithisation process in SE Europe, which gradually affected the rest of the continent. Here, to answer questions regarding diet and subsistence practices in early farming societies in the central Balkans, we combine organic residue analyses of archaeological pottery, taxonomic and isotopic study of domestic animal remains and biomolecular analyses of human dental calculus. The results from the analyses of the lipid residues from pottery suggest that milk was processed in ceramic vessels. Dairy products were shown to be part of the subsistence strategies of the earliest Neolithic communities in the region but were of varying importance in different areas of the Balkan. Conversely, milk proteins were not detected within the dental calculus. The molecular and isotopic identification of meat, dairy, plants and beeswax in the pottery lipids also provided insights into the diversity of diet in these early Neolithic communities, mainly based on terrestrial resources. We also present the first compound-specific radiocarbon dates for the region, obtained directly from absorbed organic residues extracted from pottery, identified as dairy lipids

Kepler-16: A Transiting Circumbinary Planet

We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size, and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20% and 69% as massive as the sun, and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5 degree of a single plane, suggesting that the planet formed within a circumbinary disk.Comment: Science, in press; for supplemental material see http://www.sciencemag.org/content/suppl/2011/09/14/333.6049.1602.DC1/1210923.Doyle.SOM.pd