High-Resolution Replication Profiles Define the Stochastic Nature of Genome Replication Initiation and Termination

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Machine learning accelerated likelihood-free event reconstruction in dark matter direct detection

Reconstructing the position of an interaction for any dual-phase time projection chamber (TPC) with the best precision is key to directly detecting Dark Matter. Using the likelihood-free framework, a newalgorithm to reconstruct the 2-D (x; y) position and the size of the charge signal (e) of an interaction is presented. The algorithm uses the secondary scintillation light distribution (S2) obtained by simulating events using a waveform generator. To deal with the computational effort required by the likelihood-free approach, we employ the Bayesian Optimization for LikelihoodFree Inference (BOLFI) algorithm. Together with BOLFI, prior distributions for the parameters of interest (x; y; e) and highly informative discrepancy measures to performthe analyses are introduced. We evaluate the quality of the proposed algorithm by a comparison against the currently existing alternative methods using a large-scale simulation study. BOLFI provides a natural probabilistic uncertainty measure for the reconstruction and it improved the accuracy of the reconstruction over the next best algorithm by up to 15% when focusing on events at large radii (R > 30 cm, the outer 37% of the detector). In addition, BOLFI provides the smallest uncertainties among all the tested methods.Peer reviewe

Malignant Progression in Two Children with Multiple Osteochondromas

Multiple Osteochondromas (MO) is a disease of benign bony growths with a low incidence of malignant transformation. Secondary chondrosarcoma in children is rare even in children with MO. Making a diagnosis of malignancy in low-grade cartilage tumors is challenging and requires consideration of clinical, radiographic, and histopathological factors. We report two cases of skeletally immature patients with MO who presented with rapidly enlarging and radiographically aggressive lesions consistent with malignant transformation. Both underwent allograft reconstruction of the involved site with no signs of recurrence or metastatic disease at a minimum of four-year follow-up

Rare manifestation of a c.290 C\u3eT, p.Gly97Glu VCP mutation

Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50’s was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation

Characterization of primary biogenic aerosol particles in urban, rural, and high-alpine air by DNA sequence and restriction fragment analysis of ribosomal RNA genes

This study explores the applicability of DNA analyses for the characterization of primary biogenic aerosol (PBA) particles in the atmosphere. Samples of fine particulate matter (PM<sub>2.5</sub>) and total suspended particulates (TSP) have been collected on different types of filter materials at urban, rural, and high-alpine locations along an altitude transect in the south of Germany (Munich, Hohenpeissenberg, Mt. Zugspitze). <br><br> From filter segments loaded with about one milligram of air particulate matter, DNA could be extracted and DNA sequences could be determined for bacteria, fungi, plants and animals. Sequence analyses were used to determine the identity of biological organisms, and terminal restriction fragment length polymorphism analyses (T-RFLP) were applied to estimate diversities and relative abundances of bacteria. Investigations of blank and background samples showed that filter materials have to be decontaminated prior to use, and that the sampling and handling procedures have to be carefully controlled to avoid artifacts in the analyses. <br><br> Mass fractions of DNA in PM<sub>2.5</sub> were found to be around 0.05% in urban, rural, and high-alpine aerosols. The average concentration of DNA determined for urban air was on the order of ~7 ng m<sup>−3</sup>, indicating that human adults may inhale about one microgram of DNA per day (corresponding to ~10<sup>8</sup> haploid bacterial genomes or ~10<sup>5</sup> haploid human genomes, respectively). <br><br> Most of the bacterial sequences found in PM<sub>2.5</sub> were from <i>Proteobacteria</i> (42) and some from <i>Actinobacteria</i> (10) and <i>Firmicutes</i> (1). The fungal sequences were characteristic for <i>Ascomycota</i> (3) and <i>Basidiomycota</i> (1), which are known to actively discharge spores into the atmosphere. The plant sequences could be attributed to green plants (2) and moss spores (2), while animal DNA was found only for one unicellular eukaryote (protist). <br><br> Over 80% of the 53 bacterial sequences could be matched to one of the 19 T-RF peaks found in the PM<sub>2.5</sub> samples, but only 40% of the T-RF peaks did correspond to one of the detected bacterial sequences. The results demonstrate that the T-RFLP analysis covered more of the bacterial diversity than the sequence analysis. Shannon-Weaver indices calculated from both sequence and T-RFLP data indicate that the bacterial diversity in the rural samples was higher than in the urban and alpine samples. Two of the bacterial sequences (<i>Gammaproteobacteria</i>) and five of the T-RF peaks were found at all sampling locations

Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data

The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Back- ground for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs

Histomorphology of the Tracheary Elements of Some Fabaceae Hardwood

Histomorphological investigations were carried out on six taxa of the family Fabaceae: Tamarindus indica, Danielia oliveri, Afzelia africana, Piliostigma reticulatum and Detarium microcarpum. The parameters investigated include variations in their density, vessel, fibre, ray, parenchyma and tracheid. Based on their density, the economic potential of the timber are suggested. Fibre/vessel ratios are used for accessing the degree of specialization of the species studied

Validation of the web-based self-administered 24-h dietary recall myfood24-Germany: comparison with a weighed dietary record and biomarkers

Purpose We aimed to validate myfood24-Germany, a web-based 24-h dietary recall (24HDR), by comparing its performance with a weighed dietary record (WDR) and biomarkers. Methods 97 adults (77% female) completed a 3-day WDR with a 24-h urine collection on day 3, followed by at least one 24HDR with myfood24-Germany (corresponding to day 3 of the WDR). Intake of energy and 32 nutrients assessed by myfood24-Germany and the WDR for the same day were compared (method comparison). Intakes of protein and potassium assessed by myfood24-Germany/WDR were compared with intake estimated from urinary biomarkers for protein and potassium (biomarker comparison). Results In the method comparison, significant correlations were found for energy and all tested nutrients (range 0.45–0.87). There was no significant difference between both methods in the assessed mean energy and macronutrient intake. However, myfood24-Germany underestimated mean intake of 15 nutrients. In the biomarker comparison, protein intake reported by myfood24-Germany/WDR was on average 10%/8% lower than estimated by biomarker. There was no significant difference in mean potassium intake assessed by myfood24-Germany/WDR and biomarker. However, a shared bias in the assessment of potassium intake was observed for both instruments. Concordance correlation coefficients (pc) and weighted Kappa coefficients (κ) confirmed good agreement with the biomarker estimates for myfood24-Germany/WDR in case of protein (pc = 0.58/0.66, κ = 0.51/0.53) and moderate agreement in case of potassium (pc = 0.44/0.51; κ = 0.30/0.33). Conclusion Our results suggest that myfood24-Germany is of comparable validity to traditional dietary assessment methods