3,858 research outputs found
Reconstructing pedigrees: some identifiability questions for a recombination-mutation model
Pedigrees are directed acyclic graphs that represent ancestral relationships
between individuals in a population. Based on a schematic recombination
process, we describe two simple Markov models for sequences evolving on
pedigrees - Model R (recombinations without mutations) and Model RM
(recombinations with mutations). For these models, we ask an identifiability
question: is it possible to construct a pedigree from the joint probability
distribution of extant sequences? We present partial identifiability results
for general pedigrees: we show that when the crossover probabilities are
sufficiently small, certain spanning subgraph sequences can be counted from the
joint distribution of extant sequences. We demonstrate how pedigrees that
earlier seemed difficult to distinguish are distinguished by counting their
spanning subgraph sequences.Comment: 40 pages, 9 figure
Graphs Identified by Logics with Counting
We classify graphs and, more generally, finite relational structures that are
identified by C2, that is, two-variable first-order logic with counting. Using
this classification, we show that it can be decided in almost linear time
whether a structure is identified by C2. Our classification implies that for
every graph identified by this logic, all vertex-colored versions of it are
also identified. A similar statement is true for finite relational structures.
We provide constructions that solve the inversion problem for finite
structures in linear time. This problem has previously been shown to be
polynomial time solvable by Martin Otto. For graphs, we conclude that every
C2-equivalence class contains a graph whose orbits are exactly the classes of
the C2-partition of its vertex set and which has a single automorphism
witnessing this fact.
For general k, we show that such statements are not true by providing
examples of graphs of size linear in k which are identified by C3 but for which
the orbit partition is strictly finer than the Ck-partition. We also provide
identified graphs which have vertex-colored versions that are not identified by
Ck.Comment: 33 pages, 8 Figure
Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin
BACKGROUND: Colon adenocarcinomas are refractory to a number of widely used anticancer agents. Multifactorial mechanisms have been implicated in this intrinsically resistant phenotype, including deregulation of cell death pathways. In this regard, the p53 protein has a well established role in the control of tumor cell response to DNA damaging agents; however, the relationship between p53-driven genes and drug sensitivity remains controversial. The present study investigates the role of the p53/p21 system in the response of human colon carcinoma cells to treatment with the cytotoxic agent doxorubicin (DOX) and the possibility to modify the therapeutic index of DOX by modulation of p53 and/or p21 protein levels. METHODS: The relationship between p53 and p21 protein levels and the cytotoxic effect of DOX was investigated, by MTT assay and western blot analysis, in HCT116 (p53-positive) and HT29 (p53-negative) colon cancer cells. We then assessed the effects of DOX in two isogenic cell lines derived from HCT116 by abrogating the expression and/or function of p53 and p21 (HCT116-E6 and HCT116 p21-/-, respectively). Finally, we evaluated the effect of pre-treatment with the piperidine nitroxide Tempol (TPL), an agent that was reported to induce p21 expression irrespective of p53 status, on the cytotoxicity of DOX in the four cell lines. Comparisons of IC50 values and apoptotic cell percentages were performed by ANOVA and Bonferroni's test for independent samples. C.I. calculations were performed by the combination Index method. RESULTS: Our results indicate that, in the colon carcinoma cell lines tested, sensitivity to DOX is associated with p21 upregulation upon drug exposure, and DOX cytotoxicity is potentiated by pre-treatment with TPL, but only in those cell lines in which p21 can be upregulated. CONCLUSIONS: p21 induction may significantly contribute to the response of colon adenocarcinomas cells to DOX treatment; and small molecules that can exploit p53-independent pathways for p21 induction, such as TPL, may find a place in chemotherapeutic protocols for the clinical management of colorectal cancer, where p53 function is often lost, due to genetic or epigenetic defects or to post-transcriptional inactivating mechanisms
Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells
Embryonic stem cells (ESC) have the potential to self-renew indefinitely and
to differentiate into any of the three germ layers. The molecular mechanisms
for self-renewal, maintenance of pluripotency and lineage specification are
poorly understood, but recent results point to a key role for epigenetic
mechanisms. In this study, we focus on quantifying the impact of histone 3
acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We
analyze genome-wide histone acetylation patterns and gene expression profiles
measured over the first five days of cell differentiation triggered by
silencing Nanog, a key transcription factor in ESC regulation. We explore the
temporal and spatial dynamics of histone acetylation data and its correlation
with gene expression using supervised and unsupervised statistical models. On a
genome-wide scale, changes in acetylation are significantly correlated to
changes in mRNA expression and, surprisingly, this coherence increases over
time. We quantify the predictive power of histone acetylation for gene
expression changes in a balanced cross-validation procedure. In an in-depth
study we focus on genes central to the regulatory network of Mouse ESC,
including those identified in a recent genome-wide RNAi screen and in the
PluriNet, a computationally derived stem cell signature. We find that compared
to the rest of the genome, ESC-specific genes show significantly more
acetylation signal and a much stronger decrease in acetylation over time, which
is often not reflected in an concordant expression change. These results shed
light on the complexity of the relationship between histone acetylation and
gene expression and are a step forward to dissect the multilayer regulatory
mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog
Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men
<p>Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (vË™ O2 max).</p>
<p>Purpose: This study defined the time course of changes in Hbmass, vË™ O2 max as well as running time trial performance
following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual
improvements in running performance in the field.</p>
<p>Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was
determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. vË™ O2 max
and 3,000 m time trial performance were measured pre, post administration and at the end of the study.</p>
<p>Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec
vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration
(10:4661:13 min:sec, p,0.001), while vË™ O2 max was also significantly increased post administration
(60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after
rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to
baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post
rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68,
20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration
compared to baseline (13.761.1 gNkg21, p<0.001).</p>
<p>Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after
administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated vË™ O2 max and
Hbmass.</p>
A fast framework construction and visualization method for particle-based fluid
© 2017, The Author(s). Fast and vivid fluid simulation and visualization is a challenge topic of study in recent years. Particle-based simulation method has been widely used in the art animation modeling and multimedia field. However, the requirements of huge numerical calculation and high quality of visualization usually result in a poor computing efficiency. In this work, in order to improve those issues, we present a fast framework for 3D fluid fast constructing and visualization which parallelizes the fluid algorithm based on the GPU computing framework and designs a direct surface visualization method for particle-based fluid data such as WCSPH, IISPH, and PCISPH. Considering on conventional polygonization or adaptive mesh methods may incur high computing costs and detail losses, an improved particle-based method is provided for real-time fluid surface rendering with the screen-space technology and the utilities of the modern graphics hardware to achieve the high performance rendering; meanwhile, it effectively protects fluid details. Furthermore, to realize the fast construction of scenes, an optimized design of parallel framework and interface is also discussed in our paper. Our method is convenient to enforce, and the results demonstrate a significant improvement in the performance and efficiency by being compared with several examples
Measurement of GEp/GMp in ep -> ep to Q2 = 5.6 GeV2
The ratio of the electric and magnetic form factors of the proton, GEp/GMp,
was measured at the Thomas Jefferson National Accelerator Facility (JLab) using
the recoil polarization technique. The ratio of the form factors is directly
proportional to the ratio of the transverse to longitudinal components of the
polarization of the recoil proton in the elastic
reaction. The new data presented in this article span the range 3.5 < Q2 < 5.6
GeV2 and are well described by a linear Q2 fit. Also, the ratio QF2p/F1p
reaches a constant value above Q2=2 GeV2.Comment: 6 pages, 4 figures Added two names to the main author lis
Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo
Senescence is a distinct cellular response induced by DNA-damaging agents and other sublethal stressors and may provide novel benefits in cancer therapy. However, in an ageing model, senescent fibroblasts were found to stimulate the proliferation of cocultured cells. To address whether senescence induction in cancer cells using chemotherapy induces similar effects, we used GFP-labelled prostate cancer cell lines and monitored their proliferation in the presence of proliferating or doxorubicin-induced senescent cancer cells in vitro and in vivo. Here, we show that the presence of senescent cancer cells increased the proliferation of cocultured cells in vitro through paracrine signalling factors, but this proliferative effect was significantly less than that seen with senescent fibroblasts. In vivo, senescent cancer cells failed to increase the establishment, growth or proliferation of LNCaP and DU145 xenografts in nude mice. Senescent cells persisted as long as 5 weeks in tumours. Our results demonstrate that although drug-induced senescent cancer cells stimulate the proliferation of bystander cells in vitro, this does not significantly alter the growth of tumours in vivo. Coupled with clinical observations, these data suggest that the proliferative bystander effects of senescent cancer cells are negligible and support the further development of senescence induction as therapy
Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells
Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5610 10 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral disease
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