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A C C Coolen

Bio: A C C Coolen is an academic researcher from King's College London. The author has contributed to research in topics: Random graph & Recurrent neural network. The author has an hindex of 8, co-authored 19 publications receiving 169 citations.

Papers
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Journal ArticleDOI
TL;DR: The results show that the transitional cell population contains cells other than those that are part of the pre-B’simmature and naïve development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre- B and naïve stages.
Abstract: The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes, and consequently an equally large number of potential specificities for antigen. As the process is essentially random, then cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre- B>>immature>>transitional>>naive phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire, and can be seen both in gene usage and in CDR-H3 characteristics. Age-related changes are small and only the size of the CDR-H3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B>>immature>>transitional>>naive development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naive stages.

50 citations

Journal ArticleDOI
29 Jun 2016-PLOS ONE
TL;DR: Novel Bayesian methods for the analysis of exponential decay data that exploit the evidence carried by every detected decay event and enables robust extension to advanced processing are presented and two advanced processing methods are demonstrated.
Abstract: We present novel Bayesian methods for the analysis of exponential decay data that exploit the evidence carried by every detected decay event and enables robust extension to advanced processing. Our algorithms are presented in the context of fluorescence lifetime imaging microscopy (FLIM) and particular attention has been paid to model the time-domain system (based on time-correlated single photon counting) with unprecedented accuracy. We present estimates of decay parameters for mono- and bi-exponential systems, offering up to a factor of two improvement in accuracy compared to previous popular techniques. Results of the analysis of synthetic and experimental data are presented, and areas where the superior precision of our techniques can be exploited in Forster Resonance Energy Transfer (FRET) experiments are described. Furthermore, we demonstrate two advanced processing methods: decay model selection to choose between differing models such as mono- and bi-exponential, and the simultaneous estimation of instrument and decay parameters.

37 citations

Journal ArticleDOI
TL;DR: The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD, but risk in three pathways was most frequent (35% of late cases), and lifestyle factors should be a strong focus in patient management.

33 citations

Journal ArticleDOI
TL;DR: Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery, and Interestingly there was no correlation between the level of Her2 protein expressed and Her2- HER3 heterodimer formation.
Abstract: Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker.FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Forster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61-9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding.Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.

28 citations

Journal ArticleDOI
TL;DR: Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.
Abstract: Background: Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem. Methods: We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths. Results: A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01–3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes. Conclusion: Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.

23 citations


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01 Jan 2016
TL;DR: The table of integrals series and products is universally compatible with any devices to read and is available in the book collection an online access to it is set as public so you can get it instantly.
Abstract: Thank you very much for downloading table of integrals series and products. Maybe you have knowledge that, people have look hundreds times for their chosen books like this table of integrals series and products, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they cope with some harmful virus inside their laptop. table of integrals series and products is available in our book collection an online access to it is set as public so you can get it instantly. Our book servers saves in multiple locations, allowing you to get the most less latency time to download any of our books like this one. Merely said, the table of integrals series and products is universally compatible with any devices to read.

4,085 citations

Journal ArticleDOI
TL;DR: Van Kampen as mentioned in this paper provides an extensive graduate-level introduction which is clear, cautious, interesting and readable, and could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes.
Abstract: N G van Kampen 1981 Amsterdam: North-Holland xiv + 419 pp price Dfl 180 This is a book which, at a lower price, could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes, as well as those who just enjoy a beautifully written book. It provides an extensive graduate-level introduction which is clear, cautious, interesting and readable.

3,647 citations

28 Jul 2005
TL;DR: 曼氏血吸虫感染后,宿主活化CD4^+Th2细胞L分泌IL-4、IL-5和 IL-13。
Abstract: 入侵病原体与宿主之间呈动态平衡,以维持病原体成功地寄生在宿主体内而不致宿主死亡,这是许多寄生虫感染的一个重要特征。包括曼氏血吸虫在内的许多蠕虫感染中,持续的炎症反应比病原体本身对宿主的危害更大,降低宿主的免疫反应具有重要意义。曼氏血吸虫感染后,宿主活化CD4^+Th2细胞,分泌IL-4、IL-5和IL-13。最近研究表明IL-13是肝组织纤维化的重要调节因子。

583 citations

Journal ArticleDOI
TL;DR: It is found that when the highly connected nodes are protected and have lower probability to fail, in contrast to single scale-free (SF) networks where the percolation threshold pc = 0, coupled SF networks are significantly more vulnerable with pc significantly larger than zero.
Abstract: When an initial failure of nodes occurs in interdependent networks, a cascade of failure between the networks occurs. Earlier studies focused on random initial failures. Here we study the robustness of interdependent networks under targeted attack on high or low degree nodes. We introduce a general technique which maps the targeted-attack problem in interdependent networks to the random-attack problem in a transformed pair of interdependent networks. We find that when the highly connected nodes are protected and have lower probability to fail, in contrast to single scale-free (SF) networks where the percolation threshold pc = 0, coupled SF networks are significantly more vulnerable with pc significantly larger than zero. The result implies that interdependent networks are difficult to defend by strategies such as protecting the high degree nodes that have been found useful to significantly improve robustness of single networks.

454 citations

ReportDOI
31 May 1993
TL;DR: Significant progress has been made with solution of location problems and in preprocessing and decomposition for discrete optimization and on the application of techniques from combinational optimization to nonlinear problems.
Abstract: : Significant progress has been made with solution of location problems and in preprocessing and decomposition for discrete optimization. There has also been research on the application of techniques from combinational optimization to nonlinear problems.

421 citations