Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certai... more Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.int...
Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer ... more Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly missregulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.
2010 17th IEEE International Conference and Workshops on Engineering of Computer Based Systems, 2010
Multi-Level Testing is an emerging approach for test level integration through reuse. Its princip... more Multi-Level Testing is an emerging approach for test level integration through reuse. Its principal instrument, multi-level test cases, has only been considered in the context of bottom-up reuse to date. This test level integration strategy leads to excellent test effort reductions for embedded systems. However, bottom-up reuse is incapable of dealing with components featuring complex dynamic behavior. Top-down reuse is a novel test level integration approach that enables the reuse of test cases from higher test levels at lower test levels even in presence of complex dynamic behavior. With this practice, multi-level testing becomes applicable for a large set of new systems that can now benefit from great test effort reductions. In addition, test level design at the top test levels leads to system-and hence customer-oriented testing.
2009 Testing: Academic and Industrial Conference - Practice and Research Techniques, 2009
Abstract The increasing importance of embedded software has produced a shift in the testing activ... more Abstract The increasing importance of embedded software has produced a shift in the testing activities from system testing towards software testing. This has contributed to testing the core system functionality earlier on in the test process. However, this shift has also led ...
Complementing computationally predicted regulatory sites in Tractor_DB using a pattern matching approach
In silico biology, 2005
Prokaryotic genomes annotation has focused on genes location and function. The lack of regulatory... more Prokaryotic genomes annotation has focused on genes location and function. The lack of regulatory information has limited the knowledge on cellular transcriptional regulatory networks. However, as more phylogenetically close genomes are sequenced and annotated, the implementation of phylogenetic footprinting strategies for the recognition of regulators and their regulons becomes more important. In this paper we describe a comparative genomics approach to the prediction of new gamma-proteobacterial regulon members. We take advantage of the phylogenetic proximity of Escherichia coli and other 16 organisms of this subdivision and the intensive search of the space sequence provided by a pattern-matching strategy. Using this approach we complement predictions of regulatory sites made using statistical models currently stored in Tractor_DB, and increase the number of transcriptional regulators with predicted binding sites up to 86. All these computational predictions may be reached at Tra...
Lifecycle models divide the test process into consecutive test levels that are considered indepen... more Lifecycle models divide the test process into consecutive test levels that are considered independently. This strict separation obstructs the view on the test process as a whole and fails to reflect the commonalities across test levels. Multi-level testing is an emerging approach that addresses the challenge of integrating test levels, putting particular emphasis on embedded systems. In this paper, we introduce a test level integration strategy based on reuse that is called bottom-up reuse. In addition, we present a test level instrument that seamlessly supports this strategy: multi-level test cases. We also provide a case study that reflects the positive results we have obtained in practice so far and demonstrates the feasibility of our test level integration approach. Bottom-up reuse and multi-level test cases lead to testing earlier on in the development process while reducing the effort required by test specification, test design, and test implementation.
Conservation of key members in the course of the evolution of the insulin signaling pathway
Biosystems, 2009
Our understanding of the evolution of the insulin signaling pathway (ISP) is still incomplete. On... more Our understanding of the evolution of the insulin signaling pathway (ISP) is still incomplete. One intriguing unanswered question is the explanation of the emergence of the glucostatic role of insulin in mammals. To find out whether this is due to the development of new sets of signaling transduction elements in these organisms, or to the establishment of new interactions between pre-existing proteins, we rebuilt putative orthologous ISPs in 17 eukaryotic organisms. Then, we computed the conservation of orthologous ISPs at different levels, from sequence similarity of orthologous proteins to co-evolution of interacting domains. We found that the emergence of glucostatic role in mammals can neither be explained by the development of new sets of signaling elements, nor by the establishment of new interactions between pre-existing proteins. The comparison of orthologous IRS molecules indicates that only in mammals have they acquired their complete functionality as efficient recruiters of effector sub-pathways.
Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy X
MUSCAT is a second-generation continuum camera for the Large Millimeter Telescope (LMT) "Alfonso ... more MUSCAT is a second-generation continuum camera for the Large Millimeter Telescope (LMT) "Alfonso Serrano", to observe at the 1.1 mm atmospheric window. The camera has 1500 background-limited, horn-coupled lumpedelement kinetic inductance detectors (LEKIDs) split across six arrays operating at 130-mK. The detector design for MUSCAT is based on a large-volume, double-meander geometry used as the inductive and two-polarization absorbing section of the LEKID resonator. In this paper we present the optical coupling of the meander to a choked waveguide output, the microwave design of the LEKID architecture, the device fabrication process and results demonstrating the detector sensitivity under a range of optical loads. Also presented is the performance of an aluminum absorbing layer used to minimize the optical cross-talk between detectors.
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Papers by Abel Perez