Rodrigo González

Compressed text indexes: From theory to practice

A compressed full-text self-index represents a text in a compressed form and still answers queries efficiently. This represents a significant advancement over the (full-)text indexing techniques of the previous decade, whose indexes required several times the size of the text. Although it is relatively new, this algorithmic technology has matured up to a point where theoretical research is giving way to practical developments. Nonetheless this requires significant programming skills, a deep engineering effort, and a strong algorithmic background to dig into the research results. To date only isolated implementations and focused comparisons of compressed indexes have been reported, and they missed a common API, which prevented their re-use or deployment within other applications. The goal of this article is to fill this gap. First, we present the existing implementations of compressed indexes from a practitioners point of view. Second, we introduce the Pizza&Chili site, which offers tuned implementations and a standardized API for the most successful compressed full-text self-indexes, together with effective test-beds and scripts for their automatic validation and test. Third, we show the results of our extensive experiments on these codes with the aim of demonstrating the practical relevance of this novel algorithmic technology.

Prolonged Survival of Dendritic Cell–Vaccinated Melanoma Patients Correlates With Tumor-Specific Delayed Type IV Hypersensitivity Response and Reduction of Tumor Growth Factor β-Expressing T Cells

PURPOSE The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines. PATIENTS AND METHODS Forty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records. RESULTS The overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001). CONCLUSION Our findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFbeta+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.

Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients.

Dendritic cell (DC)‐based therapy has proved to be effective in patients with a variety of malignancies. However, an optimal immunization protocol using DCs and the best means for delivering antigens has not yet been described. In this study, 20 patients with malignant melanoma in stages III or IV were vaccinated with autologous DCs pulsed with a melanoma cell lysate, alone (n = 13) or in combination with low doses of subcutaneous (s.c.) interleukin (IL)‐2 injections (n = 7), to assess toxicity, immunological and clinical responses. Monocyte‐derived DCs were morphological, phenotypic and functionally characterized in vitro. Peripheral blood mononuclear cells (PBMC), harvested from patients either prior to and after the treatment, were analysed using enzyme‐linked immunosorbent spot (ELISPOT). After vaccination, 50% of the patients tested (seven of 13) from the first group and (three of seven) from the second, showed an increase in interferon (IFN)‐γ production in response to allogeneic melanoma cell lines but not to controls. Four of five tested human leucocyte antigen (HLA)‐A2+ patients with anti‐melanoma activity also showed specific T cell responses against peptides derived from melanoma‐associated antigens. Delayed type IV hypersensitivity reaction (DTH) against melanoma cell lysate was observed in six of 13 patients from the group treated with DC vaccines only and four of seven from the group treated with the combination of DCs and IL‐2. Significant correlations were found between DTH‐positive responses against tumour lysate and both disease stability and post‐vaccination survival on the stage IV patients. There were no toxicities associated with the vaccines or evidence of autoimmunity including vitiligo. Furthermore, no significant enhancement was observed as a result of combining DC vaccination with IL‐2. Our data suggest that autologous DCs pulsed with tumour lysate may provide a standardized and widely applicable source of melanoma specific antigens for clinical use. It is safe and causes no significant side effects and has been demonstrated to be partially efficient at triggering effective anti‐melanoma immunity.

Statistical encoding of succinct data structures

In recent work, Sadakane and Grossi [SODA 2006] introduced a scheme to represent any sequence S=s1s2...sn, over an alphabet of size σ, using

Effect of endothelin on total and regional coronary resistence and on myocardial contractility

nH_k(S)+O(\frac{n}{\log_\sigma n} (k \log \sigma + \log\log n))

Improved dynamic rank-select entropy-bound structures

bits of space, where Hk(S) is the k-th order empirical entropy of S. The representation permits extracting any substring of size Θ(logσn) in constant time, and thus it completely replaces S under the RAM model. This is extremely important because it permits converting any succinct data structure requiring o(|S|) = o(nlogσ) bits in addition to S, into another requiring nHk(S)+o(nlogσ) (overall) for any k = o(logσn). They achieve this result by using Ziv-Lempel compression, and conjecture that the result can in particular be useful to implement compressed full-text indexes. In this paper we extend their result, by obtaining the same space and time complexities using a simpler scheme based on statistical encoding. We show that the scheme supports appending symbols in constant amortized time. In addition, we prove some results on the applicability of the scheme for full-text self-indexing.

Tolerogenic Dendritic Cells Derived from Donors with Natural Rubber Latex Allergy Modulate Allergen-Specific T-Cell Responses and IgE Production

Endothelin is a 21-amino acid peptide produced by the endothelium and has a potent vasoconstrictor effect. Because of the importance of the endothelium on vasomotor regulation, we studied the effect of endothelin on total and regional coronary vascular resistance and on myocardial contractility in the intact heart of anesthetized dogs. Intracoronary administration of 2 to 80 pmol/kg of endothelin produced a dose-dependent increase in coronary resistance, ischaemic decrease in myocardial contractility and atrium-ventricular blockade. The increase in resistance was greater towards the outer layer of the left ventricular wall. When the coronaries were perfused at a constant rate and vasoconstriction was prevented with adenosine or nitroglycerine, endothelin did not produce inotropic changes. These results show that endothelin is a potent vasoconstrictor of the resistance coronary vessels, producing a redistribution of transmural blood flow and a decrease in myocardial contractility secondary to ischaemia.

A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines

Operations rank and select over a sequence of symbols have many applications to the design of succinct and compressed data structures to manage text collections, structured text, binary relations, trees, graphs, and so on. We are interested in the case where the collections can be updated via insertions and deletions of symbols. Two current solutions stand out as the best in the tradeoff of space versus time (considering all the operations). One solution, by Makinen and Navarro, achieves compressed space (i.e., nH0 + o(n log σ) bits) and O(log n log σ) worst-case time for all the operations, where n is the sequence length, σ is the alphabet size, and H0 is the zero-order entropy of the sequence. The other solution, by Lee and Park, achieves O(log n(1 + log σ/log log n)) amortized time and uncompressed space, i.e. n log σ + O(n) + o(n log σ) bits. In this paper we show that the best of both worlds can be achieved. We combine the solutions to obtain nH0 + o(n log σ) bits of space and O(log n(1 + log σ/log log n)) worst-case time for all the operations. Apart from the best current solution to the problem, we obtain several by products of independent interest applicable to partial sums, text indexes, suffix arrays, the Burrows-Wheeler transform, and others.

Control of longitudinal movement of a plane using combined model reference adaptive control

Natural rubber latex (NRL; Hevea brasiliensis) allergy is an IgE-mediated reaction to latex proteins. When latex glove exposure is the main sensitizing agent, Hev b 5 is one of the major allergens. Dendritic cells (DC), the main antigen presenting cells, modulated with pharmacological agents can restore tolerance in several experimental models, including allergy. In the current study, we aimed to generate DC with tolerogenic properties from NRL-allergic patients and evaluate their ability to modulate allergen-specific T and B cell responses. Here we show that dexamethasone-treated DC (dxDC) differentiated into a subset of DC, characterized by low expression of MHC class II, CD40, CD80, CD86 and CD83 molecules. Compared with LPS-matured DC, dxDC secreted lower IL-12 and higher IL-10 after CD40L activation, and induced lower alloantigenic T cell proliferation. We also show that dxDC pulsed with the dominant Hev b 5 T-cell epitope peptide, Hev b 546–65 , inhibited both proliferation of Hev b 5-specific T-cell lines and the production of Hev b 5-specific IgE. Additionally, dxDC induced a subpopulation of IL-10-producing regulatory T cells that suppressed proliferation of Hev b 5-primed T cells. In conclusion, dxDC generated from NRL-allergic patients can modulate allergen-specific T-cell responses and IgE production, supporting their potential use in allergen-specific immunotherapy.

The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses

BackgroundGeneration of tolerogenic dendritic cells (TolDCs) for therapy is challenging due to its implications for the design of protocols suitable for clinical applications, which means not only using safe products, but also working at defining specific biomarkers for TolDCs identification, developing shorter DCs differentiation methods and obtaining TolDCs with a stable phenotype. We describe here, a short-term protocol for TolDCs generation, which are characterized in terms of phenotypic markers, cytokines secretion profile, CD4+ T cell-stimulatory ability and migratory capacity.MethodsTolDCs from healthy donors were generated by modulation with dexamethasone plus monophosphoryl lipid A (MPLA-tDCs). We performed an analysis of MPLA-tDCs in terms of yield, viability, morphology, phenotypic markers, cytokines secretion profile, stability, allogeneic and antigen-specific CD4+ T-cell stimulatory ability and migration capacity.ResultsAfter a 5-day culture, MPLA-tDCs displayed reduced expression of costimulatory and maturation molecules together to an anti-inflammatory cytokines secretion profile, being able to maintain these tolerogenic features even after the engagement of CD40 by its cognate ligand. In addition, MPLA-tDCs exhibited reduced capabilities to stimulate allogeneic and antigen-specific CD4+ T cell proliferation, and induced an anti-inflammatory cytokine secretion pattern. Among potential tolerogenic markers studied, only TLR-2 was highly expressed in MPLA-tDCs when compared to mature and immature DCs. Remarkable, like mature DCs, MPLA-tDCs displayed a high CCR7 and CXCR4 expression, both chemokine receptors involved in migration to secondary lymphoid organs, and even more, in an in vitro assay they exhibited a high migration response towards CCL19 and CXCL12.ConclusionWe describe a short-term protocol for TolDC generation, which confers them a stable phenotype and migratory capacity to lymphoid chemokines, essential features for TolDCs to be used as therapeutics for autoimmunity and prevention of graft rejection.