Testing statistical hypothesis on random trees and applications to the protein classification problem

Efficient automatic protein classification is of central importance in genomic annotation. As an independent way to check the reliability of the classification, we propose a statistical approach to test if two sets of protein domain sequences coming from two families of the Pfam database are significantly different. We model protein sequences as realizations of Variable Length Markov Chains (VLMC) and we use the context trees as a signature of each protein family. Our approach is based on a Kolmogorov--Smirnov-type goodness-of-fit test proposed by Balding et al. [Limit theorems for sequences of random trees (2008), DOI: 10.1007/s11749-008-0092-z]. The test statistic is a supremum over the space of trees of a function of the two samples; its computation grows, in principle, exponentially fast with the maximal number of nodes of the potential trees. We show how to transform this problem into a max-flow over a related graph which can be solved using a Ford--Fulkerson algorithm in polynomial time on that number. We apply the test to 10 randomly chosen protein domain families from the seed of Pfam-A database (high quality, manually curated families). The test shows that the distributions of context trees coming from different families are significantly different. We emphasize that this is a novel mathematical approach to validate the automatic clustering of sequences in any context. We also study the performance of the test via simulations on Galton--Watson related processes.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS218 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Tuning the properties of all natural polymeric scaffolds for tendon repair with cellulose microfibers

Funding Information: This paper is a part of dissemination activities of the project P4FIT. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under the Maria Skłodowska-Curie Grant Agreement N° 955685 .Peer reviewe

A proposal to assess the conservation status of roadsides in southeastern Buenos Aires

Los bordes de caminos rurales (BCR) son elementos clave para conservar la biodiversidad y los servicios ecosistémicos en los paisajes agrícolas. Su restauración y manejo requieren de protocolos sencillos que valoren (diagnostiquen) su estado de conservación y funcionalidad ecológica. En este trabajo elaboramos un índice del valor de conservación (IVC) de los BCR por medio de la construcción de un árbol de decisiones realizado a partir de la consulta a expertos. El índice, que puede asumir valores entre 4 y 30, evalúa el estado de conservación y la funcionalidad ecológica de los BCR según 11 atributos relacionados principalmente con la estructura de la vegetación. El IVC fue aplicado a 30 BCR del sudeste bonaerense (Argentina). Sus valores oscilaron entre 4 y 29. Los BCR cultivados fueron los de menor valor. Los BCR con IVC más alto (>21) se caracterizaron por la mayor riqueza de especies nativas, entomófilas y de valor cultural, la mayor cobertura de especies nativas y pastos perennes, la menor cobertura de malezas y especies invasoras, y la presencia de al menos una especie vulnerable y/o fitotelmata. Este índice representa una primera contribución aplicable al diagnóstico del estado de conservación de los BCR a través de la identificación de atributos claves de la estructura de la vegetación sugeridos por expertos. Además, el índice provee información relativamente sintética sobre el estado de los BCR, los que, pese a sus múltiples funciones ecológicas, rara vez son tenidos en cuenta para su conservación dentro de la planificación territorial.Rural roadsides (RRS) are key elements for conserving biodiversity and ecosystem services in agricultural landscapes. Their restoration and management require simple protocols to assess (diagnose) their conservation status and ecological functionality. We elaborated a conservation value index (CVI) of RRS by constructing a decision tree based on the experts’ opinion. The index, which can range between 4 and 30, evaluates the conservation status and ecological functionality of RRS according to 11 attributes related to vegetation structure. The CVI was applied to 30 RRS in southeastern Buenos Aires (Argentina). Values ranged from 4 to 29, being the cropped RRS those with the lowest value. The RRS with the highest CVI (>21) were those characterized by higher richness of native, entomophily and cultural value species, higher coverage of native species and perennial grasses, lower coverage of weeds and invasive species, and presence of at least a vulnerable and/or phytotelmata species. This index represents a first contribution applicable to the diagnosis of the conservation status of RRS through the identification of key attributes of vegetation structure suggested by experts. In addition, the index provides relatively synthetic information about the status of RRS, which in spite of their multiple ecological functions are seldom taken into account for their conservation within territorial planning

Una propuesta para valorar el estado de conservación de los bordes de caminos rurales en el sudeste bonaerense

Herrera, Lorena P. Instituto Nacional de Tecnología Agropecuaria (INTA). Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce (EEA Balcarce). Balcarce, Buenos Aires, Argentina.Sabatino, Malena C. Instituto Nacional de Tecnología Agropecuaria (INTA). Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce (EEA Balcarce). Balcarce, Buenos Aires, Argentina.Jaimes, Florencia R. Instituto Nacional de Tecnología Agropecuaria (INTA). Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce (EEA Balcarce). Balcarce, Buenos Aires, Argentina.Poggio, Santiago L. Universidad de Buenos Aires. Facultad de Agronomía. Cátedra de Producción Vegetal. Buenos Aires, Argentina.403-414Los bordes de caminos rurales (BCR) son elementos clave para conservar la biodiversidad y los servicios ecosistémicos en los paisajes agrícolas. Su restauración y manejo requieren de protocolos sencillos que valoren (diagnostiquen) su estado de conservación y funcionalidad ecológica. En este trabajo elaboramos un índice del valor de conservación (IVC) de los BCR por medio de la construcción de un árbol de decisiones realizado a partir de la consulta a expertos. El índice, que puede asumir valores entre 4 y 30, evalúa el estado de conservación y la funcionalidad ecológica de los BCR según 11 atributos relacionados principalmente con la estructura de la vegetación. El IVC fue aplicado a 30 BCR del sudeste bonaerense (Argentina). Sus valores oscilaron entre 4 y 29. Los BCR cultivados fueron los de menor valor. Los BCR con IVC más alto (mayor a 21) se caracterizaron por la mayor riqueza de especies nativas, entomófilas y de valor cultural, la mayor cobertura de especies nativas y pastos perennes, la menor cobertura de malezas y especies invasoras, y la presencia de al menos una especie vulnerable y/o fitotelmata. Este índice representa una primera contribución aplicable al diagnóstico del estado de conservación de los BCR a través de la identificación de atributos claves de la estructura de la vegetación sugeridos por expertos. Además, el índice provee información relativamente sintética sobre el estado de los BCR, los que, pese a sus múltiples funciones ecológicas, rara vez son tenidos en cuenta para su conservación dentro de la planificación territorial

Gut Epithelial Interleukin-17 Receptor a Signaling Can Modulate Distant Tumors Growth Through Microbial Regulation

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy

Guselkumab for hidradenitis suppurativa:a phase II, open-label, mode-of-action study

BACKGROUND: The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. OBJECTIVES: To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. METHODS: An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. RESULTS: Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. CONCLUSIONS: Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0-50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.</p

Omiganan Enhances Imiquimod-Induced Inflammatory Responses in Skin of Healthy Volunteers

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%–30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%–2.83; P = 0.02). Interferon regulatory factor-driven and NFκB-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases

Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response

Zika virus, influenza, and Ebola have called attention to the ways in which infectious disease outbreaks can severely – and at times uniquely – affect the health interests of pregnant women and their offspring. These examples also highlight the critical need to proactively consider pregnant women and their offspring in vaccine research and response efforts to combat emerging and re-emerging infectious diseases. Historically, pregnant women and their offspring have been largely excluded from research agendas and investment strategies for vaccines against epidemic threats, which in turn can lead to exclusion from future vaccine campaigns amidst outbreaks. This state of affairs is profoundly unjust to pregnant women and their offspring, and deeply problematic from the standpoint of public health. To ensure that the needs of pregnant women and their offspring are fairly addressed, new approaches to public health preparedness, vaccine research and development, and vaccine delivery are required. This Guidance offers 22 concrete recommendations that provide a roadmap for the ethically responsible, socially just, and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens. The Guidance was developed by the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group – a multidisciplinary, international team of 17 experts specializing in bioethics, maternal immunization, maternal-fetal medicine, obstetrics, pediatrics, philosophy, public health, and vaccine research and policy – in consultation with a variety of external experts and stakeholders.Fil: Krubiner, Carleigh B.. University Johns Hopkins; Estados UnidosFil: Faden, Ruth R.. University Johns Hopkins; Estados UnidosFil: Karron, Ruth A.. University Johns Hopkins; Estados UnidosFil: Little, Margaret O.. University Of Georgetown; Estados UnidosFil: Lyerly, Anne D.. University of North Carolina; Estados UnidosFil: Abramson, Jon S.. University Wake Forest; Estados UnidosFil: Beigi, Richard H.. Magee-Womens Hospital of University of Pittsburgh Medical Center; Estados UnidosFil: Cravioto, Alejandro R.. Universidad Nacional Autónoma de México; MéxicoFil: Durbin, Anna P.. University Johns Hopkins; Estados UnidosFil: Gellin, Bruce G.. Sabin Vaccine Institute; Estados UnidosFil: Gupta, Swati B.. IAVI; Estados UnidosFil: Kaslow, David C.. PATH; Estados UnidosFil: Kochhar, Sonali. Global Healthcare Consulting; IndiaFil: Luna, Florencia. Facultad Latinoamericana de Ciencias Sociales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Saenz, Carla. Pan American Health Organization; Estados UnidosFil: Sheffield, Jeanne S.. University Johns Hopkins; Estados UnidosFil: Tindana, Paulina O.. Navrongo Health Research Centre; GhanaFil: The Prevent Working Group. No especifíca

Genetic transfer from several apomictic tetraploid Paspalum species to an elite group of sexual plants

Basic findings from classical genetic studies are available for exploiting apomixis in the breeding of several forage grass genera. Most Paspalum species are multiploid with a sexual diploid cytotype and conspecific apomictic polyploid (mainly tetraploid) cytotypes. Experimental tetraploidized diploids reproduce sexually and, when crossed with natural apomictic tetraploids, yield hybrid populations that segregate for reproductive mode. Genetic studies indicated that apomixis is inherited as a monogenic dominant factor. We recombined 50 selected sexual hybrids obtained from crosses between a tetraploidized sexual genotype of P. plicatulum and 9 natural apomictic tetraploid accessions of 6 species of the Plicatula group. A synthetic sexual tetraploid population (SSTP) of 600 individuals from mixed seed of the 50 intercrossed hybrids was space-planted in the field. Based on evaluations of plant vigor, seed set, ergot tolerance, regrowth after flowering, and cold tolerance, 31 plants were selected. Crosses between most selected plants and two testers, which belonged to P. guenoarum, were performed, and the generated progeny was planted into the field following a randomized block design with 3 replications. The progeny test was evaluated for seed fertility, biomass yield, and cold tolerance. This procedure allowed selection of 10 elite plants from the SSTP. These plants should contain genes recombined from six apomictic species, without the genetic determinants for apomixis. They may be polycrossed to generate an improved sexual population, or crossed with other apomictic genotypes to obtain improved apomictic hybrids.Fil: Novo, Patricia Elda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Acuña, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Urbani, Mario Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Galdeano, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Espinoza, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Quarin, Camilo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentin