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1.
Proc Natl Acad Sci U S A ; 119(14): e2112336119, 2022 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-35349336

RESUMEN

SignificanceOur full-scale comparison of Africa and South America's lowland tropical tree floras shows that both Africa and South America's moist and dry tree floras are organized similarly: plant families that are rich in tree species on one continent are also rich in tree species on the other continent, and these patterns hold across moist and dry environments. Moreover, we confirm that there is an important difference in tree species richness between the two continents, which is linked to a few families that are exceptionally diverse in South American moist forests, although dry formations also contribute to this difference. Plant families only present on one of the two continents do not contribute substantially to differences in tree species richness.


Asunto(s)
Árboles , Clima Tropical , Biodiversidad , Bosques , Plantas , América del Sur
2.
Clin Exp Immunol ; 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38700066

RESUMEN

Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of cutaneous leishmaniasis.

3.
Gastroenterology ; 163(5): 1351-1363.e15, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35810781

RESUMEN

BACKGROUND & AIMS: Genes and gluten are necessary but insufficient to cause celiac disease (CeD). Altered gut microbiota has been implicated as an additional risk factor. Variability in sampling site may confound interpretation and mechanistic insight, as CeD primarily affects the small intestine. Thus, we characterized CeD microbiota along the duodenum and in feces and verified functional impact in gnotobiotic mice. METHODS: We used 16S rRNA gene sequencing (Illumina) and predicted gene function (PICRUSt2) in duodenal biopsies (D1, D2 and D3), aspirates, and stool from patients with active CeD and controls. CeD alleles were determined in consented participants. A subset of duodenal samples stratified according to similar CeD risk genotypes (controls DQ2-/- or DQ2+/- and CeD DQ2+/-) were used for further analysis and to colonize germ-free mice for gluten metabolism studies. RESULTS: Microbiota composition and predicted function in CeD was largely determined by intestinal location. In the duodenum, but not stool, there was higher abundance of Escherichia coli (D1), Prevotella salivae (D2), and Neisseria (D3) in CeD vs controls. Predicted bacterial protease and peptidase genes were altered in CeD and impaired gluten degradation was detected only in mice colonized with CeD microbiota. CONCLUSIONS: Our results showed luminal and mucosal microbial niches along the gut in CeD. We identified novel microbial proteolytic pathways involved in gluten detoxification that are impaired in CeD but not in controls carrying DQ2, suggesting an association with active duodenal inflammation. Sampling site should be considered a confounding factor in microbiome studies in CeD.


Asunto(s)
Enfermedad Celíaca , Microbioma Gastrointestinal , Ratones , Animales , Enfermedad Celíaca/complicaciones , ARN Ribosómico 16S/genética , Glútenes/metabolismo , Péptido Hidrolasas
4.
Entropy (Basel) ; 25(5)2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37238468

RESUMEN

Canonical Correlation Analysis (CCA) infers a pairwise linear relationship between two groups of random variables, X and Y. In this paper, we present a new procedure based on Rényi's pseudodistances (RP) aiming to detect linear and non-linear relationships between the two groups. RP canonical analysis (RPCCA) finds canonical coefficient vectors, a and b, by maximizing an RP-based measure. This new family includes the Information Canonical Correlation Analysis (ICCA) as a particular case and extends the method for distances inherently robust against outliers. We provide estimating techniques for RPCCA and show the consistency of the proposed estimated canonical vectors. Further, a permutation test for determining the number of significant pairs of canonical variables is described. The robustness properties of the RPCCA are examined theoretically and empirically through a simulation study, concluding that the RPCCA presents a competitive alternative to ICCA with an added advantage in terms of robustness against outliers and data contamination.

5.
Entropy (Basel) ; 24(5)2022 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-35626501

RESUMEN

The Rao's score, Wald and likelihood ratio tests are the most common procedures for testing hypotheses in parametric models. None of the three test statistics is uniformly superior to the other two in relation with the power function, and moreover, they are first-order equivalent and asymptotically optimal. Conversely, these three classical tests present serious robustness problems, as they are based on the maximum likelihood estimator, which is highly non-robust. To overcome this drawback, some test statistics have been introduced in the literature based on robust estimators, such as robust generalized Wald-type and Rao-type tests based on minimum divergence estimators. In this paper, restricted minimum Rényi's pseudodistance estimators are defined, and their asymptotic distribution and influence function are derived. Further, robust Rao-type and divergence-based tests based on minimum Rényi's pseudodistance and restricted minimum Rényi's pseudodistance estimators are considered, and the asymptotic properties of the new families of tests statistics are obtained. Finally, the robustness of the proposed estimators and test statistics is empirically examined through a simulation study, and illustrative applications in real-life data are analyzed.

6.
J Med Internet Res ; 22(12): e20832, 2020 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-33275111

RESUMEN

BACKGROUND: Recent advancements in active assisted living (AAL) technologies allow older adults to age well in place. However, sensing technologies increase the complexity of data collection points, making it difficult for users to consent to data collection. One possible solution for improving transparency in the consent management process is the use of blockchain, an immutable and timestamped ledger. OBJECTIVE: This study aims to provide a conceptual framework based on technology aimed at mitigating trust issues in the consent management process. METHODS: The consent management process was modeled using established methodologies to obtain a mapping of trust issues. This mapping was then used to develop a conceptual framework based on previous monitoring and surveillance architectures for connected devices. RESULTS: In this paper, we present a model that maps trust issues in the informed consent process; a conceptual framework capable of providing all the necessary underlining technologies, components, and functionalities required to develop applications capable of managing the process of informed consent for AAL, powered by blockchain technology to ensure transparency; and a diagram showing an instantiation of the framework with entities comprising the participants in the blockchain network, suggesting possible technologies that can be used. CONCLUSIONS: Our conceptual framework provides all the components and technologies that are required to enhance the informed consent process. Blockchain technology can help overcome several privacy challenges and mitigate trust issues that are currently present in the consent management process of data collection involving AAL technologies.


Asunto(s)
Actividades Cotidianas/psicología , Cadena de Bloques/normas , Anciano , Humanos
7.
Rheumatology (Oxford) ; 58(12): 2193-2202, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31184752

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA. METHODS: Patients received 48 weeks' treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48-72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed. RESULTS: At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups. CONCLUSION: Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety. TRAIL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02149121.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Sustitución de Medicamentos , Rituximab/uso terapéutico , Adulto , Biosimilares Farmacéuticos , Método Doble Ciego , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Resultado del Tratamiento , Estados Unidos
8.
J Neuroeng Rehabil ; 16(1): 123, 2019 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-31653265

RESUMEN

BACKGROUND: Trans-spinal direct current stimulation (tsDCS) is a non-invasive technique with promising neuromodulatory effects on spinal cord (SC) circuitry. Computational studies are essential to guide effective tsDCS protocols for specific clinical applications. This study aims to combine modelling and experimental studies to determine the electrode montage that maximizes electric field (E-field) delivery during cervical tsDCS. METHODS: Current and E-field distributions in the cervical SC were predicted for four electrode montages in a human realistic model using computational methods. A double-blind crossover and randomized exploratory study was conducted using the montage that maximized E-field delivery. tsDCS was applied for 15 min in 10 healthy subjects (anodal, cathodal, sham, with polarity assigned to the cervical electrode), with a current intensity of 2.5 mA, resulting in a total current charge density delivery of 90 mC/cm2. Upper limb motor (transcranial magnetic stimulation) and sensory evoked potentials (MEP, SEP), M-waves, H-reflex and F-wave responses were analysed. Central and peripheral conduction times were determined using MEP. Repeated measures ANOVA and Friedman test were used for statistical analysis (significance level α = 0.05). RESULTS: All montages presented higher current density and E-field magnitudes in the cervical SC region between the electrodes. However, electrodes at C3 and T3 spinous processes (C3-T3) originated the highest E-field magnitude (0.50 V/m). Using C3-T3 montage we observed significant changes in N9 SEP latency (p = 0.006), but significance did not persist in pairwise comparisons (sham-anodal: p = 0.022; sham-cathodal: p = 0.619; anodal-cathodal: p = 0.018; α = 0.017, Bonferroni corrected). MEP latency and central motor conduction time (CMCT) modified significantly on stimulation (p = 0.007 and p = 0.015, respectively). In addition, pairwise comparisons confirmed significant differences between sham and cathodal conditions after Bonferroni correction for MEP latency (sham-anodal: p = 0.868; sham-cathodal: p = 0.011; anodal-cathodal: p = 0.023) and CMCT (sham-anodal: p = 0.929; sham-cathodal: p = 0.010; anodal-cathodal: p = 0.034). CONCLUSIONS: Computational models predicted higher E-field delivery in the cervical SC for the C3-T3 montage. Polarity-dependent effects in motor responses were reported using this montage consistent with spinal motor modulation. tsDCS experimental protocol designs should be guided by modelling studies to improve effectiveness.


Asunto(s)
Médula Cervical/fisiología , Simulación por Computador , Terapia por Estimulación Eléctrica/métodos , Potenciales Evocados Motores/fisiología , Adulto , Estudios Cruzados , Método Doble Ciego , Electrodos , Femenino , Humanos , Masculino , Modelos Neurológicos , Extremidad Superior , Adulto Joven
9.
Biochemistry ; 57(26): 3741-3751, 2018 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-29812904

RESUMEN

Nicotine oxidoreductase (NicA2) is a bacterial flavoenzyme, which catalyzes the first step of nicotine catabolism by oxidizing S-nicotine into N-methyl-myosmine. It has been proposed as a biotherapeutic for nicotine addiction because of its nanomolar substrate binding affinity. The first crystal structure of NicA2 has been reported, establishing NicA2 as a member of the monoamine oxidase (MAO) family. However, substrate specificity and structural determinants of substrate binding and/or catalysis have not been explored. Herein, analysis of the pH-rate profile, single-turnover kinetics, and binding data establish that pH does not significantly affect the catalytic rate and product release is not rate-limiting. The X-ray crystal structure of NicA2 with S-nicotine refined to 2.65 Å resolution reveals a hydrophobic binding site with a solvent exclusive cavity. Hydrophobic interactions predominantly orient the substrate, promoting the binding of a deprotonated species and supporting a hydride-transfer mechanism. Notably, NicA2 showed no activity against neurotransmitters oxidized by the two isoforms of human MAO. To further probe the substrate range of NicA2, enzyme activity was evaluated using a series of substrate analogues, indicating that S-nicotine is the optimal substrate and substitutions within the pyridyl ring abolish NicA2 activity. Moreover, mutagenesis and kinetic analysis of active-site residues reveal that removal of a hydrogen bond between the pyridyl ring of S-nicotine and the hydroxyl group of T381 has a 10-fold effect on KM, supporting the role of this bond in positioning the catalytically competent form of the substrate. Together, crystallography combined with kinetic analysis provides a deeper understanding of this enzyme's remarkable specificity.


Asunto(s)
Proteínas Bacterianas/metabolismo , Nicotina/metabolismo , Oxidorreductasas/metabolismo , Pseudomonas putida/enzimología , Proteínas Bacterianas/química , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Modelos Moleculares , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Nicotina/química , Oxidorreductasas/química , Pseudomonas putida/química , Pseudomonas putida/metabolismo , Especificidad por Sustrato
11.
Bioorg Med Chem ; 26(14): 4234-4239, 2018 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-30037753

RESUMEN

MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.


Asunto(s)
Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Solubilidad , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie
12.
PLoS Genet ; 11(12): e1005602, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26636962

RESUMEN

South America has a complex demographic history shaped by multiple migration and admixture events in pre- and post-colonial times. Settled over 14,000 years ago by Native Americans, South America has experienced migrations of European and African individuals, similar to other regions in the Americas. However, the timing and magnitude of these events resulted in markedly different patterns of admixture throughout Latin America. We use genome-wide SNP data for 437 admixed individuals from 5 countries (Colombia, Ecuador, Peru, Chile, and Argentina) to explore the population structure and demographic history of South American Latinos. We combined these data with population reference panels from Africa, Asia, Europe and the Americas to perform global ancestry analysis and infer the subcontinental origin of the European and Native American ancestry components of the admixed individuals. By applying ancestry-specific PCA analyses we find that most of the European ancestry in South American Latinos is from the Iberian Peninsula; however, many individuals trace their ancestry back to Italy, especially within Argentina. We find a strong gradient in the Native American ancestry component of South American Latinos associated with country of origin and the geography of local indigenous populations. For example, Native American genomic segments in Peruvians show greater affinities with Andean indigenous peoples like Quechua and Aymara, whereas Native American haplotypes from Colombians tend to cluster with Amazonian and coastal tribes from northern South America. Using ancestry tract length analysis we modeled post-colonial South American migration history as the youngest in Latin America during European colonization (9-14 generations ago), with an additional strong pulse of European migration occurring between 3 and 9 generations ago. These genetic footprints can impact our understanding of population-level differences in biomedical traits and, thus, inform future medical genetic studies in the region.


Asunto(s)
ADN Mitocondrial/genética , Etnicidad/genética , Genética de Población , Genoma Humano , Argentina , Población Negra/genética , Colombia , Genómica , Haplotipos , Humanos , Indígenas Norteamericanos/genética , Perú , Grupos Raciales , América del Sur , Población Blanca/genética
13.
Ann Rheum Dis ; 76(6): 1020-1030, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28213566

RESUMEN

OBJECTIVES: Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA. METHODS: In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)-C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28-CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24). RESULTS: 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012-June 2013). Mavrilimumab treatment significantly reduced DAS28-CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: -1.90 (0.14), 100 mg: -1.64 (0.13), 30 mg: -1.37 (0.14), placebo: -0.68 (0.14); p<0.001; all dosages compared with placebo).Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified. CONCLUSIONS: Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential. TRIAL REGISTRATION NUMBER: NCT01706926; results.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/sangre , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Retratamiento , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
14.
Ann Rheum Dis ; 76(2): 346-354, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27117698

RESUMEN

OBJECTIVES: To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS). METHODS: This open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT-P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group). RESULTS: Overall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively. CONCLUSIONS: This is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment. TRIAL REGISTRATION NUMBER: NCT01571206; Results.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Sustitución de Medicamentos , Infliximab/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos/inmunología , Anticuerpos Monoclonales/inmunología , Antirreumáticos/inmunología , Biosimilares Farmacéuticos , Resistencia a Medicamentos/inmunología , Femenino , Humanos , Infliximab/inmunología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
15.
Ann Rheum Dis ; 76(2): 355-363, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27130908

RESUMEN

OBJECTIVES: To assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade) to its biosimilar CT-P13 (Remsima, Inflectra) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions. METHODS: This open-label extension study recruited patients with RA who had completed the 54-week, randomised, parallel-group study comparing CT-P13 with RP (PLANETRA; NCT01217086). CT-P13 (3 mg/kg) was administered intravenously every 8 weeks from weeks 62 to 102. All patients received concomitant methotrexate. Endpoints included American College of Rheumatology 20% (ACR20) response, ACR50, ACR70, immunogenicity and safety. Data were analysed for patients who received CT-P13 for 102 weeks (maintenance group) and for those who received RP for 54 weeks and then switched to CT-P13 (switch group). RESULTS: Overall, 302 of 455 patients who completed the PLANETRA study enrolled into the extension. Of these, 158 had received CT-P13 (maintenance group) and 144 RP (switch group). Response rates at week 102 for maintenance versus switch groups, respectively, were 71.7% vs 71.8% for ACR20, 48.0% vs 51.4% for ACR50 and 24.3% vs 26.1% for ACR70. The proportion of patients with antidrug antibodies was comparable between groups (week 102: 40.3% vs 44.8%, respectively). Treatment-emergent adverse events occurred in similar proportions of patients in the two groups during the extension study (53.5% and 53.8%, respectively). CONCLUSIONS: Comparable efficacy and tolerability were observed in patients who switched from RP to its biosimilar CT-P13 for an additional year and in those who had long-term CT-P13 treatment for 2 years. TRIAL REGISTRATION NUMBER: NCT01571219; Results.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Sustitución de Medicamentos , Infliximab/uso terapéutico , Adolescente , Adulto , Anciano , Anticuerpos/inmunología , Anticuerpos Monoclonales/inmunología , Antirreumáticos/inmunología , Biosimilares Farmacéuticos , Quimioterapia Combinada , Femenino , Humanos , Infliximab/inmunología , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
16.
J Theor Biol ; 403: 38-44, 2016 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-27188251

RESUMEN

In this work we redefine the concept of biological importance and how to compute it, based on a model of complex networks and random walk. We call this new procedure, theoretical knock-out (KO). The proposed method generalizes the procedure presented in a recent study about Oral Tolerance. To devise this method, we make two approaches: algebraically and algorithmically. In both cases we compute a vector on an asymptotic state, called flux vector. The flux is given by a random walk on a directed graph that represents a biological phenomenon. This vector gives us the information about the relative flux of walkers on a vertex which represents a biological agent. With two vector of this kind, we can calculate the relative mean error between them by averaging over its coefficients. This quantity allows us to assess the degree of importance of each vertex of a complex network that evolves in time and has experimental background. We find out that this procedure can be applied in any sort of biological phenomena in which we can know the role and interrelationships of its agents. These results also provide experimental biologists to predict the order of importance of biological agents on a mounted complex network.


Asunto(s)
Técnicas de Inactivación de Genes , Redes Reguladoras de Genes , Modelos Teóricos , Algoritmos
17.
Chemistry ; 21(43): 15211-7, 2015 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-26471437

RESUMEN

The different factors that control the alkene Prins cyclization catalyzed by iron(III) salts have been explored by means of a joint experimental-computational study. The iron(III) salt/trimethylsilyl halide system has proved to be an excellent promoter in the synthesis of crossed all-cis disubstituted tetrahydropyrans, minimizing the formation of products derived from side-chain exchange. In this iron(III)-catalyzed Prins cyclization reaction between homoallylic alcohols and non-activated alkenes, two mechanistic pathways can be envisaged, namely the classical oxocarbenium route and the alternative [2+2] cycloaddition-based pathway. It is found that the [2+2] pathway is disfavored for those alcohols having non-activated and non-substituted alkenes. In these cases, the classical pathway, via the key oxocarbenium ion, is preferred. In addition, the final product distribution strongly depends upon the nature of the substituent adjacent to the hydroxy group in the homoallylic alcohol, which can favor or hamper a side 2-oxonia-Cope rearrangement.

18.
Proc Natl Acad Sci U S A ; 109(17): 6710-5, 2012 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-22493252

RESUMEN

Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven after-effects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity-specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS.


Asunto(s)
Conducta Animal , Estimulación Eléctrica , Aprendizaje , Cráneo/fisiología , Sinapsis/fisiología , Animales , Conejos , Corteza Somatosensorial/fisiología
19.
Environ Manage ; 55(2): 296-307, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25344658

RESUMEN

The loss in forest area due to human occupancy is not the only threat to the remaining biodiversity: forest fragments are susceptible to additional human impact. Our aim was to investigate the effect of human impact on tree community features (species composition and abundance, and structural descriptors) and check if there was a decrease in the number of slender trees, an increase in the amount of large trees, and also a reduction in the number of tree species that occur in 20 fragments of Atlantic montane semideciduous forest in southeastern Brazil. We produced digital maps of each forest fragment using Landsat 7 satellite images and processed the maps to obtain morphometric variables. We used investigative questionnaires and field observations to survey the history of human impact. We then converted the information into scores given to the extent, severity, and duration of each impact, including proportional border area, fire, trails, coppicing, logging, and cattle, and converted these scores into categorical levels. We used linear models to assess the effect of impacts on tree species abundance distribution and stand structural descriptors. Part of the variation in floristic patterns was significantly correlated to the impacts of fire, logging, and proportional border area. Structural descriptors were influenced by cattle and outer roads. Our results provided, for the first time, strong evidence that tree species occurrence and abundance, and forest structure of Atlantic seasonal forest fragments respond differently to various modes of disturbance by humans.


Asunto(s)
Ecosistema , Actividades Humanas , Árboles/crecimiento & desarrollo , Animales , Biodiversidad , Brasil , Bovinos/fisiología , Conservación de los Recursos Naturales , Desastres , Incendios , Bosques , Humanos
20.
J Contemp Dent Pract ; 16(3): 167-71, 2015 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-26057912

RESUMEN

The aim of this study was evaluate the dental enamel after whitening treatment with Opalescence Boost PF™ 38%, correlating the structural alterations in the surface of the enamel with its respective pH and verify if whitened teeth submitted to different finishing and polishing techniques show similar surface texture to healthy teeth (control group). Sixty premolars were divided in 6 groups (n = 10), which had been immersed in artificial saliva during all the experiment. Protocol whitening was performed according to the manufacturer recommendations, and then the specimens were submitted to different polishing technique with Sof-Lex Pop On™ disks, Flex Diamond™ felt disks using two different micrometric polishing pastes (Enamelize™ and Diamond Polish™) and two nanometric polishing pastes (Lummina-E Diamond and Lummina-E Alumina), according to the groups. Representative specimens were analyzed in scanning electronic microscopy (SEM). Whitening gel used in this experiment had modified the morphologic aspect of the enamel surface. It was found that two nanometric polishing pastes (G5 and G6) promoted a less rough surface compared to control group even after the whitening process.


Asunto(s)
Esmalte Dental/ultraestructura , Profilaxis Dental/métodos , Peróxido de Hidrógeno/uso terapéutico , Blanqueadores Dentales/uso terapéutico , Óxido de Aluminio/química , Diamante/química , Humanos , Concentración de Iones de Hidrógeno , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Nanopartículas/química , Distribución Aleatoria , Saliva Artificial/química , Blanqueamiento de Dientes/métodos
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