Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an ...anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma.
We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861.
Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 11% patients receiving benralizumab vs 13 6% patients receiving placebo) and injection site reactions (60 16% vs eight 4%) occurred more frequently with benralizumab than with placebo.
Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted.
MedImmune.
Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often ...render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor-ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of "catch bonds" and on the recent observations that B-cell synapses retract and pull antigen generating a "retracting force", and propose some testable predictions that can lead to future research.
Endosomes are intracellular vesicles that mediate the communication of the cell with its extracellular environment. They are an essential part of the cell's machinery regulating intracellular ...trafficking via the endocytic pathway. Many viruses, which in order to replicate require a host cell, attach themselves to the cellular membrane; an event which usually initiates uptake of a viral particle through the endocytic pathway. In this way viruses hijack endosomes for their journey towards intracellular sites of replication and avoid degradation without host detection by escaping the endosomal compartment. Recent experimental techniques have defined the role of endosomal maturation in the ability of enveloped viruses to release their genetic material into the cytoplasm. Endosome maturation depends on a family of small hydrolase enzymes (or GTPases) called Rab proteins, arranged on the cytoplasmic surface of its membrane. Here, we model endosomes as intracellular compartments described by two variables (its levels of active Rab5 and Rab7 proteins) and which can undergo coagulation (or fusion) and fragmentation (or fission). The key element in our approach is the "per-cell endosomal distribution" and its dynamical (Boltzmann) equation. The Boltzmann equation allows us to derive the dynamics of the total number of endosomes in a cell, as well as the mean and the standard deviation of its active Rab5 and Rab7 levels. We compare our mathematical results with experiments of Dengue viral escape from endosomes. The relationship between endosomal active Rab levels and pH suggests a mechanism that can account for the observed variability in viral escape times, which in turn regulate the viability of a viral intracellular infection.
Resveratrol (RVTL) is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of ...RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg) induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX)-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article discusses methods to identify plants by analysing leaf complexity based on estimating their fractal dimension. Leaves were analyzed according to the complexity of their internal and ...external shapes. A computational program was developed to process, analyze and extract the features of leaf images, thereby allowing for automatic plant identification. Results are presented from two experiments, the first to identify plant species from the Brazilian Atlantic forest and Brazilian Cerrado scrublands, using fifty leaf samples from ten different species, and the second to identify four different species from genus Passiflora, using twenty leaf samples for each class. A comparison is made of two methods to estimate fractal dimension (box-counting and multiscale Minkowski). The results are discussed to determine the best approach to analyze shape complexity based on the performance of the technique, when estimating fractal dimension and identifying plants.
In hazardous environments, where conditions present risks for humans, the maintenance and interventions are often done with teleoperated remote systems or mobile robotic manipulators to avoid human ...exposure to dangers. The increasing need for safe and efficient teleoperation requires advanced environmental awareness and collision avoidance. The up-to-date screen-based 2D or 3D interfaces do not fully allow the operator to immerse in the controlled scenario. This problem can be addressed with the emerging Mixed Reality (MR) technologies with Head-Mounted Devices (HMDs) that offer stereoscopic immersion and interaction with virtual objects. Such human-robot interfaces have not yet been demonstrated in telerobotic interventions in particle physics accelerators. Moreover, robotic operations often require a few experts to collaborate, which increases the system complexity and requires sharing a multi-user Augmented Reality (AR) workspace. The multi-user telerobotics with shared control in the AR has not yet been approached in the industrial state-of-the-art. In this work, the developed MR human-robot interface using the AR HMD is presented. The interface adapts to the constrained wireless networks in particle accelerator facilities and provides reliable high-precision interaction and specialized visualization. The multimodal operation uses hands, eyes and user motion tracking, and voice recognition for control, as well as offers video, 3D point cloud and audio feedback from the robot. Multiple experts can collaborate in the AR workspace locally or remotely, share the robot's control and monitor robotic teleoperation. Ten (10) operators tested the interface in intervention scenarios in the European Organization for Nuclear Research (CERN) with complete network characterization and measurements to conclude if operational requirements were met and if the network architecture could support single and multi-user communication load. The interface system has proved to be operationally ready at the Technical Readiness Level (TRL) 8 - and was validated through successful tests and demonstration in single and multi-user missions. Some areas of system limitations and further work were identified, such as optimising the network architecture for multi-user scenarios or high-level interface actions applying automatic interaction strategies with the robot depending on network conditions.
Background Genome-wide association studies (GWASs) of asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB) , IL33 , IL-1 receptor–like 1 and IL-18 receptor 1 ...(IL1RL1-IL18R1) , RAD50-IL13 , thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36) , and HLA-DR/DQ regions. Objective A GWAS of asthma was performed in a non-Hispanic white population. Methods A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases. Results Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α–induced nuclear factor κB inflammation pathway, were associated with asthma: rs1422673 ( P = 3.44 × 10−7 ) and rs10036748 ( P = 1.41 × 10−6 , r 2 = 0.67). rs1422673 was also associated with asthma in the published GABRIEL ( P = .018) and EVE ( P = 1.31 × 10−5 ) studies. The minor allele T of rs20541 in IL13 is the risk allele for asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively. Conclusions Our study suggests that single nucleotide polymorphisms associated with both asthma and autoimmune diseases might have opposite effects on immunopathogenesis.
In this paper, we study inference in a heteroscedastic measurement error model with known error variances. Instead of the normal distribution for the random components, we develop a model that ...assumes a skew-t distribution for the true covariate and a centred Student's t distribution for the error terms. The proposed model enables to accommodate skewness and heavy-tailedness in the data, while the degrees of freedom of the distributions can be different. Maximum likelihood estimates are computed via an EM-type algorithm. The behaviour of the estimators is also assessed in a simulation study. Finally, the approach is illustrated with a real data set from a methods comparison study in Analytical Chemistry.
Este artículo discute si expresiones del arte como La Fragua, teatro jesuita en Honduras, pueden insertarse en la sociología como sistema general de comunicación propuesta por Niklas Luhmann; sobre ...todo, en lo que respecta a su comprensión distinta sobre el conflicto y la violencia y su función como comunicación negativa. En esta dirección, apoyado en el concepto de medios de comunicación simbólicamente generalizados, pieza central de la arquitectura teórica de Luhmann, este escrito ensaya una interpretación de Teatro La Fragua, de las expectativas de su propuesta artística en el contexto de la violencia en Honduras, cuya espiral de letalidad aumentó después del golpe de Estado ocurrido en 2009.
Realidad: Revista de Ciencias Sociales y Humanidades No. 162, 2023: 36-50.
The reliability of wireless communication in a network of mobile wireless robot nodes depends on the received radio signal strength (RSS). When the robot nodes are deployed in hostile environments ...with ionizing radiations (such as in some scientific facilities), there is a possibility that some electronic components may fail randomly (due to radiation effects), which causes problems in wireless connectivity. The objective of this paper is to maximize robot mission capabilities by maximizing the wireless network capacity and to reduce the risk of communication failure. Thus, in this paper, we consider a multi-node wireless tethering structure called the "server-relay-client" framework that uses (multiple) relay nodes in between a server and a client node. We propose a robust stochastic optimization (RSO) algorithm using a multi-sensor-based RSS sampling method at the relay nodes to efficiently improve and balance the RSS between the source and client nodes to improve the network capacity and to provide redundant networking abilities. We use pre-processing techniques, such as exponential moving averaging and spatial averaging filters on the RSS data for smoothing. We apply a receiver spatial diversity concept and employ a position controller on the relay node using a stochastic gradient ascent method for self-positioning the relay node to achieve the RSS balancing task. The effectiveness of the proposed solution is validated by extensive simulations and field experiments in CERN facilities. For the field trials, we used a youBot mobile robot platform as the relay node, and two stand-alone Raspberry Pi computers as the client and server nodes. The algorithm has been proven to be robust to noise in the radio signals and to work effectively even under non-line-of-sight conditions.
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