Liquid-crystalline ordering of antimicrobial peptide-DNA complexes controls TLR9 activation.

Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor-9 (TLR9; refs , , , , ). It is also known that the formation of DNA-antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self-assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR-Ligand Off-Rates Measurements on Living Cells.

The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide-MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8(+) T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor-specific CD8(+) T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide-MHC multimer technology, which uses reversible Ni(2+)-nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow-cytometric-based measurements of monomeric TCR-pMHC dissociation rates of living CD8(+) T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR-pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment.

Directional dominance on stature and cognition in diverse human populations.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

ENRAIZAMIENTO DE VITROPLANTAS DE MEMBRILLO (Cydonia oblonga) POR MEDIO DE INMERSIÓN TEMPORAL AUTOMATIZADA Y SU ACLIMATACIÓN

RESUMEN El membrillo (Cydonia oblonga) es un frutal no tradicional en Costa Rica que presenta propiedades médicas y nutricionales, sin embargo la lentitud del crecimiento y enraizamiento dificulta obtener poblaciones homogéneas mediante técnicas convencionales. Es por esta razón que esta investigación tuvo como objetivo la producción de material vegetal uniforme en tiempos reducidos empleando sistemas de inmersión temporal (RITA ®). Se utilizó como referencia un medio de enraizamiento semisólido MS, suplementado con 0,1 mg L-1 ANA; 0,3 mg L-1 AIB y 3% de sacarosa a un pH de 6,5; desarrollado por el Centro de Investigación en Biotecnología(CIB), del Instituto Tecnológico de Costa Rica (IT CR), en Cartago. Se realizaron cuatro variaciones en la concentración de sacarosa (1%, 2%, 3% y 4%) en medio líquido. Cada ensayo fue evaluado con vitroplantas previamente expuestas al medio correspondiente empleado en los tratamientos, de forma estacionaria por un período de 15 días, y con vitroplantas sin tratamiento previo (ocho tratamientos en total). La comparación de los porcentajes de enraizamiento mostraron una influencia directa en la dosis de sacarosa utilizada, obteniéndose los mejores resultados con 2% de sacarosa sin pretratamiento (73,3%). Las vitroplantas se aclimataron en cilindros a base de turba previamente desinfectados con fungicidas y se colocaron en cámaras húmedas a una temperatura promedio de 20,5 °C y una humedad relativa de 75,5% estableciendo ciclos de fertilización semanales. Se obtuvo un 80% de sobrevivencia a la aclimatación, debido a que algunas plántulas presentaron un estrangulamiento del tallo provocado por un ataque fúngico. Los conidióforos identificados por microscopia óptica y electrónica de barrido mostraron la presencia de Cladosporium spp., el cual fue controlado con las moléculas fungicidas carbendazima e iprodione.

El papel y el impacto del tutor en el Aprendizaje Basado en Problemas: una revisión de la evidencia empírica

Este artículo pretende estudiar el impacto del tutor de ABP en los aprendizajes de los estudiantes de educación superior mediante la revisión de los estudios empríricos publicados. El análisis se desarrolla sobre tres ejes el rendimiento de los grupos de trabajo; sus dinámicas y funcionamiento interno; y la percepción y el grado de satisfacción de los estudiantes frente a la tutoría , y se concluye con una reflexión sobre el papel que debería jugar el tutor de ABP de acuerdo con la noción de «congruencia cognitiva» de H. G. Schmidt y J. H. Moust.

Correcting surface coil excitation inhomogeneities in single-shot SPEN MRI.

Given their high sensitivity and ability to limit the field of view (FOV), surface coils are often used in magnetic resonance spectroscopy (MRS) and imaging (MRI). A major downside of surface coils is their inherent radiofrequency (RF) B1 heterogeneity across the FOV, decreasing with increasing distance from the coil and giving rise to image distortions due to non-uniform spatial responses. A robust way to compensate for B1 inhomogeneities is to employ adiabatic inversion pulses, yet these are not well adapted to all imaging sequences - including to single-shot approaches like echo planar imaging (EPI). Hybrid spatiotemporal encoding (SPEN) sequences relying on frequency-swept pulses provide another ultrafast MRI alternative, that could help solve this problem thanks to their built-in heterogeneous spatial manipulations. This study explores how this intrinsic SPEN-based spatial discrimination, could be used to compensate for the B1 inhomogeneities inherent to surface coils. Experiments carried out in both phantoms and in vivo rat brains demonstrate that, by suitably modulating the amplitude of a SPEN chirp pulse that progressively excites the spins in a direction normal to the coil, it is possible to compensate for the RF transmit inhomogeneities and thus improve sensitivity and image fidelity.

False normal Lung Clearance Index in infants with cystic fibrosis due to software algorithms.

BACKGROUND: Lung clearance index (LCI), a marker of ventilation inhomogeneity, is elevated early in children with cystic fibrosis (CF). However, in infants with CF, LCI values are found to be normal, although structural lung abnormalities are often detectable. We hypothesized that this discrepancy is due to inadequate algorithms of the available software package. AIM: Our aim was to challenge the validity of these software algorithms. METHODS: We compared multiple breath washout (MBW) results of current software algorithms (automatic modus) to refined algorithms (manual modus) in 17 asymptomatic infants with CF, and 24 matched healthy term-born infants. The main difference between these two analysis methods lies in the calculation of the molar mass differences that the system uses to define the completion of the measurement. RESULTS: In infants with CF the refined manual modus revealed clearly elevated LCI above 9 in 8 out of 35 measurements (23%), all showing LCI values below 8.3 using the automatic modus (paired t-test comparing the means, P < 0.001). Healthy infants showed normal LCI values using both analysis methods (n = 47, paired t-test, P = 0.79). The most relevant reason for false normal LCI values in infants with CF using the automatic modus was the incorrect recognition of the end-of-test too early during the washout. CONCLUSION: We recommend the use of the manual modus for the analysis of MBW outcomes in infants in order to obtain more accurate results. This will allow appropriate use of infant lung function results for clinical and scientific purposes. Pediatr Pulmonol. 2015; 50:970-977. © 2015 Wiley Periodicals, Inc.

Eye-tracking of nodule detection in lung CT volumetric data.

PURPOSE: Signal detection on 3D medical images depends on many factors, such as foveal and peripheral vision, the type of signal, and background complexity, and the speed at which the frames are displayed. In this paper, the authors focus on the speed with which radiologists and naïve observers search through medical images. Prior to the study, the authors asked the radiologists to estimate the speed at which they scrolled through CT sets. They gave a subjective estimate of 5 frames per second (fps). The aim of this paper is to measure and analyze the speed with which humans scroll through image stacks, showing a method to visually display the behavior of observers as the search is made as well as measuring the accuracy of the decisions. This information will be useful in the development of model observers, mathematical algorithms that can be used to evaluate diagnostic imaging systems. METHODS: The authors performed a series of 3D 4-alternative forced-choice lung nodule detection tasks on volumetric stacks of chest CT images iteratively reconstructed in lung algorithm. The strategy used by three radiologists and three naïve observers was assessed using an eye-tracker in order to establish where their gaze was fixed during the experiment and to verify that when a decision was made, a correct answer was not due only to chance. In a first set of experiments, the observers were restricted to read the images at three fixed speeds of image scrolling and were allowed to see each alternative once. In the second set of experiments, the subjects were allowed to scroll through the image stacks at will with no time or gaze limits. In both static-speed and free-scrolling conditions, the four image stacks were displayed simultaneously. All trials were shown at two different image contrasts. RESULTS: The authors were able to determine a histogram of scrolling speeds in frames per second. The scrolling speed of the naïve observers and the radiologists at the moment the signal was detected was measured at 25-30 fps. For the task chosen, the performance of the observers was not affected by the contrast or experience of the observer. However, the naïve observers exhibited a different pattern of scrolling than the radiologists, which included a tendency toward higher number of direction changes and number of slices viewed. CONCLUSIONS: The authors have determined a distribution of speeds for volumetric detection tasks. The speed at detection was higher than that subjectively estimated by the radiologists before the experiment. The speed information that was measured will be useful in the development of 3D model observers, especially anthropomorphic model observers which try to mimic human behavior.

Cancer testiculaire: un modèle pour optimiser le suivi radiologique [Testicular cancer: a model to optimize the radiological follow-up].

Le cancer testiculaire, bien que peu fréquent, revêt une importance particulière en oncologie ; il représente actuellement un modèle pour optimiser un suivi radiologique tout en essayant de diminuer l'apparition de tumeurs radio-induites.En effet, cette pathologie présente un taux très élevé de survie nécessitant, au vu du jeune âge des patients, des bilans radiologiques à long terme, auxquels pourront être liés des effets secondaires, en particulier les tumeurs secondaires.Afin de diminuer cela, les recommandations de prise en charge ont évolué et les protocoles de radiologie s'améliorent afin d'exposer à moins de rayonnements ionisants pour un résultat identique.Il est donc devenu primordial de maintenir un suivi optimal tout en essayant d'en minimiser la toxicité. Despite being rare cancers, testicular seminoma and non-seminoma play an important role in oncology: they represent a model on how to optimize radiological follow-up, aiming at a lowest possible radiation exposure and secondary cancer risk. Males diagnosed with testicular cancer undergo frequently prolonged follow-up with CT-scans with potential toxic side effects, in particular secondary cancers. To reduce the risks linked to ionizing radiation, precise follow-up protocols have been developed. The number of recommended CT-scanners has been significantly reduced over the last 10 years. The CT scanners have evolved technically and new acquisition protocols have the potential to reduce the radiation exposure further.