Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Funding: British Women’s Heart and Health Study is funded by the Department of Health grant no. 90049 and the British Heart Foundation grant no. PG/09/022. British Regional Heart Study is supported by the British Heart Foundation (grant RG/ 13/16/30528). CB (COPDBEAT) received funding from the Medical Research Council UK (grant no. G0601369), CB (COPDBEAT) and AJW (UKCOPD) were supported by the National Institute for Health Research (NIHR Leicester Biomedical Research Unit). MB (COPDBEAT) received funding from the NIHR (grant no. PDF-2013-06-052). Hertfordshire Cohort Study received support from the Medical Research Council, Arthritis Research UK, the International Osteoporosis Foundation and the British Heart Foundation; NIHR Biomedical Research Centre in Nutrition, University of Southampton; NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Generation Scotland: Scottish Family Health Study is funded by the Chief Scientist Office, Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council grant HR03006. EU COPD Gene Scan is funded by the European Union, grant no. QLG1-CT-2001-01012. English Longitudinal Study of Aging is funded by the Institute of Aging, NIH grant No. AG1764406S1. GoDARTs is funded by the Wellcome Trust grants 072960, 084726 and 104970. MDT has been supported by MRC fellowship G0902313. UK Biobank Lung Exome Variant Evaluation study was funded by a Medical Research Council strategic award to MDT, IPH, DPS and LVW (MC_PC_12010)

A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase

Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease. However, compliance with dietary treatment is difficult and when it is for life, as now recommended by an internationally used set of guidelines, is probably unrealistic. Herein we describe experiments on a mouse model using another modality for treatment of PKU compatible with better compliance using ancillary phenylalanine ammonia lyase (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase (EC 1.14.16.1), which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N′-nitrosourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (PAL reduces HPA)—both pharmacologic (with a clear dose–response effect vs. HPA after PAL injection) and physiologic (protected enteral PAL is significantly effective vs. HPA). These findings open another way to facilitate treatment of this classic genetic disease.

CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia

This report describes a tumor-associated antigen, termed CML66, initially cloned from a chronic myelogenous leukemia (CML) cDNA expression library. CML66 encodes a 583-aa protein with a molecular mass of 66 kDa and no significant homology to other known genes. CML66 gene is localized to human chromosome 8q23, but the function of this gene is unknown. CML66 is expressed in leukemias and a variety of solid tumor cell lines. When examined by Northern blot, expression in normal tissues was restricted to testis and heart, and no expression was found in hematopoietic tissues. When examined by quantitative reverse transcription–PCR, expression in CML cells was 1.5-fold higher than in normal peripheral blood mononuclear cells. The presence of CML66-specific antibody in patient serum was confirmed by Western blot and the development of high titer IgG antibody specific for CML66 correlated with immune induced remission of CML in a patient who received infusion of normal donor lymphocytes for treatment of relapse. CML66 antibody also was found in sera from 18–38% of patients with lung cancer, melanoma, and prostate cancer. These findings suggest that CML66 may be immunogenic in a wide variety of malignancies and may be a target for antigen-specific immunotherapy.

Retinal microglia are activated by systemic fungal infection

Purpose: To determine whether systemic fungal infection could cause activation of retinal microglia and therefore could be potentially harmful for patients with retinal degenerative diseases. Methods: Activation of retinal microglia was measured in a model of sublethal invasive candidiasis in C57BL/6J mice by (i) confocal immunofluorescence and (ii) flow cytometry analysis, using anti-CD11b, anti-Iba1, anti-MHCII and anti-CD45 antibodies. Results: Systemic fungal infection causes activation of retinal microglia, with phenotypic changes in morphology, surface markers expression, and microglial re-location in retinal layers. Conclusions: As an excessive or prolonged microglial activation may lead to chronic inflammation with severe pathological side effects, causing or worsening the course of retinal dystrophies, a systemic infection may represent a risk factor to be considered in patients with ocular neurodegenerative diseases, such as diabetic retinopathy, glaucoma, age-related macular degeneration or retinitis pigmentosa.

Microglia activation in a model of retinal degeneration and TUDCA neuroprotective effects

Background: Retinitis pigmentosa is a heterogeneous group of inherited neurodegenerative retinal disorders characterized by a progressive peripheral vision loss and night vision difficulties, subsequently leading to central vision impairment. Chronic microglia activation is associated with various neurodegenerative diseases including retinitis pigmentosa. The objective of this study was to quantify microglia activation in the retina of P23H rats, an animal model of retinitis pigmentosa, and to evaluate the therapeutic effects of TUDCA (tauroursodeoxycholic acid), which has been described as a neuroprotective compound. Methods: For this study, homozygous P23H line 3 and Sprague-Dawley (SD) rats were injected weekly with TUDCA (500 mg/kg, ip) or vehicle (saline) from 20 days to 4 months old. Vertical retinal sections and whole-mount retinas were immunostained for specific markers of microglial cells (anti-CD11b, anti-Iba1 and anti-MHC-II). Microglial cell morphology was analyzed and the number of retinal microglial was quantified. Results: Microglial cells in the SD rat retinas were arranged in regular mosaics homogenously distributed within the plexiform and ganglion cell layers. In the P23H rat retina, microglial cells increased in number in all layers compared with control SD rat retinas, preserving the regular mosaic distribution. In addition, a large number of amoeboid CD11b-positive cells were observed in the P23H rat retina, even in the subretinal space. Retinas of TUDCA-treated P23H animals exhibited lower microglial cell number in all layers and absence of microglial cells in the subretinal space. Conclusions: These results report novel TUDCA anti-inflammatory actions, with potential therapeutic implications for neurodegenerative diseases, including retinitis pigmentosa.

Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration

All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA), the major component of bear bile, to P23H rats preserves cone and rod structure and function, together with their contact with postsynaptic neurons. The neuroprotective effects of safranal and TUDCA make these compounds potentially useful for therapeutic applications in retinal degenerative diseases.

Rendimiento académico del ABP en Anatomía

Desde que en la Universidad de Alicante se implantaron los nuevos planes de estudios EEES en el curso 2010-11, hasta la actualidad, se ha estado aplicando la metodología docente colaborativa de aprendizaje basado en problemas (ABP) en asignaturas del área de Anatomía Humana y Embriología impartidas en los primeros cursos de las titulaciones de Grado en “Enfermería”, “Nutrición Humana y Dietética”, “Óptica y Optometría” y “Ciencias de la Actividad Física y del Deporte”. El objetivo de este estudio es comparar los resultados de aprendizaje a través del rendimiento académico obtenido en la evaluación continua según diferentes metodologías docentes. En general, las calificaciones obtenidas en la evaluación de la exposición oral en grupo del trabajo ABP fueron mucho mejores en todas las asignaturas a lo largo de los últimos 5 años. Los resultados de las pruebas objetivas de respuesta múltiple usadas para evaluar los logros de aprendizaje mediante el uso de clases magistrales de teoría y prácticas de laboratorio fueron algo inferiores. Se plantea la posibilidad de incrementar el número de actividades de ABP y asignar un mayor peso en la ponderación de los criterios de evaluación de la asignatura.

Ensayo de evaluación a distancia frente a evaluación presencial

El sistema de evaluación debe valorar las competencias adquiridas por el estudiante según los conocimientos, habilidades y aptitudes que ha desarrollado a lo largo del proceso de enseñanza-aprendizaje. Este proceso debe ser válido, además de confiable y práctico. Es necesario estudiar los diversos métodos de evaluación disponibles y su idoneidad para las distintas actividades de los grados. El hecho de disponer de herramientas que permiten realizar una evaluación a distancia nos hizo plantearnos la idoneidad de este sistema. Así pues, con el objeto de evaluar la fiabilidad de la evaluación a distancia, se realizó una experiencia en la que se compararon las calificaciones obtenidas en actividades prácticas y seminarios, empleando ambas modalidades de evaluación: presencial y a distancia, mediante las herramientas del campus virtual. Como pudimos comprobar, no hubo diferencias significativas según la modalidad de evaluación, por lo que, con los datos de los que disponemos, podemos aceptar ambos sistemas como igualmente efectivos. Estudiamos también el efecto de la realización de una prueba previa de autoevaluación. En este caso sí encontramos como consecuencia un ligero incremento en la nota, por lo que recomendamos esta actividad para la mejora del rendimiento académico.

Análisis de los procesos de la evaluación en las nuevas titulaciones de grado

Para poder calificar de forma adecuada las competencias adquiridas por el alumno, las asignaturas de los grados requieren la aplicación de distintos procedimientos de evaluación. Existen múltiples y diversos modelos, métodos y técnicas de evaluación disponibles, que no son igualmente válidos para cualquier tipo de actividad. Planteamos esta red con el objetivo fundamental de profundizar en la revisión y el análisis de los métodos de evaluación empleados en diversas asignaturas de títulos de grado de Ciencias de la Salud de la Universidad de Alicante. Analizamos las calificaciones obtenidas en las distintas actividades realizadas durante los cursos académicos 2012 a 2015. Realizamos una experiencia piloto para evaluar la eficacia y fiabilidad de un sistema de evaluación a distancia mediante el uso del campus virtual. A la vista de los resultados, discutimos y sugerimos posibles formas de mejora del proceso evaluador habitualmente empleado, entre los que destacamos ajustar el peso de cada actividad en la calificación global e introducir cuestionarios de autoevaluación.

Catharine Waugh McCullouch papers in the Mary Earhart Dillon collection, 1869-1945

Collection primarily documents McCulloch's research on women's legal status, and her work with the Illinois Equal Suffrage Association, the National American Woman Suffrage Association, and the League of Women Voters. There is also documentation of women in the legal profession, of McCulloch's friendships with the other women suffragists and lawyers, and some biographical material. The papers contain little information about her family or social life.