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Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG 1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro . They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src.

Mesenchymal stem cells (MSCs) have great potential for cell-based therapies. However, lack of cell-specific markers thwarts full realization of this as it prevents their identification in vivo, and subsequent purification. In the present study, to ensure cell purity multiple individual clones were derived from the bone marrow of BALB/b and BALB/c mice, and subsequently defined as MSCs by demonstrating their multipotentiality and self-renewal ability. In an effort to define the molecular signature of such MSCs and identify potentially cell-specific markers, an extensive genome-wide microarray analysis was performed comparing eight individual undifferentiated MSC clones to four different controls—corresponding differentiated MSC clones, bone marrow adherent cells, freshly isolated bone marrow cells, and embryonic fibroblasts. Strikingly, all MSC clones expressed differentially high levels of six-transmembrane epithelial antigen of the prostate (STEAP1 and STEAP2). Further, both STEAP members showed an extremely similar expression profile to stem cell antigen-1 (Sca-1) as demonstrated by two-dimensional hierarchical cluster analysis. Most importantly, differentially high levels of STEAP1 and STEAP2 proteins were also detected in human multipotent bone marrow adherent cultures. Thus, STEAPs may represent novel markers of MSCs in man as well as mice. Depletion of STEAP1 in human MSCs using RNAi resulted in decreased cell adhesion to tissue culture plastic. Further work is now needed to fully uncover its function in these cells, and to explore its potential as a marker of MSCs.

The object of this study is to assess informative possibilities of some technical indicators of the Test of Photos of Professions (BBT – Berufsbilder test), a projective method to clarify professional inclination, proposed by Martin Achtnich. This psychological evaluation technique is composed of 96 photos of professionals, performing various types of activities. The test subject classifies the photos into three groups: positive (agreeable), negative (disagreeable) and indifferent (neutral). Among those chosen positively, five preferences are chosen and a story is developed that includes them, an activity that is requested two times during the Vocational Guidance process: in the beginning (or middle) and at the end of the intervention. In this study, 160 stories were created by 80 youths, between 15 and 20 years of age, in public and private schools in a mid-sized Brazilian city. The stories were compared in three analytical categories: protagonist, professional conflict and resolution. The results were submitted to Wilcoxon nonparametric statistical analysis (p < .05), significant and relevant indicators of resolution being found in the process of occupational choice. This technical resource was shown, from this empirical evidence, to be promising for use in evaluation of intervention processes of Vocational Guidance. El objetivo de este estudio es evaluar las posibilidades informativas de algunos indicadores técnicos del Test de Fotos de Profesiones (BBT – Berufsbilder test), un método proyectivo para clarificar la inclinación profesional, propuesto por Martin Achtnich. Esta técnica de evaluación psicológica se compone de 96 fotografías de profesionales, realizando varios tipos de actividades. El sujeto del test clasifica las fotos en tres grupos: positivas (agradables), negativas (desagradables) e indiferentes (neutrales). Entre las fotos clasificadas positivamente, se eligen tres preferencias y se desarrolla una historieta que las incluya, actividad que es llevada a cabo dos veces durante el proceso de Orientación Vocacional: al principio (o en medio) y al final de la intervención. En este estudio, 80 jóvenes, de edades entre los 15 y los 20 años, procedentes de escuelas públicas y privadas de una ciudad de tamaño intermedio de Brasil, crearon 160 historietas. Se dividieron las historietas en tres categorías analíticas: protagonista, conflicto profesional, y resolución. Los resultados se sometieron al análisis estadístico no paramétrico Wilcoxon (p < .05), ), encontrando indicadores significativos y relevantes de haber llegado a resolución en el proceso de elección profesional. Debido a esta evidencia empírica, este recurso técnico se muestra prometedor para la evaluación de los procesos de intervención de Orientación Vocacional.

The object of this study is to assess informative possibilities of some technical indicators of the Test of Photos of Professions (BBT–Berufsbilder test), a projective method to clarify professional inclination, proposed by Martin Achtnich. This psychological evaluation technique is composed of 96 photos of professionals, performing various types of activities. The test subject classifies the photos into three groups: positive (agreeable), negative (disagreeable) and indifferent (neutral). Among those chosen positively, five preferences are chosen and a story is developed that includes them, an activity that is requested two times during the Vocational Guidance process: in the beginning (or middle) and at the end of the intervention. In this study, 160 stories were created by 80 youths, between 15 and 20 years of age, in public and private schools in a mid-sized Brazilian city. The stories were compared in three analytical categories: protagonist, professional conflict and resolution. The results were submitted to Wilcoxon nonparametric statistical analysis (p < .05), significant and relevant indicators of resolution being found in the process of occupational choice. This technical resource was shown, from this empirical evidence, to be promising for use in evaluation of intervention processes of Vocational Guidance. Keywords: BBT, Berufsbilder test, vocational guidance, projective test El objetivo de este estudio es evaluar las posibilidades informativas de algunos indicadores tecnicos del Test de Fotos de Profesiones (BBT– Berufsbilder test), un metodo proyectivo para clarificar la inclinacion profesional, propuesto por Martin Achtnich. Esta tecnica de evaluacion psicologica se compone de 96 fotografias de profesionales, realizando varios tipos de actividades. El sujeto del test clasifica las fotos en tres grupos: positivas (agradables), negativas (desagradables) e indiferentes (neutrales). Entre las fotos clasificadas positivamente, se eligen tres preferencias y se desarrolla una historieta que las incluya, actividad que es llevada a cabo dos veces durante el proceso de Orientacion Vocacional: al principio (o en medio) y al final de la intervencion. En este estudio, 80 jovenes, de edades entre los 15 y los 20 anos, procedentes de escuelas publicas y privadas de una ciudad de tamano intermedio de Brasil, crearon 160 historietas. Se dividieron las historietas en tres categorias analiticas: protagonista, conflicto profesional, y resolucion. Los resultados se sometieron al analisis estadistico no parametrico Wilcoxon (p < .05), ), encontrando indicadores significativos y relevantes de haber llegado a resolucion en el proceso de eleccion profesional. Debido a esta evidencia empirica, este recurso tecnico se muestra prometedor para la evaluacion de los procesos de intervencion de Orientacion Vocacional. Palabras clave: BBT, Berufsbilder test, orientacion vocacional, test proyectivo