Bestrophin1: A Gene that Causes Many Diseases

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that lead to the gradual loss of vision in and around the macular area. There are no treatments for patients suffering from bestrophinopathies, and no measures can be taken to prevent visual deterioration in those who have inherited disease-causing mutations. Bestrophinopathies are caused by mutations in the Bestrophin1 gene (BEST1), a protein found exclusively in the retinal pigment epithelial (RPE) cells of the eye. Mutations in BEST1 affect the function of the RPE leading to the death of overlying retinal cells and subsequent vision loss. The pathogenic mechanisms arising from BEST1 mutations are still not fully understood, and it is not clear how mutations in BEST1 lead to diseases with distinct clinical features. This chapter discusses BEST1, the use of model systems to investigate the effects of mutations and the potential to investigate individual bestrophinopathies using induced pluripotent stem cells

Detection of intergalactic red-giant-branch stars in the Virgo cluster

It has been suspected for nearly 50 years that clusters of galaxies contain a population of intergalactic stars, ripped from galaxies during cluster formation or when the galaxies' orbits take them through the cluster center. Support for the existence of such a population of free-floating stars comes from measurements of the diffuse light in clusters, and from recent detections of planetary nebulae with positions and/or velocities far removed from any observed cluster galaxy. But estimates for the mass of the diffuse population and its distribution relative to the galaxies are still highly uncertain. Here we report the direct detection of intergalactic stars in deep images of a blank field in the Virgo Cluster. The data suggest that approximately 10% of the stellar mass of the cluster is in intergalactic stars. We observe a relatively homogeneous distribution of stars, with evidence of a slight gradient toward M87.Comment: Accepted for publication in Nature. 10 pages, 2 postscript figures included. Uses nature.sty and astrobib.sty. (Astrobib is available from http://www.stsci.edu/software/TeX.html.

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Platinum drugs in the treatment of non-small-cell lung cancer

The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours

Validation and reliability of the Malaysian English version of the psychosocial impact of dental aesthetics questionnaire for adolescents

Background: The Malay version of the Psychosocial Impact of Dental Aesthetics Questionnaire (Malay PIDAQ) has been shown to be valid and reliable for use by Malaysian adolescents. In a multi-ethnicity country like Malaysia, some adolescents’ mother tongue may be influenced by their racial background and may not necessarily be proficient in the national Malay language. An instrument validated for one language only may not be able to capture the psychometric information from these adolescents. English is the second national language in Malaysia and is widely used as the lingua franca among Malaysians of different ethnicities. The aim of the study was to validate an English version of the PIDAQ adapted for use by Malaysian adolescents. Methods: The published English version of PIDAQ was pilot tested on 12- to 17-year-old adolescents, resulting in a few modifications to the 23 items to suit the Malaysian variety of English. The psychometric properties of the adapted English PIDAQ were tested on 393 adolescents who attended orthodontic practices and schools. Malocclusion was assessed using the Malocclusion Index, which is an aggregation of Perception of Occlusion Scale and the Aesthetic Component of the Index of Orthodontic Treatment Need by the subjects (MI-S) and investigators (MI-D). Data were analysed for internal consistency and age-associated invariance, discriminant and construct validities, reproducibility and floor and ceiling effects using AMOS v.20 and SPSS v.20. Results: Confirmatory factor analysis showed good fit statistics (comparative fit index = 0.900, root-mean-square error of approximation = 0.066). Internal consistency of all subscales in all age groups were adequate (Cronbach’s alpha = 0.72-0.85) while the reproducibility test was acceptable (intra-class correlations = 0.59-0.78). For all PIDAQ subscales, the MI-S and MI-D scores of those with severe malocclusion differed significantly (p<0.001) from those with no or slight malocclusion. Construct validity showed significant association between the PIDAQ subscales with ranking of perceived dental appearance, need for braces and impact of malocclusion on daily activities. There were no floor or ceiling effects. Conclusion: The adapted English PIDAQ demonstrated adequate psychometric properties to be valid and reliable for assessment of psychological impacts of dental aesthetics among Malaysian adolescents