Functional modelling of a novel mutation in <em>BBS5</em>

Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy disorder with 18 known causative genes (BBS1-18). The primary clinical features are renal abnormalities, rod-cone dystrophy, post-axial polydactyly, learning difficulties, obesity and male hypogonadism.Results: We describe the clinical phenotype in three Saudi siblings in whom we have identified a novel mutation in exon 12 of BBS5 (c.966dupT; p.Ala323CysfsX57). This single nucleotide duplication creates a frame shift results in a predicted elongated peptide. Translation blocking Morpholino oligonucleotides were used to create zebrafish bbs5 morphants. Morphants displayed retinal layering defects, abnormal cardiac looping and dilated, cystic pronephric ducts with reduced cilia expression. Morphants also displayed significantly reduced dextran clearance via the pronephros compared to wildtype embryos, suggesting reduced renal function in morphants. The eye, kidney and heart defects reported in morphant zebrafish resemble the human phenotype of BBS5 mutations. The pathogenicity of the novel BBS5 mutation was determined. Mutant mRNA was unable to rescue pleiotropic phenotypes of bbs5 morphant zebrafish and in cell culture we demonstrate a mislocalisation of mutant BBS5 protein which fails to localise discretely with the basal body.Conclusions: We conclude that this novel BBS5 mutation has a deleterious function that accounts for the multisystem ciliopathy phenotype seen in affected human patients. \ua9 2014 Al-Hamed et al.; licensee BioMed Central Ltd

Counting on the mental number line to make a move: sensorimotor ('pen') control and numerical processing

Mathematics is often conducted with a writing implement. But is there a relationship between numerical processing and sensorimotor ‘pen’ control? We asked participants to move a stylus so it crossed an unmarked line at a location specified by a symbolic number (1–9), where number colour indicated whether the line ran left–right (‘normal’) or vice versa (‘reversed’). The task could be simplified through the use of a ‘mental number line’ (MNL). Many modern societies use number lines in mathematical education and the brain’s representation of number appears to follow a culturally determined spatial organisation (so better task performance is associated with this culturally normal orientation—the MNL effect). Participants (counter-balanced) completed two consistent blocks of trials, ‘normal’ and ‘reversed’, followed by a mixed block where line direction varied randomly. Experiment 1 established that the MNL effect was robust, and showed that the cognitive load associated with reversing the MNL not only affected response selection but also the actual movement execution (indexed by duration) within the mixed trials. Experiment 2 showed that an individual’s motor abilities predicted performance in the difficult (mixed) condition but not the easier blocks. These results suggest that numerical processing is not isolated from motor capabilities—a finding with applied consequences

Between-Population Outbreeding Affects Plant Defence

Between-population crosses may replenish genetic variation of populations, but may also result in outbreeding depression. Apart from direct effects on plant fitness, these outbreeding effects can also alter plant-herbivore interactions by influencing plant tolerance and resistance to herbivory. We investigated effects of experimental within- and between-population outbreeding on herbivore resistance, tolerance and plant fitness using plants from 13 to 19 Lychnis flos-cuculi populations. We found no evidence for outbreeding depression in resistance reflected by the amount of leaf area consumed. However, herbivore performance was greater when fed on plants from between-population compared to within-population crosses. This can reflect outbreeding depression in resistance and/or outbreeding effects on plant quality for the herbivores. The effects of type of cross on the relationship between herbivore damage and plant fitness varied among populations. This demonstrates how between-population outbreeding effects on tolerance range from outbreeding depression to outbreeding benefits among plant populations. Finally, herbivore damage strengthened the observed outbreeding effects on plant fitness in several populations. These results raise novel considerations on the impact of outbreeding on the joint evolution of resistance and tolerance, and on the evolution of multiple defence strategies

Coexistence of Trichome Variation in a Natural Plant Population: A Combined Study Using Ecological and Candidate Gene Approaches

The coexistence of distinct phenotypes within populations has long been investigated in evolutionary ecology. Recent studies have identified the genetic basis of distinct phenotypes, but it is poorly understood how the variation in candidate loci is maintained in natural environments. In this study, we examined fitness consequences and genetic basis of variation in trichome production in a natural population of Arabidopsis halleri subsp. gemmifera. Half of the individuals in the study population produced trichomes while the other half were glabrous, and the leaf beetle Phaedon brassicae imposed intensive damage to both phenotypes. The fitness of hairy and glabrous plants showed no significant differences in the field during two years. A similar result was obtained when sibling hairy and glabrous plants were transplanted at the same field site, whereas a fitness cost of trichome production was detected under a weak herbivory condition. Thus, equivalent fitness of hairy and glabrous plants under natural herbivory allows their coexistence in the contemporary population. The pattern of polymorphism of the candidate trichome gene GLABROUS1 (GL1) showed no evidence of long-term maintenance of trichome variation within the population. Although balancing selection under fluctuating biotic environments is often proposed to explain the maintenance of defense variation, the lack of clear evidence of balancing selection in the study population suggests that other factors such as gene flow and neutral process may have played relatively large roles in shaping trichome variation at least for the single population level

Zebrafish: a vertebrate tool for studying basal body biogenesis, structure, and function.

Understanding the role of basal bodies (BBs) during development and disease has been largely overshadowed by research into the function of the cilium. Although these two organelles are closely associated, they have specific roles to complete for successful cellular development. Appropriate development and function of the BB are fundamental for cilia function. Indeed, there are a growing number of human genetic diseases affecting ciliary development, known collectively as the ciliopathies. Accumulating evidence suggests that BBs establish cell polarity, direct ciliogenesis, and provide docking sites for proteins required within the ciliary axoneme. Major contributions to our knowledge of BB structure and function have been provided by studies in flagellated or ciliated unicellular eukaryotic organisms, specifically Tetrahymena and Chlamydomonas. Reproducing these and other findings in vertebrates has required animal in vivo models. Zebrafish have fast become one of the primary organisms of choice for modeling vertebrate functional genetics. Rapid ex-utero development, proficient egg laying, ease of genetic manipulation, and affordability make zebrafish an attractive vertebrate research tool. Furthermore, zebrafish share over 80 % of disease causing genes with humans. In this article, we discuss the merits of using zebrafish to study BB functional genetics, review current knowledge of zebrafish BB ultrastructure and mechanisms of function, and consider the outlook for future zebrafish-based BB studies

Targeting histone deacetyalses in the treatment of B- and T-cell malignancies

HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin’s lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin’s lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romidepsin, have been approved in the US for the treatment of relapsed and refractory cutaneous T cell lymphomas (CTCL). Initially, these agents were developed with the idea that they affected transcriptional activation and thus gene expression, by modulating chromatin condensation and decondensation. It is now clear that their effects go beyond chromatin and by affecting the acetylation status of histones and other intra-cellular proteins, they modify gene expression and cellular function via multiple pathways. Gene expression profiles and functional genetic analysis has led to further understanding of the various molecular pathways that are affected by these agents including cell cycle regulation, pathways of cellular proliferation, apoptosis and angiogenesis all important in lymphomagenesis. There is also increasing data to support the effects of these agents on T cell receptor and immune function which may explain the high level of activity of these agents in T cell lymphomas and hodgkin’s lymphoma. There is ample evidence of epigenetic dysregulation in lymphomas which may underlie the mechanisms of action of these agents but how these agents work is still not clear. Current HDAC inhibitors can be divided into at least four classes based on their chemical structure. At present several of these HDAC inhibitors are in clinical trials both as single agents and in combination with chemotherapy or other biological agents. They are easy to administer and are generally well tolerated with minimal side effects. Different dosing levels and schedules and the use of isospecific HDAC inhibitors are some of the strategies that are being employed to increase the therapeutic effect of these agents in the treatment of lymphomas. There may also be class differences that translate into specific activity against different lymphoma. HDAC inhibitors will likely be incorporated into combinations of targeted therapies both in the upfront and relapsed setting for lymphomas

Performance studies of the CMS strip tracker before installation

Peer reviewe

Birds use structural properties when selecting materials for different parts of their nests

Bird nests can have various roles but all act as the location for incubation, so at least have to serve to hold and support the incubating bird and its clutch of eggs. Nest construction is species specific and the use of materials varies between different parts of the nest. At present we know very little about the role that these materials play in the structural characteristics of the nest. This study examined materials from deconstructed nests from four species of thrush (Turdidae) and two species of finch (Fringillidae) that all constructed nests made of woody stems. It was hypothesised that structural properties would vary within the different regions of a nest, with thicker and stronger materials being found in parts of the nest needing the most support. Secondly, it was predicted that structural properties would vary little between nests of members of the same family, but would be quite different between nests of different families. Nests were deconstructed to quantify the materials used in the cup lining, and the upper and lower parts of the outer nest. The 20 thickest pieces of material were selected from each nest part and for each piece, and their diameter and mass quantified. Each piece was then subjected to a three-point bending test using an Instron universal testing machine to determine its rigidity and bending strength. Placement of materials in the nest was non-random in all species. The materials used in the outer part of the nest were thicker, stronger and stiffer than those materials found in the cup lining. The extent to which these structural properties varied between families depended on where the material was taken from the nest. Both strength and rigidity strongly positively correlated with the diameter of the piece of material. We hypothesise that birds are not directly aware of the structural properties of the material per se but rather assess diameter and mass of the material when they pick it up by the bill. Using this information they decide on whether the piece is suitable for that appropriate stage of nest construction

Progress in achieving quantitative classification of psychopathology

Résumé: Les lacunes des classifications de la psychopathologie fondées sur des consensus d’experts ont conduit à de nombreuses tentatives actuelles pour classer la psychopathologie de manière quantitative. Dans cet article, nous passons en revue les progrès accomplis dans la réalisation d’une classification quantitative et empirique de la psychopathologie. Une littérature empirique substantielle montre que la psychopathologie est généralement plus dimensionnelle que catégorielle. Et lorsque la distinction entre une psychopathologie discrète et une psychopathologie continue est traitée comme une question de recherche, par opposition à une distinction basée sur un argument d’autorité, alors les preuves scientifiques soutiennent clairement l’hypothèse d’une psychopathologie continue. En outre, un corpus de littérature connexe montre comment les dimensions de la psychopathologie peuvent être organisées selon une hiérarchie qui va de dimensions très larges d’un niveau de type « spectre » à des groupes spécifiques et étroits de symptômes. De cette manière, une approche quantitative résout le « problème de la comorbidité » en modélisant explicitement la cooccurrence entre les signes et les symptômes au sein d’une hiérarchie détaillée et variée, maniant des concepts dimensionnels qui ont une utilité clinique directe. De nombreuses preuves concernant la structure dimensionnelle et hiérarchique de la psychopathologie ont conduit à la formation du consortium Hierarchical Taxonomy of Psychopathology (HiTOP, taxonomie hiérarchique de la psychopathologie). Il s’agit d’un groupe de 70 chercheurs travaillant ensemble pour étudier la classification empirique de la psychopathologie. Dans cet article, nous décrivons les objectifs et les axes de recherches actuels du consortium HiTOP. Ces objectifs concernent la poursuite des recherches sur l’organisation empirique de la psychopathologie ; le lien entre la personnalité et la psychopathologie ; l’utilité des construits empiriques de la psychopathologie, à la fois pour la recherche et pour la clinique ; et enfin, le développement de nouveaux modèles exhaustifs et d’instruments d’évaluation correspondant aux construits psychopathologiques dérivés d’une approche empirique. / Abstract: Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad “spectrum level” dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the “problem of comorbidity” by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach