5-HT(2B) receptors are required for serotonin-selective antidepressant actions

The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.

An investigation of functional diversity of endogenous cellulase and expression of other digestive enzyme genes in freshwater crayfish (Cherax) species

The project evaluated potential of soluble cellulose as a cheap feed ingredient for major farmed Australian freshwater crayfish species testing their growth performance, digestive enzyme activity and digestive enzyme gene expression patterns. Test animals showed an innate capacity to utilise a range of carbohydrate sources including complex structural polysaccharides. Results suggest that more plant-derived ingredient can be incorporated in formulated low-cost feeds for the culture industry.

Cross cultural adaptation and validation of a Spanish version of the lower limb functional index

Background: The Lower Limb Functional Index (LLFI) is a relatively recently published regional outcome measure. The development article showed the LLFI had robust and valid clinimetric properties with sound psychometric and practical characteristics when compared to the Lower Limb Extremity Scale (LEFS) criterion standard. Objective: The purpose of this study was cross cultural adaptation and validation of the LLFI Spanish-version (LLFI-Sp) in a Spanish population. Methods: A two stage observational study was conducted. The LLFI was initially cross-culturally adapted to Spanish through double forward and single backward translation; then subsequently validated for the psychometric characteristics of validity, internal consistency, reliability, error score and factor structure. Participants (n = 136) with various lower limb conditions of >12 weeks duration completed the LLFI-Sp, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Euroqol Health Questionnaire 5 Dimensions (EQ-5D-3 L). The full sample was employed to determine internal consistency, concurrent criterion validity, construct validity and factor structure; a subgroup (n = 45) determined reliability at seven days concurrently completing a global rating of change scale. Results: The LLFI-Sp demonstrated high but not excessive internal consistency (α = 0.91) and high reliability (ICC = 0.96). The factor structure was one-dimensional which supported the construct validity. Criterion validity with the WOMAC was strong (r = 0.77) and with the EQ-5D-3 L fair and inversely correlated (r = -0.62). The study limitations included the lack of longitudinal data and the determination of responsiveness. Conclusions: The LLFI-Sp supports the findings of the original English version as being a valid lower limb regional outcome measure. It demonstrated similar psychometric properties for internal consistency, validity, reliability, error score and factor structure.

Comparison of eight published static finite element models of the intact lumbar spine : predictive power of models improves when combined together

Finite element (FE) model studies have made important contributions to our understanding of functional biomechanics of the lumbar spine. However, if a model is used to answer clinical and biomechanical questions over a certain population, their inherently large inter-subject variability has to be considered. Current FE model studies, however, generally account only for a single distinct spinal geometry with one set of material properties. This raises questions concerning their predictive power, their range of results and on their agreement with in vitro and in vivo values. Eight well-established FE models of the lumbar spine (L1-5) of different research centres around the globe were subjected to pure and combined loading modes and compared to in vitro and in vivo measurements for intervertebral rotations, disc pressures and facet joint forces. Under pure moment loading, the predicted L1-5 rotations of almost all models fell within the reported in vitro ranges, and their median values differed on average by only 2° for flexion-extension, 1° for lateral bending and 5° for axial rotation. Predicted median facet joint forces and disc pressures were also in good agreement with published median in vitro values. However, the ranges of predictions were larger and exceeded those reported in vitro, especially for the facet joint forces. For all combined loading modes, except for flexion, predicted median segmental intervertebral rotations and disc pressures were in good agreement with measured in vivo values. In light of high inter-subject variability, the generalization of results of a single model to a population remains a concern. This study demonstrated that the pooled median of individual model results, similar to a probabilistic approach, can be used as an improved predictive tool in order to estimate the response of the lumbar spine.

A vibrational spectroscopic study of the silicate mineral harmotome – (Ba,Na,K)1-2(Si,Al)8O16⋅6H2O – A natural zeolite

The mineral harmotome (Ba,Na,K)1-2(Si,Al)8O16⋅6H2O is a crystalline sodium calcium silicate which has the potential to be used in plaster boards and other industrial applications. It is a natural zeolite with catalytic potential. Raman bands at 1020 and 1102 cm−1 are assigned to the SiO stretching vibrations of three dimensional siloxane units. Raman bands at 428, 470 and 491 cm−1 are assigned to OSiO bending modes. The broad Raman bands at around 699, 728, 768 cm−1 are attributed to water librational modes. Intense Raman bands in the 3100 to 3800 cm−1 spectral range are assigned to OH stretching vibrations of water in harmotome. Infrared spectra are in harmony with the Raman spectra. A sharp infrared band at 3731 cm−1 is assigned to the OH stretching vibration of SiOH units. Raman spectroscopy with complimentary infrared spectroscopy enables the characterization of the silicate mineral harmotome.

The functional significance of fruit exocarp on host selection and oviposition by Queensland fruit fly, Bactrocera tryoni (Froggatt) (Tephritidae: Diptera)

Queensland fruit fly is Australia's most serious insect pest of horticulture. The fly lays its eggs into fruit, where they hatch into maggots which destroy the fruit. Understanding egg laying behaviour, known as oviposition, is a critical but under-researched aspect of fruit fly biology. This thesis focused on three aspects of oviposition: the role of fruit peel as a physical barrier to oviposition; the quality of fruit for maggot development; and the structure and wear of the egg laying organ – the ovipositor. Results showed that flies selected fruit based on their suitability for offspring survival, not because of the softness or hardness of fruit peel. Previously reported use of holes or wounds in fruit peel by ovipositing females was determined to be a mechanism which saved the female time, not a mechanism to reduce ovipositor wear. The results offer insights into the evolution of host use by fruit flies and their sustainable management.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Wearable neuroimaging and emotion : investigating emotional responses to architectural environments with functional near-infrared spectroscopy (fNIRS)

Supported by contemporary theories of architectural aesthetics and neuro-aesthetics this paper presents a case for the use of portable fNIRS imaging in the assessment of emotional responses to spatial environments experienced by both blind and sighted. The aim of the paper is to outline the implications of fNIRS for spatial research and practice within the field of architecture, thereby suggesting a potential taxonomy of particular formations of space and affect. Empirical neurological study of affect and spatial experience from an architectural design perspective remains in many instances unchartered. Clinical research using the portable non-invasive neuro-imaging device, functional near infrared spectroscopy (fNIRS) is proving convincing in its ability to detect emotional responses to visual, spatio-auditory and task based stimuli, providing a firm basis to potentially track cortical activity in the appraisal of architectural environments. Additionally, recent neurological studies have sought to explore the manifold sensory abilities of the visually impaired to better understand spatial perception in general. Key studies reveal that early blind participants perform as well as sighted due to higher auditory and somato-sensory spatial acuity. For instance, face vision enables the visually impaired to detect environments through skin pressure, enabling at times an instantaneous impression of the layout of an unfamiliar environment. Studies also report pleasant and unpleasant emotional responses such as ‘weightedness’ or ‘claustrophobia’ within certain interior environments, revealing a deeper perceptual sensitivity then would be expected. We conclude with justification that comparative fNIRS studies between the sighted and blind concerning spatial experience have the potential to provide greater understanding of emotional responses to architectural environments.

Cross-cultural adaptation, reliability and validity of the Spanish version of the upper limb functional index

Background The Upper Limb Functional Index (ULFI) is an internationally widely used outcome measure with robust, valid psychometric properties. The purpose of study is to develop and validate a ULFI Spanish-version (ULFI-Sp). Methods A two stage observational study was conducted. The ULFI was cross-culturally adapted to Spanish through double forward and backward translations, the psychometric properties were then validated. Participants (n = 126) with various upper limb conditions of >12 weeks duration completed the ULFI-Sp, QuickDASH and the Euroqol Health Questionnaire 5 Dimensions (EQ-5D-3 L). The full sample determined internal consistency, concurrent criterion validity, construct validity and factor structure; a subgroup (n = 35) determined reliability at seven days. Results The ULFI-Sp demonstrated high internal consistency (α = 0.94) and reliability (r = 0.93). Factor structure was one-dimensional and supported construct validity. Criterion validity with the EQ-5D-3 L was fair and inversely correlated (r = −0.59). The QuickDASH data was unavailable for analysis due to excessive missing responses. Conclusions The ULFI-Sp is a valid upper limb outcome measure with similar psychometric properties to the English language version.

The antigen 43 structure reveals a molecular velcro-like mechanism of autotransporter-mediated bacterial clumping

Aggregation and biofilm formation are critical mechanisms for bacterial resistance to host immune factors and antibiotics. Autotransporter (AT) proteins, which represent the largest group of outer-membrane and secreted proteins in Gram-negative bacteria, contribute significantly to these phenotypes. Despite their abundance and role in bacterial pathogenesis, most AT proteins have not been structurally characterized, and there is a paucity of detailed information with regard to their mode of action. Here we report the structure–function relationships of Antigen 43 (Ag43a), a prototypic self-associating AT protein from uropathogenic Escherichia coli. The functional domain of Ag43a displays a twisted L-shaped β-helical structure firmly stabilized by a 3D hydrogen-bonded scaffold. Notably, the distinctive Ag43a L shape facilitates self-association and cell aggregation. Combining all our data, we define a molecular “Velcro-like” mechanism of AT-mediated bacterial clumping, which can be tailored to fit different bacterial lifestyles such as the formation of biofilms.