Cloning and expression of a human kinesin heavy chain gene: interaction of the COOH-terminal domain with cytoplasmic microtubules in transfected CV-1 cells.

To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances

Fluvio-Marine Sediment Partitioning as a Function of Basin Water Depth

Progradational fluvio-deltaic systems tend towards but cannot reach equilibrium, a state in which the longitudinal profile does not change shape and all sediment is bypassed beyond the shoreline. They cannot reach equilibrium because progradation of the shoreline requires aggradation along the longitudinal profile. Therefore progradation provides a negative feedback, unless relative sea level falls at a sufficient rate to cause non-aggradational extension of the longitudinal profile. How closely fluvio-deltaic systems approach equilibrium is dependent on their progradation rate, which is controlled by water depth and downstream allogenic controls, and governs sediment partitioning between the fluvial, deltaic, and marine domains. Here, six analogue models of coastal fluvio-deltaic systems and small prograding shelf margins are examined to better understand the effect of water depth, subsidence, and relative sea-level variations upon longitudinal patterns of sediment partitioning and grain-size distribution that eventually determine large-scale stratigraphic architecture. Fluvio-deltaic systems prograding in relatively deep-water environments are characterized by relatively low progradation rates compared to shallow-water systems. This allows these deeper water systems to approach equilibrium more closely, enabling them to construct less concave and steeper longitudinal profiles that provide low accommodation to fluvial systems. Glacio-eustatic sea-level variations and subsidence modulate the effects of water depth on the longitudinal profile. Systems are closest to equilibrium during falling relative sea level and early lowstand, resulting in efficient sediment transport towards the shoreline at those times. Additionally, the strength of the response to relative sea-level fall differs dependent on water depth. In systems prograding into deep water, relative sea-level fall causes higher sediment bypass rates and generates significantly stronger erosion than in shallow-water systems, which increases the probability of incised-valley formation. Water depth in the receiving basin thus forms a first-order control on the sediment partitioning along the longitudinal profile of fluvio-deltaic systems and the shelf clinoform style. It also forms a control on the availability of sand-grade sediment at the shoreline that can potentially be remobilized and redistributed into deeper marine environments. Key findings are subsequently applied to literature of selected shelf clinoform successions

Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation

© 2016 Royal Australasian College of Physicians Background: Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts. Aims: To explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer. Methods: A cross-sectional anonymous survey was administered from July to December 2015 online and in eight adult outpatient palliative care and/or cancer services. Respondents were eligible if they were ≥18 years, had advanced cancer and poor appetite/taste problems/weight loss and might consider participating in a medicinal cannabis trial. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products. Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns. Results: There were 204 survey respondents, of whom 26 (13%) reported prior medicinal cannabis use. Tablets/capsules were the preferred delivery mode (n = 144, 71%), followed by mouth spray (n = 84, 42%) and vaporiser (n = 83, 41%). Explanations for preferences (n = 134) most commonly cited convenience (n = 66; 49%). A total of 82% (n = 168) of respondents indicated that they had no trial-related concerns, but a small number volunteered concerns about adverse effects (n = 14) or wanted more information/advice (n = 8). Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial. Conclusion: Justification of modes other than tablets/capsules and variable understanding about cannabis and trials will need addressing in trial-related information to optimise recruitment and ensure that consent is properly informed

Source parameters of the great Sumatran megathrust earthquakes of 1797 and 1833 inferred from coral microatolls

Large uplifts and tilts occurred on the Sumatran outer arc islands between 0.5° and 3.3°S during great historical earthquakes in 1797 and 1833, as judged from relative sea level changes recorded by annually banded coral heads. Coral data for these two earthquakes are most complete along a 160-km length of the Mentawai islands between 3.2° and 2°S. Uplift there was as great as 0.8 m in 1797 and 2.8 m in 1833. Uplift in 1797 extended 370 km, between 3.2° and 0.5°S. The pattern and magnitude of uplift imply megathrust ruptures corresponding to moment magnitudes (M_w) in the range 8.5 to 8.7. The region of uplift in 1833 ranges from 2° to at least 3.2°S and, judging from historical reports of shaking and tsunamis, perhaps as far as 5°S. The patterns and magnitude of uplift and tilt in 1833 are similar to those experienced farther north, between 0.5° and 3°N, during the giant Nias-Simeulue megathrust earthquake of 2005; the outer arc islands rose as much as 3 m and tilted toward the mainland. Elastic dislocation forward modeling of the coral data yields megathrust ruptures with moment magnitudes ranging from 8.6 to 8.9. Sparse accounts at Padang, along the mainland west coast at latitude 1°S, imply tsunami runups of at least 5 m in 1797 and 3–4 m in 1833. Tsunamis simulated from the pattern of coral uplift are roughly consistent with these reports. The tsunami modeling further indicates that the Indian Ocean tsunamis of both 1797 and 1833, unlike that of 2004, were directed mainly south of the Indian subcontinent. Between about 0.7° and 2.1°S, the lack of vintage 1797 and 1833 coral heads in the intertidal zone demonstrates that interseismic submergence has now nearly equals coseismic emergence that accompanied those earthquakes. The interseismic strains accumulated along this reach of the megathrust have thus approached or exceeded the levels relieved in 1797 and 1833

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

Social support moderates the relationship between stressors and task performance through self-efficacy

This study examined the relationship between social support and objective task performance in a field setting. A sample of 197 participants, mean age 23.13 years (SD 3.56) completed measures of stressors, social support, and self-efficacy prior to performance. Moderated hierarchical regression analysis revealed significant(p < .05) main effects for stressors (R2 = .12) and social support (ΔR2 = .14) in relation to performance, in the hypothesized directions. A significant interaction (ΔR2 = .06) suggested that social support moderated (buffered) the relationship between stressors and task performance. Moderated mediation analysis demonstrated that social support was associated with increases in self-efficacy, and self-efficacy was associated with enhanced performance, but that this effect was only salient at moderate to high levels of stressors

Paleogeodetic records of seismic and aseismic subduction from central Sumatran microatolls, Indonesia

We utilize coral microatolls in western Sumatra to document vertical deformation associated with subduction. Microatolls are very sensitive to fluctuations in sea level and thus act as natural tide gauges. They record not only the magnitude of vertical deformation associated with earthquakes (paleoseismic data), but also continuously track the long-term aseismic deformation that occurs during the intervals between earthquakes (paleogeodetic data). This paper focuses on the twentieth century paleogeodetic history of the equatorial region. Our coral paleogeodetic record of the 1935 event reveals a classical example of deformations produced by seismic rupture of a shallow subduction interface. The site closest to the trench rose 90 cm, whereas sites further east sank by as much as 35 cm. Our model reproduces these paleogeodetic data with a 2.3 m slip event on the interface 88 to 125 km from the trench axis. Our coral paleogeodetic data reveal slow submergence during the decades before and after the event in the areas of coseismic emergence. Likewise, interseismic emergence occurred before and after the 1935 event in areas of coseismic submergence. Among the interesting phenomenon we have discovered in the coral record is evidence of a large aseismic slip or “silent event” in 1962, 27 years after the 1935 event. Paleogeodetic deformation rates in the decades before, after, and between the 1935 and 1962 events have varied both temporally and spatially. During the 25 years following the 1935 event, submergence rates were dramatically greater than in prior decades. During the past four decades, however, rates have been lower than in the preceding decades, but are still higher than they were prior to 1935. These paleogeodetic records enable us to model the kinematics of the subduction interface throughout the twentieth century

Health-related quality of life measured using the EQ-5D-5L: South Australian population norms

© 2016 The Author(s). Background: Although a five level version of the widely-used EuroQol 5 dimensions (EQ-5D) instrument has been developed, population norms are not yet available for Australia to inform the future valuation of health in economic evaluations. The aim of this study was to estimate HrQOL normative values for the EQ-5D-5L preference-based measure in a large, randomly selected, community sample in South Australia. Methods: The EQ-5D-5L instrument was included in the 2013 South Australian Health Omnibus Survey, an interviewer-administered, face-to-face, cross-sectional survey. Respondents rated their level of impairment across dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and global health rating on a visual analogue scale (EQ-VAS). Utility scores were derived using the newly-developed UK general population-based algorithm and relationships between utility and EQ-VAS scores and socio-demographic factors were also explored using multivariate regression analyses. Results: Ultimately, 2,908 adults participated in the survey (63.4 % participation rate). The mean utility and EQ-VAS scores were 0.91 (95 CI 0.90, 0.91) and 78.55 (95 % CI 77.95, 79.15), respectively. Almost half of respondents reported no problems across all dimensions (42.8 %), whereas only 7.2 % rated their health >90 on the EQ-VAS (100=the best health you can imagine). Younger age, male gender, longer duration of education, higher annual household income, employment and marriage/de facto relationships were all independent, statistically significant predictors of better health status (p<0.01) measured with the EQ-VAS. Only age and employment status were associated with higher utility scores, indicating fundamental differences between these measures of health status. Conclusions: This is the first Australian study to apply the EQ-5D-5L in a large, community sample. Overall, findings are consistent with EQ-5D-5L utility and VAS scores reported for other countries and indicate that the majority of South Australian adults report themselves in full health. When valuing health in Australian economic evaluations, the utility population norms can be used to estimate HrQOL. More generally, the EQ-VAS score may be a better measure of population health given the smaller ceiling effect and broader coverage of HrQOL dimensions. Further research is recommended to update EQ-5D-5L population norms using the Australian general population specific scoring algorithm once this becomes publically available

The role of valuation and bargaining in optimising transboundary watercourse treaty regimes

In the face of water scarcity, growing water demands, population increase, ecosystem degradation, climate change, and so on transboundary watercourse states inevitably have to make difficult decisions on how finite quantities of water are distributed. Such waters, and their associated ecosystem services, offer multiple benefits. Valuation and bargaining can play a key role in the sharing of these ecosystems services and their associated benefits across sovereign borders. Ecosystem services in transboundary watercourses essentially constitute a portfolio of assets. Whilst challenging, their commodification, which creates property rights, supports trading. Such trading offers a means by which to resolve conflicts over competing uses and allows states to optimise their ‘portfolios’. However, despite this potential, adoption of appropriate treaty frameworks that might facilitate a market-based approach to the discovery and allocation of water-related ecosystem services at the transboundary level remains both a challenge, and a topic worthy of further study. Drawing upon concepts in law and economics, this paper therefore seeks to advance the study of how treaty frameworks might be developed in a way that supports such a market-based approach to ecosystem services and transboundary waters