410 resultados para novel inhibitor screening


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Substantial research efforts have been expended to deal with the complexity of concurrent systems that is inherent to their analysis, e.g., works that tackle the well-known state space explosion problem. Approaches differ in the classes of properties that they are able to suitably check and this is largely a result of the way they balance the trade-off between analysis time and space employed to describe a concurrent system. One interesting class of properties is concerned with behavioral characteristics. These properties are conveniently expressed in terms of computations, or runs, in concurrent systems. This article introduces the theory of untanglings that exploits a particular representation of a collection of runs in a concurrent system. It is shown that a representative untangling of a bounded concurrent system can be constructed that captures all and only the behavior of the system. Representative untanglings strike a unique balance between time and space, yet provide a single model for the convenient extraction of various behavioral properties. Performance measurements in terms of construction time and size of representative untanglings with respect to the original specifications of concurrent systems, conducted on a collection of models from practice, confirm the scalability of the approach. Finally, this article demonstrates practical benefits of using representative untanglings when checking various behavioral properties of concurrent systems.

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Background: The incidence of mandibular fractures in the Northern Territory of Australia is very high, especially among Indigenous people. Alcohol intoxication is implicated in the majority of facial injuries, and substance use is therefore an important target for secondary prevention. The current study tests the efficacy of a brief therapy, Motivational Care Planning, in improving wellbeing and substance misuse in youth and adults hospitalised with alcohol-related facial trauma. Methods and design: The study is a randomised controlled trial with 6 months of follow-up, to examine the effectiveness of a brief and culturally adapted intervention in improving outcomes for trauma patients with at-risk drinking admitted to the Royal Darwin Hospital maxillofacial surgery unit. Potential participants are identified using AUDIT-C questionnaire. Eligible participants are randomised to either Motivational Care Planning (MCP) or Treatment as Usual (TAU). The outcome measures will include quantity and frequency of alcohol and other substance use by Timeline Followback. The recruitment target is 154 participants, which with 20% dropout, is hoped to provide 124 people receiving treatment and follow-up. Discussion: This project introduces screening and brief interventions for high-risk drinkers admitted to the hospital with facial trauma. It introduces a practical approach to integrating brief interventions in the hospital setting, and has potential to demonstrate significant benefits for at-risk drinkers with facial trauma.

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Brief interventions are effective for problem drinking and reductions are known to occur in association with screening and assessment. The present study sought to assess, among participants (N=202) in a clinical trial, how much change occurred between baseline assessment and a one-session brief intervention (S1), and the predictors of early change. The primary focus was on changes in the Beck Depression Inventory Fast Screen scores and alcohol consumption (standard drinks per week) prior to random allocation to nine further sessions addressing either depression, alcohol, or both problems. There were large and clinically significant reductions between baseline and S1, with the strongest predictors being baseline scores in the relevant domain and change in the other domain. Client engagement was also predictive of early depression changes. Monitoring progress in both domains from first contact, and provision of empathic care, followed by brief intervention appear to be useful for this high prevalence comorbidity.

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Background: General practitioners (GPs) and nurses are ideally placed to address the significant unmet demand for the treatment of cannabis-related problems given the numbers of people who regularly seek their care. The aim of this study was to evaluate differences between GPs and nurses’ perceived knowledge, beliefs, and behaviors toward cannabis use and its screening and management. Methods: This study involved 161 nurses and 503 GPs who completed a survey distributed via conference satchels to delegates of Healthed seminars focused on topics relevant to women and children’s health. Differences between GPs and nurses were analyzed using χ2- tests and two-sample t-tests, while logistic regression examined predictors of service provision. Results: GPs were more likely than nurses to have engaged in cannabis-related service provision, but also more frequently reported barriers related to time, interest, and having more important issues to address. Nurses reported less knowledge, skills, and role legitimacy. Perceived screening skills predicted screening and referral to alcohol and other drug (AOD) services, while knowing a regular user increased the likelihood of referrals only. Conclusions: Approaches to increase cannabis-related screening and intervention may be improved by involving nurses, and by leveraging the relationship between nurses and doctors, in primary care.

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Food preferences have been identified as a key determinant of children’s food acceptance and consumption. The aim of this study was to identify factors that influence children’s liking for fruits, vegetables and non-core foods. Participants were Australian mothers (median age at delivery=31 years, 18-46 years) and their two-year-old children (M=25 months, SD=1 month; 52% female) allocated to the control group (N=230) of the NOURISH RCT. The effects of repeated exposure to new foods, maternal food preferences and child food neophobia on toddlers’ liking of vegetables, fruits and non-core foods and the proportion never tried were examined via hierarchical regression models; adjusting for key maternal (age, BMI, education) and child covariates (birth weight Z-score, gender), duration of breastfeeding and age of introduction to solids. Maternal preferences corresponded with child preferences. Food neophobia among toddlers was associated with liking fewer vegetables and fruits, and trying fewer vegetables. Number of repeated exposures to new food was not significantly associated with food liking at this age. Results highlight the need to: (i) encourage parents to offer a wide range of foods, regardless of their own food preferences, and (ii) provide parents with guidance on managing food neophobia.

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Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSC) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of epithelial–mesenchymal transition (EMT), thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling pathways as well as elevated in stem cell-enriched factions is a critical determinant of mesenchymal and stem cell properties, in cells induced to undergo EMT- and CSC-enriched breast cancer cell lines. More specifically, attenuation of FOXC2 expression using lentiviral short hairpin RNA led to inhibition of the mesenchymal phenotype and associated invasive and stem cell properties, which included reduced mammosphere-forming ability and tumor initiation. Whereas, overexpression of FOXC2 was sufficient to induce CSC properties and spontaneous metastasis in transformed human mammary epithelial cells. Furthermore, a FOXC2-induced gene expression signature was enriched in the claudin-low/basal B breast tumor subtype that contains EMT and CSC features. Having identified PDGFR-β to be regulated by FOXC2, we show that the U.S. Food and Drug Administration-approved PDGFR inhibitor, sunitinib, targets FOXC2-expressing tumor cells leading to reduced CSC and metastatic properties. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies for the treatment of claudin-low/basal B breast tumors or other EMT-/CSC-enriched tumors.

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This paper describes a generalised linear mixed model (GLMM) approach for understanding spatial patterns of participation in population health screening, in the presence of multiple screening facilities. The models presented have dual focus, namely the prediction of expected patient flows from regions to services and relative rates of participation by region- service combination, with both outputs having meaningful implications for the monitoring of current service uptake and provision. The novelty of this paper lies with the former focus, and an approach for distributing expected participation by region based on proximity to services is proposed. The modelling of relative rates of participation is achieved through the combination of different random effects, as a means of assigning excess participation to different sources. The methodology is applied to participation data collected from a government-funded mammography program in Brisbane, Australia.

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Background: High levels of distress and need for self-care information by patients commencing chemotherapy suggest that current prechemotherapy education is suboptimal. We conducted a randomised, controlled trial of a prechemotherapy education intervention (ChemoEd) to assess impact on patient distress, treatment-related concerns, and the prevalence and severity of and bother caused by six chemotherapy side-effects. Patients and methods: One hundred and ninety-two breast, gastrointestinal, and haematologic cancer patients were recruited before the trial closing prematurely (original target 352). ChemoEd patients received a DVD, question-prompt list, self-care information, an education consultation ≥24 h before first treatment (intervention 1), telephone follow-up 48 h after first treatment (intervention 2), and a face-to-face review immediately before second treatment (intervention 3). Patient outcomes were measured at baseline (T1: pre-education) and immediately preceding treatment cycles 1 (T2) and 3 (T3). Results: ChemoEd did not significantly reduce patient distress. However, a significant decrease in sensory/psychological (P = 0.027) and procedural (P = 0.03) concerns, as well as prevalence and severity of and bother due to vomiting (all P = 0.001), were observed at T3. In addition, subgroup analysis of patients with elevated distress at T1 indicated a significant decrease (P = 0.035) at T2 but not at T3 (P = 0.055) in ChemoEd patients. Conclusions: ChemoEd holds promise to improve patient treatment-related concerns and some physical/psychological outcomes; however, further research is required on more diverse patient populations to ensure generalisability.

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This paper analyses effects of winding structure on capacitive coupling reduction appearing in the planar magnetic elements at high frequencies. Capacitive coupling appears between the conductive layers of the planar transformers resulting in high current spikes and consequently high power dissipation. With finite element analysis, the equivalent capacitive coupling of magnetic elements is calculated for different structures of planar windings. Finally, a new winding structure with minimum capacitive coupling is introduced for the planar magnetic elements, which is verified by simulation and experiments.

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At present, for mechanical power transmission, Cycloidal drives are most preferred - for compact, high transmission ratio speed reduction, especially for robot joints and manipulator applications. Research on drive-train dynamics of Cycloidal drives is not well-established. This paper presents a testing rig for Cycloidal drives, which would produce data for development of mathematical models and investigation of drive-train dynamics, further aiding in optimising its design

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Unlike most genera in the early-divergent angiosperm family Annonaceae, Pseuduvaria exhibits a diversity of floral sex expression. Most species are structurally andromonoecious (or possibly androdioecious), although the hermaphroditic flowers have been inferred to be functionally pistillate, with sterile staminodes. Pseuduvaria presents an ideal model for investigating the evolution of floral sex in early-divergent angiosperms, although detailed empirical studies are currently lacking. The phenology and pollination ecology of the Australian endemic species Pseuduvaria mulgraveana are studied in detail, including evaluations of floral scent chemistry, pollen viability, and floral visitors. Results showed that the flowers are pollinated by small diurnal nitidulid beetles and are protogynous. Pollen from both hermaphroditic and staminate flowers are shown to be equally viable. The structurally hermaphroditic flowers are nevertheless functionally pistillate as anther dehiscence is delayed until after petal abscission and hence after the departure of pollinators. This mechanism to achieve functional unisexuality of flowers has not previously been reported in angiosperms. It is known that protogyny is widespread amongst early-divergent angiosperms, including the Annonaceae, and is effective in preventing autogamy. Delayed anther dehiscence represents a further elaboration of this, and is effective in preventing geitonogamy since very few sexually mature flowers occur simultaneously in an individual. We highlight the necessity for field-based empirical interpretations of functional floral sex expression prior to evaluations of evolutionary processes.

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The VESUVIO project aims to provide unique prototype instrumentation at the ISIS-pulsed neutron source and to establish a routine experimental and theoretical program in neutron scattering spectroscopy at eV energies. This instrumentation will be specifically designed for high momentum, , and energy transfer inelastic neutron scattering studies of microscopic dynamical processes in materials and will represent a unique facility for EU researchers. It will allow to derive single-particle kinetic energies and single-particle momentum distributions, n(p), providing additional and/or complementary information to other neutron inelastic spectroscopic techniques.

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Reasons for performing study: Many domestic horses and ponies are sedentary and obese due to confinement to small paddocks and stables and a diet of infrequent, high-energy rations. Severe health consequences can be associated with this altered lifestyle. Objectives: The aims of this study were to investigate the ability of horses to learn to use a dynamic feeder system and determine the movement and behavioural responses of horses to the novel system. Methods: A dynamic feed station was developed to encourage horses to exercise in order to access ad libitum hay. Five pairs of horses (n = 10) were studied using a randomised crossover design with each pair studied in a control paddock containing a standard hay feeder and an experimental paddock containing the novel hay feeder. Horse movement was monitored by a global positioning system (GPS) and horses observed and their ability to learn to use the system and the behavioural responses to its use assessed. Results: With initial human intervention all horses used the novel feeder within 1 h. Some aggressive behaviour was observed between horses not well matched in dominance behaviour. The median distance walked by the horses was less (P = 0.002) during a 4 h period (117 [57–185] m) in the control paddock than in the experimental paddock (630 [509–719] m). Conclusions: The use of an automated feeding system promotes increased activity levels in horses housed in small paddocks, compared with a stationary feeder.

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Research into hyperinsulinemic laminitis has progressed significantly in recent years with the use of the prolonged-euglycemic, hyperinsulinemic clamp (p-EHC). Previous investigations of laminitis pathophysiology have focused on digital vascular dysfunction, inflammation, altered glucose metabolism within the lamellae, and lamellar basement membrane breakdown by metalloproteinases. The etiopathogenesis of laminitis occurring in association with hyperinsulinemia is yet to be fully characterized, but it may not involve these mechanisms. Insulin stimulates cellular proliferation and can also affect other body systems, such as the insulin-like growth factor (IGF) system. Insulin-like growth factor-1 (IGF-1) is structurally homologous to insulin and, like insulin, binds with strong affinity to a specific tyrosine kinase receptor on the cell surface to produce its effects, which include promoting cell proliferation. Receptors for IGF-1 (IGF-1R) are present in the lamellar epidermis. An alternative theory for the pathogenesis of hyperinsulinemic laminitis is that uncontrolled cell proliferation, mediated through both the insulin receptor (InsR) and IGF-1R, leads to lengthening, weakening, and failure of the lamellae. An analysis of the proliferative activity of lamellar epidermal cells during the developmental and acute phases of hyperinsulinemic laminitis, and lamellar gene expression of the InsR and IGF-1R was undertaken.