Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

P53 mutations are responsible for drug-resistance of tumour cells which impacts on the efficacy of treatment. Alternative tumour suppressor pathways need to be explored to treat p53- deficient tumours. The E3 ubiquitin ligase, ITCH, negatively regulates the tumour suppressor protein TP73, providing a therapeutic target to enhance the sensitivity of the tumour cells to the treatment. In the present study, two p53-mutant neuroblastoma cell lines were used as in vitro models. Using immunostaining, western blot and qPCR methods, we firstly identified that ITCH was expressed on p53-mutant neuroblastoma cell lines. Transfection of these cell lines with ITCH siRNA could effectively silence the ITCH expression, and result in the stabilization of TP73 protein, which mediated the apoptosis of the neuroblastoma cells upon irradiation treatment. Finally, in vivo delivery of the ITCH siRNA using nanoparticles to the neuroblastoma xenograft mouse model showed around 15–20% ITCH silencing 48 hours after transfection. Our data suggest that ITCH could be silenced both in vitro and in vivo using nanoparticles, and silencing of ITCH sensitizes the tumour cells to irradiation treatment. This strategy could be further explored to combine the chemotherapy/radiotherapy treatment to enhance the therapeutic effects on p53-deficient neuroblastoma

Observation of a possible superflare on Proxima Centauri

We report the observation on UT 2017 July 1 of an unusually powerful flare detected in near-infrared continuum photometry of Proxima Centauri. During a campaign monitoring the star for possible exoplanet transits, we identified an increase in Sloan i' flux leading to an observed peak at BJD 2457935.996 that was at least 10 per cent over pre-flare flux in this band. It was followed by a two-component rapid decline in the first 100 s that became a slower exponential decay with time constant of 1350 s. A smaller flare event 1300 s after the first added an incremental peak flux increase of 1 per cent of pre-flare flux. Since the onset of the flare was not fully time resolved at a cadence of 62 s, its actual peak value is unknown but greater than the time average over a single exposure of 20 s. The i' band is representative of broad optical and near-IR continuum flux over which the integrated energy of the flare is 100 times the stellar luminosity. This meets the criteria that established the concept of superflares on similar stars. The resulting implied ultraviolet flux and space weather could have had an extreme effect on the atmospheres of planets within the star's otherwise habitable zone

Violence risk identification, assessment, and management practices in inpatient psychiatry

Serious mental illness is a major risk factor for violence. Research suggests that many committed psychiatric inpatients have perpetrated violence before, during, and after hospitalization. Despite the prevalence and implications of violence among committed psychiatric patients, the responsibility of health care professionals to identify, assess and manage violence risk, and the development of identification and assessment tools to assist health care professionals in discharging their responsibility, little is actually known about what practices are being used to identify, assess, and manage violence in inpatient psychiatry units. The purpose of this study is to obtain a better understanding of violence risk identification, assessment, and management practices used by inpatient psychiatric units. Specifically, this study involved semistructured interviews with key informants from 13 inpatient psychiatry units in the largest health region in Western Canada. Every inpatient psychiatry unit that was invited to take part in this study agreed to participate. Data were analyzed using frequency and content analysis. The analysis revealed limited use of formal identification and assessment instruments for violence and diversity with respect to strategies used to manage violence. These findings have implications for highlighting promising practices that are currently being used, and identifying potential areas for future improvement

Mental health-related limitations and political leadership in Germany: A multidisciplinary analysis of legal, psychiatric, and ethical frameworks.

In recent years, political events have reignited contentious debates about psychiatry and democratic governance. This discourse has largely centred around the ethics and morality of public commentary, particularly in relation to the American Psychiatric Association's Goldwater Rule. Yet, few studies have examined the practical implications of health-related limitations due to mental illness in national leadership and the constitutional and legal provisions that surround these issues, including voluntary or involuntary proceedings. Accordingly, this theoretical paper analyses these topics in a German context using the position at the head of the executive: the chancellorship. Germany was selected as a case example as the biggest democracy in Europe with modern legal frameworks representative of the post-World War Two era in European constitutionalism, and for its economic and political influence within the European Union. Throughout this paper, we do not speculate on the mental health of any individual (past or present), but instead explore jurisdictional mechanisms around health-related limitations in German high office. Consequently, we outline relevant constitutional and legal scenarios, and how short- or long-term medical incapacity may determine requisite responses and contingent complexities. This underpins our discussion, where we consider legal ambiguities, functional capacity, and ethical concerns in psychiatric practice

Towards Autonomous Operation of Robonaut 2

The Robonaut 2 (R2) platform, as shown in Figure 1, was designed through a collaboration between NASA and General Motors to be a capable robotic assistant with the dexterity similar to a suited astronaut [1]. An R2 robot was sent to the International Space Station (ISS) in February 2011 and, in doing so, became the first humanoid robot in space. Its capabilities are presently being tested and expanded to increase its usefulness to the crew. Current work on R2 includes the addition of a mobility platform to allow the robot to complete tasks (such as cleaning, maintenance, or simple construction activities) both inside and outside of the ISS. To support these new activities, R2's software architecture is being developed to provide efficient ways of programming robust and autonomous behavior. In particular, a multi-tiered software architecture is proposed that combines principles of low-level feedback control with higher-level planners that accomplish behavioral goals at the task level given the run-time context, user constraints, the health of the system, and so on. The proposed architecture is shown in Figure 2. At the lowest-level, the resource level, there exists the various sensory and motor signals available to the system. The sensory signals for a robot such as R2 include multiple channels of force/torque data, joint or Cartesian positions calculated through the robot's proprioception, and signals derived from objects observable by its cameras

Innovative development of the Octopus (cf) tetricus fishery in Western Australia

In 2010 the broad-scale introduction of a new gear type, the trigger trap, saw a 260% (33 t in 2009 to 119 t in 2010) increase in octopus landings in the Western Australian Developmental Octopus Fishery (DOF). Deployed in waters previously unfished by the DOF, initial catches demonstrated that trigger traps were more efficient and captured a different component of the population, compared to open-ended shelter pots traditionally used in the fishery. This shift caused a surge of interest in commercial octopus fishing

Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid pharmacokinetics in pre-clinical neuroblastoma models. Here we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance retinoic acid action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signaling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans

The Algorithm Theoretical Basis Document for the GLAS Atmospheric Data Products

The purpose of this document is to present a detailed description of the algorithm theoretical basis for each of the GLAS data products. This will be the final version of this document. The algorithms were initially designed and written based on the authors prior experience with high altitude lidar data on systems such as the Cloud and Aerosol Lidar System (CALS) and the Cloud Physics Lidar (CPL), both of which fly on the NASA ER-2 high altitude aircraft. These lidar systems have been employed in many field experiments around the world and algorithms have been developed to analyze these data for a number of atmospheric parameters. CALS data have been analyzed for cloud top height, thin cloud optical depth, cirrus cloud emittance (Spinhirne and Hart, 1990) and boundary layer depth (Palm and Spinhirne, 1987, 1998). The successor to CALS, the CPL, has also been extensively deployed in field missions since 2000 including the validation of GLAS and CALIPSO. The CALS and early CPL data sets also served as the basis for the construction of simulated GLAS data sets which were then used to develop and test the GLAS analysis algorithms

Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes.

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function