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High-Entropy Liquid Metal Process for Transparent Ultrathin p-Type Gallium Oxide
No full textThe naturally self-limiting oxide formed on the surface of liquid metals can be exfoliated and transferred onto various substrates. This oxide layer with a thickness of a few nanometers is typically highly transparent and can be engineered for applications in large-area optoelectronics. While the incorporation of solvated elements into the interfacial oxide of post-transition metal-based liquid metals is demonstrated for n-doping, achieving p-doping in such ultrathin oxide layers remains a significant challenge. In this study, the use of dissolved indium (In), platinum (Pt), gold (Au), palladium (Pd), and copper (Cu) in gallium (Ga)-based alloys is investigated to create a high-entropy liquid metal system. This allows the exfoliation of a p-doped ultrathin oxide layer, predominantly composed of gallium oxide (Ga2O3). The incorporation of these post-transition metals in this high-entropy system results in their atomic dispersion, with Cu exhibiting limited surface presence. The atomically dispersed Pt, Au, and Pd metals scavenge oxygen during exfoliation at moderate temperatures and release them during cooling down, promoting the emergence of trivalent metallic In in Ga oxide layer. This work presents a novel doping strategy at moderate temperatures to achieve p-doped liquid-metal-derived ultrathin Ga2O3 layers, which maintain high transparency
Art and Science: An Oxymoron?
No full textArtist-in-residence programs have become increasingly popular, yet little research exists on their broader impact beyond artistic outcomes. This one-year project aimed to explore the intersection of arts and science, a collaboration between a tertiary art school and The Doherty Institute for Infection and Immunity in Melbourne
Anthelmintic Potential of Agelasine Alkaloids from the Australian Marine Sponge Agelas axifera
No full textA recent high-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract from the Australian marine sponge Agelas axifera with in vitro activity against an economically important parasitic nematode, Haemonchus contortus (barber's pole worm). The bioassay-guided fractionation of the CH2Cl2/MeOH extract from A. axifera led to the purification of a new diterpene alkaloid, agelasine Z (1), together with two known compounds agelasine B (2) and oxoagelasine B (3). Brominated compounds (-)-mukanadin C (4) and 4-bromopyrrole-2-carboxylic acid (5) were also isolated from neighbouring UV-active fractions. All compounds, together with agelasine D (6) from NatureBank's pure compound library, were tested for in vitro anthelmintic activity against exsheathed third-stage (xL3s) and fourth-stage larvae (L4s) of H. contortus and young adult Caenorhabditis elegans. Compounds 1, 2 and 6 induced an abnormal "skinny" phenotype, while compounds 2 and 6 also reduced the motility of H. contortus L4s by 50.5% and 51.8% at 100 µM, respectively. The minimal activity of agelasines against C. elegans young adults suggests a possible species-specific mechanism warranting further investigation. For the first time, the unexpected lability of agelasine H-8' was explored using kinetic studies, revealing rapid deuterium exchange in MeOH-d4 at room temperature
Pairwise valid instruments
No full textFinding valid instruments is difficult. We propose Validity Set Instrumental Variable (VSIV) estimation, a method for estimating local average treatment effects (LATEs) in heterogeneous causal effect models when the instruments are partially invalid. We consider settings with pairwise valid instruments, that is, instruments that are valid for a subset of instrument value pairs. VSIV estimation exploits testable implications of instrument validity to remove invalid pairs and provides estimates of the LATEs for all remaining pairs, which can be aggregated into a single parameter of interest using researcher-specified weights. We show that the proposed VSIV estimators are asymptotically normal under weak conditions and remove or reduce the asymptotic bias relative to standard LATE estimators (that is, LATE estimators that do not use testable implications to remove invalid variation). We evaluate the finite sample properties of VSIV estimation in application-based simulations and apply our method to estimate the returns to college education using parental education as an instrument
Improving event-based methods for modelling flood risk in a variable and non-stationary climate
No full textWhile it may be easy to simulate the rise and fall of a flood hydrograph, it is surprisingly challenging to reproduce the magnitude-frequency relationship of a selected flood attribute (i.e. a flood frequency curve) under historic or current conditions, particularly over the range of spatial and temporal scales relevant to flood behaviour at different locations within a single catchment. Under climate change, these challenges only get harder. This article discusses the key aspects of flood behaviour that need to be considered when deriving magnitude-frequency relationships in a non-stationary climate, as commonly required by the industry for planning and design purposes. Specific attention is given to sources of (irreducible) uncertainty that are a function of natural variability, and those sources of (reducible) uncertainty that are due to data limitations and imperfect knowledge. Discussion is provided on the design information and tools that are required to shift practice from a reliance on deterministic models to stochastic frameworks, and the hydroclimatic factors needed to accommodate the non-stationary effects of global warming. The article concludes with an outline of additional investigations needed to support the development and application of enhanced methods, and includes commentary on the disconnect between hydrologic practice and academic research. This article is part of the discussion meeting issue 'Hydrology in the 21st century: challenges in science, to policy and practice'
The Replication Function of Rabies Virus P Protein Is Regulated by a Novel Phosphorylation Site in the N-Terminal N Protein-Binding Region
No full textThe rabies virus (RABV) phosphoprotein (P protein) has multiple functions, including acting as the essential non-catalytic cofactor of the viral polymerase (L protein) for genome replication and transcription; the principal viral antagonist of the interferon (IFN)-mediated innate immune response; and the chaperone for the viral nucleoprotein (N protein). Although P protein is known to undergo phosphorylation by cellular kinases, the location and functions of the phosphorylation sites remains poorly defined. Here, we report the identification by mass-spectrometry (MS) of residues of P protein that are modified by phosphorylation in mammalian cells, including several novel sites. Analysis of P protein with phospho-mimetic and phospho-inhibitory mutations of three novel residues/clusters that were commonly identified by MS (Ser48, Ser183/187, Ser217/219/220) indicate that phosphorylation at each of these sites does not have a major influence on nuclear trafficking or antagonistic functions toward IFN signalling pathways. However, phosphorylation of Ser48 in the N-terminus of P protein impaired function in transcription/replication and in the formation of replication structures that contain complexes of P and N proteins, suggestive of altered interactions of these proteins. The crystal structure of P protein containing the S48E phospho-mimetic mutation indicates that Ser48 phosphorylation facilitates the binding of residues 41-52 of P protein into the RNA-binding groove of non-RNA-bound N protein (N0), primarily through the formation of a salt bridge with Arg434 of N protein. These data indicate that Ser48 modification regulates the cycling of P-N0 chaperone complexes that deliver N protein to RNA to enable transcription/replication, such that enhanced interaction due to S48E phospho-mimetic mutation reduces N protein delivery to the RNA, inhibiting subsequent transcription/replication processes. These data are, to our knowledge, the first to implicate phosphorylation of RABV P protein in conserved replication functions of the P gene
Artificial Intelligence in Cancer Immunotherapy: Navigating Challenges and Unlocking Opportunities
No full text‘It Is Like a Cross-Stitch … All Joined Together But Not Making a Very Nice Pattern’: A Qualitative Study of Patient Perspectives on Physical Health Inequalities in Severe Mental Illness
No full textBACKGROUND: People with severe mental illness (SMI) have worse physical health than the general population and face a range of challenges with their healthcare. This study aimed to explore the interplay of issues across system, service, social and individual levels that impact healthcare experiences and outcomes from the perspective of people with comorbid SMI and physical health needs. METHODS: A qualitative study was conducted. Fifteen individuals participated through focus groups and interviews (mean age = 55 years; range = 39-74 years). Participants were secondary mental health service users living with comorbid SMI and physical health condition(s) in South East London, the United Kingdom. Data were analysed through a process of inductive thematic analysis with reflexive elements. RESULTS: Seven themes were generated, demonstrating the interplay of system, service, social and individual-level issues. The first two focused on prevailing issues described by participants, including 'systemic barriers to effective and equitable social and health care' and 'interpersonal stigma exacerbating inequalities'. The third and fourth themes described the consequences of these issues: 'services turning to medication in response to multiple constraints' and 'inequities limiting individual actions'. Themes 5 and 6 centred on creating equitable conditions for people with SMI and physical healthcare needs, including 'the role of informal and formal social supports' and 'patient perspectives on what works in health services'. The seventh cross-cutting theme described the 'intertwined nature of mental and physical health'. IMPLICATIONS: This study highlights systemic barriers and interpersonal stigma as sources of inequality for people with comorbid SMI and physical health needs. The findings highlight the need for investment in social and healthcare roles, services and systems which can be responsive to compounding risks experienced by these individuals. Both physical and mental health needs, and their interactions, should be considered, along with the cumulative impact of poor socio-economic conditions and stressors. PATIENT OR PUBLIC CONTRIBUTION: A service user steering group, comprising five people with lived experience of SMI, was convened to support the study. The group met to inform the development of research questions, topic guides and participant materials, support the interpretation of findings, and provide input on the paper
Guidelines for perioperative care in elective colorectal surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations 2025
No full textTherapy process factors in early psychosis: The effect of working alliance on clinical symptoms and cognitive biases in Ultra High Risk young people
No full textApproximately 25 % of individuals at Ultra High Risk (UHR) transition to a full psychotic disorder. Cognitive biases are thought to play a role in this risk, and improvements in cognitive biases have been associated with better clinical outcomes. Early intervention is crucial, yet no therapeutic approach has proven superior, and treatment adherence remains a challenge. Therapeutic alliance, shown to enhance adherence and clinical outcomes, might also influence depression and cognitive biases, but its role in these domains among UHR patients remains unclear. A total of 202 UHR participants (59.4 % females, mean age 17.4), taking part in the sequential multiple-assignment randomized trial (SMART), completed questionnaires assessing cognitive biases, attenuated psychotic symptoms, quality of life, general and social functioning, depression, and overall psychopathology at baseline, and at 6- and 12-month follow-ups. Additionally, both patients and their corresponding therapists rated working alliance following the 6- and 12-month treatment periods. The results revealed that patient-rated therapeutic alliance significantly predicted improvements in attenuated psychotic symptoms, cognitive biases, general psychopathology, social functioning, and quality of life, with the strongest effects observed when measured 6 months into treatment. The relationship between working alliance and decreases in attenuated psychotic symptoms, as well as between working alliance and reduction in general psychopathology, turned out to be mediated by improvements in cognitive biases. Therapist-rated working alliance did not significantly predict clinical improvements, showing only a minor association with quality of life. Strengthening the therapeutic alliance and prioritizing cognitive bias modification early in interventions for UHR patients may improve treatment outcomes. Further research is needed to validate these findings