A Single Model for the Thermodynamics and Kinetics of Metal Exsolution from Perovskite Oxides.

Exsolution has emerged as an outstanding route for producing oxide-supported metal nanoparticles. For ABO3-perovskite oxides, various late transition-metal cations can be substituted into the lattice under oxidizing conditions and exsolved as metal nanoparticles after reduction. A consistent and comprehensive description of the point-defect thermodynamics and kinetics of this phenomenon is lacking, however. Herein, supported by hybrid density-functional-theory calculations, we propose a single model that explains diverse experimental observations, such as why substituent transition-metal cations (but not host cations) exsolve from perovskite oxides upon reduction; why different substituent transition-metal cations exsolve under different conditions; why the metal nanoparticles are embedded in the surface; why exsolution occurs surprisingly rapidly at relatively low temperatures; and why the reincorporation of exsolved species involves far longer times and much higher temperatures. Our model's foundation is that the substituent transition-metal cations are reduced to neutral species within the perovskite lattice as the Fermi level is shifted upward within the bandgap upon sample reduction. The calculations also indicate unconventional influences of oxygen vacancies and A-site vacancies. Our model thus provides a fundamental basis for improving existing, and creating new, exsolution-generated catalysts.

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic ß cell Pyroptosis upon Viral Infection.

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and ß cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated ß cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both ß cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced ß cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated ß cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of ß cell damage during viral exposure.

Life is better but not without challenges: experiences following discharge from community-based residential mental health rehabilitation-a qualitative content analysis.

PURPOSE: Community-based residential mental health rehabilitation units for people experiencing severe and persistent mental illness are increasingly available in Australia. Research completed 20 years ago suggested that people leaving these services often experienced impoverished social lives and other challenges in the community. It is unclear whether contemporary consumers experience similar difficulties. This qualitative study explored contemporary consumers' experiences after leaving community-based residential services. METHODS: An inductive qualitative content analysis of individual interviews was completed with consumers 12-18 months following discharge from three community care units (CCUs) in Queensland, Australia. The interview schedule explored three questions: (1) What does life look like after leaving the CCU, (2) Has the CCU impacted their life, and (3) How could the CCU experience be improved? A convenience sample was used, with sampling continuing until thematic saturation was achieved. A member of the research team who had relevant lived experience actively supported the analysis and interpretation. RESULTS: Seventeen interviews were completed. Three themes were identified: 'life is better but not without challenges', 'the CCU helps you get ready to go out into the world', and 'strict rules are important but rigid expectations can be hard; things could be better'. CONCLUSION: Consumers reflected positively on their lives post-discharge from a community-based residential rehabilitation unit and viewed the service as having supported improvements in their lives. The findings suggest the appropriateness of optimism about the possibility of sustained improvements in quality of life after leaving community-based transitional residential rehabilitation support.

Untangling the genetics of beta cell dysfunction and death in type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. SCOPE OF REVIEW: Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. MAJOR CONCLUSIONS: We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.

Attitudes toward psychedelics and psychedelic-assisted therapy among potential mental health service users and the general population in Australia.

OBJECTIVE: Despite rapid advances in psychedelic sciences and the increasing number of countries legalizing psychedelics for the treatment of mental illnesses, the attitudes, knowledge and readiness of both mental health consumers and the general population remain largely unknown. METHODS: A cross-sectional survey was conducted among Australians, targeting individuals with mental illness as potential mental health service users. A sub-sample of individuals free of mental illness was also surveyed to assess attitudes in the general population. Participants completed the Attitudes on Psychedelics Questionnaire, the Basic Knowledge of Psychedelics Test and a questionnaire by Corrigan et al. to capture attitudes toward psychedelic therapy by mental health service users. RESULTS: Of the 502 respondents, 64.5% self-identified as having a mental illness. A significant proportion favored legalizing psychedelics for medical use (43%) and were open to their use (52.4%), yet fewer viewed their effects positively (24%) or considered them safe (33%). Most participants reported to be psychedelic naive (61%). Participants with mental illness had significantly more experience with psychedelics than participant free of mental illness (44.1% vs 29.7%). Experience, perceived knowledge and actual knowledge significantly predicted attitudes toward legalization, effects, risks and openness to psychedelics. CONCLUSIONS: While a large proportion of Australians are in favor of legalizing psychedelics for medical purposes, concerns about safety remain. People with self-identified mental illness, those with previous recreational psychedelic experience and those with greater knowledge of psychedelics were more likely to have positive attitudes toward psychedelics and psychedelic-assisted therapy.

Composition-dependent morphologies of CeO2 nanoparticles in the presence of Co-adsorbed H2O and CO2: a density functional theory study.

Catalytic activity is affected by surface morphology, and specific surfaces display greater activity than others. A key challenge is to define synthetic strategies to enhance the expression of more active surfaces and to maintain their stability during the lifespan of the catalyst. In this work, we outline an ab initio approach, based on density functional theory, to predict surface composition and particle morphology as a function of environmental conditions, and we apply this to CeO2 nanoparticles in the presence of co-adsorbed H2O and CO2 as an industrially relevant test case. We find that dissociative adsorption of both molecules is generally the most favourable, and that the presence of H2O can stabilise co-adsorbed CO2. We show that changes in adsorption strength with temperature and adsorbate partial pressure lead to significant changes in surface stability, and in particular that co-adsorption of H2O and CO2 stabilizes the {100} and {110} surfaces over the {111} surface. Based on the changes in surface free energy induced by the adsorbed species, we predict that cuboidal nanoparticles are favoured in the presence of co-adsorbed H2O and CO2, suggesting that cuboidal particles should experience a lower thermodynamic driving force to reconstruct and thus be more stable as catalysts for processes involving these species.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes ( CFHR1 and LRP6 ) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

Defining the passage of wisdom: A taxonomy of supervision for RANZCP trainees and Fellows.

OBJECTIVE: Trainees and Fellows of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) work in complex interpersonal and organisational environments. Engagement in supervision can be a helpful way for trainees and Fellows to achieve interpersonal, professional, and organisational success. Supervision comes in many forms depending on the stage and state of one's career. An awareness of different supervision models is relevant to trainees' understanding of what is expected of them and their supervisors in their work and educational contexts. This paper explores the taxonomy of supervision models available to RANZCP trainees and Fellows in Australia and New Zealand. CONCLUSION: Supervision is a heterogeneous concept with multiple aims, outcomes, and processes that change with ones' stage of career.

BiVO4 Photoanodes Enhanced with Metal Phosphide Co-Catalysts: Relevant Properties to Boost Photoanode Performance.

Achieving highly performant photoanodes for oxygen evolution is key to developing photoelectrochemical devices for solar water splitting. In this work, BiVO4 photoanodes are enhanced with a series of core-shell structured bimetallic nickel-cobalt phosphides (MPs), and key insights into the role of co-catalysts are provided. The best BiVO4 /Ni1.5 Co0.5 P and BiVO4 /Ni0.5 Co1.5 P photoanodes achieve a 3.5-fold increase in photocurrent compared with bare BiVO4 . It is discovered that this enhanced performance arises from a synergy between work function, catalytic activity, and capacitive ability of the MPs. Distribution of relaxation times analysis reveals that the contact between the MPs, BiVO4 , and the electrolyte gives rise to three routes for hole injection into the electrolyte, all of which are significantly improved by the presence of a second metal cation in the co-catalyst. Kinetic studies demonstrate that the significantly improved interfacial charge injection is due to a lower charge-transfer resistance, enhanced oxygen-evolution reaction kinetics, and larger surface hole concentrations, providing deeper insights into the carrier dynamics in these photoanode/co-catalyst systems for their rational design.

Genetic risk converges on regulatory networks mediating early type 2 diabetes.

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

Identifying pathways to metal-organic framework collapse during solvent activation with molecular simulations.

Metal-organic framework (MOF) materials are a vast family of nanoporous solids with potential applications ranging from drug delivery to environmental remediation. Application of MOFs in these scenarios is hindered, however, by difficulties in MOF 'activation' after initial synthesis - removal of the synthesis solvent from the pores to make the pore space accessible - often leading to framework collapse if improperly performed. While experimental studies have correlated collapse to specific solvent properties and conditions, the mechanism of activation-collapse is currently unknown. Developing this understanding would enable researchers to create better activation protocols for MOFs, accelerating discovery and process intensification. To achieve this goal, we simulated solvent removal using grand-canonical Monte Carlo and free energy perturbation methods. By framing activation as a fluid desorption problem, we investigated activation processes in the isoreticular metal organic framework (IRMOF) family of MOFs for different solvents. We identified two pathways for solvent activation - the solvent either desorbs uniformly from each individual pore or forms coexisting phases during desorption. These mesophases in turn lead to large capillary stresses within the framework, corroborating experimental hypotheses for the cause of activation-collapse. Finally, we found that the activation energy of solvent removal increased with pore size and connectivity due to the increased stability of solvent mesophases, matching experimental findings. Using these simulations, it is possible to screen MOF activation procedures, enabling rapid identification of ideal solvents and conditions and thus enabling faster development of MOFs for practical applications.

Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. Here, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34K conditionally distinct expression quantitative trait locus (eQTL) signals in 18K genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared to primary signals, non-primary signals had lower effect sizes, lower minor allele frequencies, and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTL with conditionally distinct genome-wide association study signals for 28 cardiometabolic traits identified 3,605 eQTL signals for 1,861 genes. Inclusion of non-primary eQTL signals increased colocalized signals by 46%. Among 30 genes with ≥2 pairs of colocalized signals, 21 showed a mediating gene dosage effect on the trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

An immunomodulating peptide with potential to suppress tumour growth and autoimmunity.

Cancers and autoimmune diseases commonly co-exist and immune checkpoint inhibitor therapy (ICI) exacerbates autoimmune pathologies. We recently described a lipidic peptide, designated IK14004, that promotes expansion of immunosuppressive T regulatory (Treg) cells and uncouples interleukin-2 from interferon-gamma production while activating CD8+ T cells. Herein, we report IK14004-mediated inhibition of Lewis lung cancer (LLC) growth and re-invigoration of splenocyte-derived exhausted CD4+ T cells. In human immune cells from healthy donors, IK14004 modulates expression of the T cell receptor α/ß subunits, induces Type I IFN expression, stimulates natural killer (NK) cells to express NKG2D/NKp44 receptors and enhances K562 cytotoxicity. In both T and NK cells, IK14004 alters the IL-12 receptor ß1/ß2 chain ratio to favour IL-12p70 binding. Taken together, this novel peptide offers an opportunity to gain further insight into the complexity of ICI immunotherapy so that autoimmune responses may be minimised without promoting tumour evasion from the immune system.

An integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D associated genes and regulatory signals.

Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody+ (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions. We broadly nominate effector cell types for all T1D GWAS signals. We further nominated higher-resolution contexts, including effector cell types, regulatory elements, and genes for three independent T1D risk variants acting through islet cells within the pancreas at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we created isogenic gene knockouts DLK1-/-, RASGRP1-/-, and TOX-/-, and the corresponding regulatory region knockout, RASGRP1Δ, and DLK1Δ hESCs. Loss of RASGRP1 or DLK1, as well as knockout of the regulatory region of RASGRP1 or DLK1, increased ß cell apoptosis. Additionally, pancreatic ß cells derived from isogenic hESCs carrying the risk allele of rs3783355A/A exhibited increased ß cell death. Finally, RNA-seq and ATAC-seq identified five genes upregulated in both RASGRP1-/- and DLK1-/- ß-like cells, four of which are associated with T1D. Together, this work reports an integrative approach for combining single cell multi-omics, GWAS, and isogenic hESC-derived ß-like cells to prioritize the T1D associated signals and their underlying context-specific cell types, genes, SNPs, and regulatory elements, to illuminate biological functions and molecular mechanisms.

Infrared and Raman Diagnostic Modeling of Phosphate Adsorption on Ceria Nanoparticles.

Cerium dioxide (CeO2; ceria) nanoparticles (CeNPs) are promising nanozymes that show a variety of biological activity. Effective nanozymes need to retain their activity in the face of surface speciation in biological environments, and characterizing surface speciation is therefore critical to understanding and controlling the therapeutic capabilities of CeNPs. In particular, adsorbed phosphates can impact the enzymatic activity exploited to convert phosphate prodrugs into therapeutics in vivo and also define the early stages of the phosphate-scavenging processes that lead to the transformation of active CeO2 into inactive CePO4. In this work, we utilize ab initio lattice-dynamics calculations to study the interaction of phosphates with the three major surfaces of ceria and to predict the infrared (IR) and Raman spectral signatures of adsorbed phosphate species. We find that phosphates adsorb strongly to CeO2 surfaces in a range of stable binding configurations, of which 5-fold coordinated P species in a trigonal bipyramidal coordination may represent a stable intermediate in the early stages of phosphate scavenging. We find that the phosphate species show characteristic spectral fingerprints between 500 and 1500 cm-1, whereas the bare CeO2 surfaces show no active modes above 600 cm-1, and the 5-fold coordinated P species in particular show potential diagnostic P-O stretching modes between 650 and 700 cm-1 in both IR and Raman spectra. This comprehensive exploration of different binding modes for phosphates on CeO2 and the set of reference spectra provides an important step toward the experimental characterization of phosphate speciation and, ultimately, control of its impact on the performance of ceria nanozymes.

Using a modular massively parallel reporter assay to discover context-specific regulatory grammars in type 2 diabetes.

Recent genome-wide association studies have established that most complex disease-associated loci are found in noncoding regions where defining their function is nontrivial. In this study, we leverage a modular massively parallel reporter assay (MPRA) to uncover sequence features linked to context-specific regulatory activity. We screened enhancer activity across a panel of 198-bp fragments spanning over 10k type 2 diabetes- and metabolic trait-associated variants in the 832/13 rat insulinoma cell line, a relevant model of pancreatic beta cells. We explored these fragments' context sensitivity by comparing their activities when placed up-or downstream of a reporter gene, and in combination with either a synthetic housekeeping promoter (SCP1) or a more biologically relevant promoter corresponding to the human insulin gene ( INS ). We identified clear effects of MPRA construct design on measured fragment enhancer activity. Specifically, a subset of fragments (n = 702/11,656) displayed positional bias, evenly distributed across up- and downstream preference. A separate set of fragments exhibited promoter bias (n = 698/11,656), mostly towards the cell-specific INS promoter (73.4%). To identify sequence features associated with promoter preference, we used Lasso regression with 562 genomic annotations and discovered that fragments with INS promoter-biased activity are enriched for HNF1 motifs. HNF1 family transcription factors are key regulators of glucose metabolism disrupted in maturity onset diabetes of the young (MODY), suggesting genetic convergence between rare coding variants that cause MODY and common T2D-associated regulatory variants. We designed a follow-up MPRA containing HNF1 motif-enriched fragments and observed several instances where deletion or mutation of HNF1 motifs disrupted the INS promoter-biased enhancer activity, specifically in the beta cell model but not in a skeletal muscle cell line, another diabetes-relevant cell type. Together, our study suggests that cell-specific regulatory activity is partially influenced by enhancer-promoter compatibility and indicates that careful attention should be paid when designing MPRA libraries to capture context-specific regulatory processes at disease-associated genetic signals.

A guide to support trainee's success in the psychotherapy written case submission.

OBJECTIVE: Many trainees find the Psychotherapy Written Case (PWC) requirement of the Royal Australian and New Zealand College of Psychiatrists training program challenging. The skills developed and assessed through this experience are critical to the competencies expected of a psychiatrist. However, the process of psychodynamic psychotherapy is often dramatically different from the expectations associated with early clinical placements in acute psychiatric settings. To support trainees in achieving success in the PWC, a guide to the written report was developed based on a review of existing resources and various stakeholder perspectives. CONCLUSIONS: The submission should reflect a training case rather than an idealised or fictionalised story attempting to demonstrate the therapist's competence. The PWC submission must meet the requirements of a general psychiatric report and provide a considered reflection on the experience of the novice therapist.

An immunomodulating peptide to counteract solar radiation-induced immunosuppression and DNA damage.

Ultraviolet radiation (UVR) induces immunosuppression and DNA damage, both of which contribute to the rising global incidence of skin cancer including melanoma. Nucleotide excision repair, which is activated upon UVR-induced DNA damage, is linked to expression of interleukin-12 (IL-12) which serves to limit immunosuppression and augment the DNA repair process. Herein, we report an immunomodulating peptide, designated IK14800, that not only elicits secretion of IL-12, interleukin-2 (IL-2) and interferon-gamma (IFN-γ) but also reduces DNA damage in the skin following exposure to UVR. Combined with re-invigoration of exhausted CD4+ T cells, inhibition of UVR-induced MMP-1 release and suppression of B16F10 melanoma metastases, IK14800 offers an opportunity to gain further insight into mechanisms underlying the development and progression of skin cancers.