TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

Mammalian cells internalize bacteriophages and use them as a resource to enhance cellular growth and survival.

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a resource to promote cellular growth and metabolism.

Striving to support the supporters: A mixed methods evaluation of the strive support groups for caregivers of individuals with an eating disorder.

This mixed-methods study evaluated a peer-led support group for ED caregivers; the Eating Disorders Families Australia strive support groups. Quantitatively, 110 past or current strive attendees completed an online survey assessing their own and their care recipients' demographic profiles, strive's impact on caregiving experiences, and caregivers' psychological distress, burden, caregiving skills and self-efficacy. Qualitative assessment comprised open-ended survey questions about caregivers' strive experiences, reinforced by in-depth focus group assessment of nine participants. Quantitative analyses revealed that participants felt more confident and supported, and less isolated in their caregiving since attending strive. Caregivers displayed mid-range psychological distress and caregiver burden, and moderate caregiver skills and self-efficacy. Qualitatively, the most helpful aspects of strive were the shared experience among participants, education, and support. The most difficult elements were emotional distress and overly dominant members. Reflections discussed the necessity of caregiver support and factors impacting strive attendance. Participants recommended resuming face-to-face contact and differentiating groups based on participant characteristics (e.g. care recipients' age/stage of illness). The current findings provide support for the importance and overall positive contribution of support groups led by caregivers, such as strive.

Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2'-O-methyl gapmer oligonucleotides.

Oligonucleotide-based therapeutics have the capacity to engage with nucleic acid immune sensors to activate or block their response, but a detailed understanding of these immunomodulatory effects is currently lacking. We recently showed that 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) exhibited sequence-dependent inhibition of sensing by the RNA sensor Toll-Like Receptor (TLR) 7. Here we discovered that 2'OMe ASOs can also display sequence-dependent inhibitory effects on two major sensors of DNA, namely cyclic GMP-AMP synthase (cGAS) and TLR9. Through a screen of 80 2'OMe ASOs and sequence mutants, we characterized key features within the 20-mer ASOs regulating cGAS and TLR9 inhibition, and identified a highly potent cGAS inhibitor. Importantly, we show that the features of ASOs inhibiting TLR9 differ from those inhibiting cGAS, with only a few sequences inhibiting both pathways. Together with our previous studies, our work reveals a complex pattern of immunomodulation where 95% of the ASOs tested inhibited at least one of TLR7, TLR9 or cGAS by ≥30%, which may confound interpretation of their in vivo functions. Our studies constitute the broadest analysis of the immunomodulatory effect of 2'OMe ASOs on nucleic acid sensing to date and will support refinement of their therapeutic development.

Setting the top 10 eating disorder research and translation priorities for Australia.

OBJECTIVES: People with eating disorders, as well as their caregivers, experience high symptom burden, reduced quality of life and increased risk of early mortality. A lack of resources, disjointed vision and limited uptake of the evidence have limited the translation and implementation of research into practice. Little is known about what stakeholders (people with a lived experience, caregivers, health care professionals, researchers and policymakers) see as the most important research priorities. This study aimed to identify Australia's top 10 consensus-derived research and translation priorities for eating disorders. METHODS: Participants (n = 606) included people with a lived experience, carers, health care professionals (clinicians) and researchers working in eating disorders. The methodology aligned with the James Lind Alliance priority setting process, which involved oversight by a co-design advisory committee and utilised a national online interim priority setting survey and co-design workshops to identify the top 10 research and translation priorities. RESULTS: The initial national consultations elicited 1210 issues from 480 individuals. From this, 606 participants shortlisted 59 plain language questions in order of personal priority. In total, 16 questions were consistently ranked as important. As a final step, 24 individuals (with equal representation from all 4 stakeholder groups) attended the final prioritisation workshop to co-establish the top 10 research and translation priorities. CONCLUSION: The findings highlight the need for people with a lived experience, carers, health professionals and researchers to work collaboratively to develop co-designed research and translation activities that address the key areas of early intervention, prevention, understanding the aetiology of eating disorders and effective treatment of people experiencing eating disorders.

Are two occupational therapists better than one? Occupational therapists' perspectives of intra-disciplinary practice within community health.

INTRODUCTION: Intra-disciplinary practice is rarely discussed in occupational therapy and the broader health-care literature. Community-based occupational therapists often work autonomously in clients' homes and consequently have limited access to routine intra-disciplinary practices. Additionally, the community-based role covers a large scope of practice requiring comprehensive expertise. This study aimed to describe occupational therapists' perspectives on intra-disciplinary practice within community health settings. METHODS: This study utilised an online cross-sectional survey design, collecting quantitative and qualitative data to explore perspectives of occupational therapists working within Australian community health services. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. Both forms of data were compared and contrasted. RESULTS/FINDINGS: Eighty occupational therapists completed the survey. Seventy-eight participants (97%) previously used or currently use intra-disciplinary practice in their workplace. Participants predominantly consult their peers when client needs are perceived as complex. Participants indicated that intra-disciplinary practice can benefit the client, therapist, and workplace. Enablers and barriers to the use of intra-disciplinary practice had overlapping themes, including access to therapists, attitudes towards intra-disciplinary practice, management support, and funding influences. Most participants expressed a desire to utilise intra-disciplinary practices (n = 70, 87%) and were also likely or extremely likely to incorporate it into their clinical work (n = 73, 91%). Participants who did not want to utilise intra-disciplinary practices or who were unsure provided reasons related to cost, practice inefficiencies, and being uncertain of the benefit. CONCLUSIONS: Occupational therapists perceive intra-disciplinary practice as beneficial for problem-solving and an opportunity for knowledge sharing that supports therapist confidence with clinical reasoning. Conversely, some therapists believe its use may lead to client confusion, a greater need for communication and coordination among therapists, and that power differentials between therapists may discourage equal collaboration. Greater understanding of intra-disciplinary practice will help guide how it is used and supported in community health settings.

Rational design of antisense oligonucleotides modulating the activity of TLR7/8 agonists.

Oligonucleotide-based therapeutics have become a reality, and are set to transform management of many diseases. Nevertheless, the modulatory activities of these molecules on immune responses remain incompletely defined. Here, we show that gene targeting 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) can have opposing activities on Toll-Like Receptors 7 and 8 (TLR7/8), leading to divergent suppression of TLR7 and activation of TLR8, in a sequence-dependent manner. Surprisingly, TLR8 potentiation by the gapmer ASOs was blunted by locked nucleic acid (LNA) and 2'-methoxyethyl (2'MOE) modifications. Through a screen of 192 2'OMe ASOs and sequence mutants, we characterized the structural and sequence determinants of these activities. Importantly, we identified core motifs preventing the immunosuppressive activities of 2'OMe ASOs on TLR7. Based on these observations, we designed oligonucleotides strongly potentiating TLR8 sensing of Resiquimod, which preserve TLR7 function, and promote strong activation of phagocytes and immune cells. We also provide proof-of-principle data that gene-targeting ASOs can be selected to synergize with TLR8 agonists currently under investigation as immunotherapies, and show that rational ASO selection can be used to prevent unintended immune suppression of TLR7. Taken together, our work characterizes the immumodulatory effects of ASOs to advance their therapeutic development.

Amaryllidaceae Alkaloid Cherylline Inhibits the Replication of Dengue and Zika Viruses.

Dengue fever, caused by dengue virus (DENV), is the most prevalent arthropod-borne viral disease and is endemic in many tropical and subtropical parts of the world, with an increasing incidence in temperate regions. The closely related flavivirus Zika virus (ZIKV) can be transmitted vertically in utero and causes congenital Zika syndrome and other birth defects. In adults, ZIKV is associated with Guillain-Barré syndrome. There are no approved antiviral therapies against either virus. Effective antiviral compounds are urgently needed. Amaryllidaceae alkaloids (AAs) are a specific class of nitrogen-containing compounds produced by plants of the Amaryllidaceae family with numerous biological activities. Recently, the AA lycorine was shown to present strong antiflaviviral properties. Previously, we demonstrated that Crinum jagus contained lycorine and several alkaloids of the cherylline, crinine, and galanthamine types with unknown antiviral potential. In this study, we explored their biological activities. We show that C. jagus crude alkaloid extract inhibited DENV infection. Among the purified AAs, cherylline efficiently inhibited both DENV (50% effective concentration [EC50], 8.8 µM) and ZIKV replication (EC50, 20.3 µM) but had no effect on HIV-1 infection. Time-of-drug-addition and -removal experiments identified a postentry step as the one targeted by cherylline. Consistently, using subgenomic replicons and replication-defective genomes, we demonstrate that cherylline specifically hinders the viral RNA synthesis step but not viral translation. In conclusion, AAs are an underestimated source of antiflavivirus compounds, including the effective inhibitor cherylline, which could be optimized for new therapeutic approaches.

Australian adolescent population norms for the child health utility index 9D-results from the young minds matter survey.

OBJECTIVE: Patient-reported outcomes of health-related quality-of-life (HRQoL) are important descriptors of population health. A recent Australian adolescent population survey provided a unique opportunity to derive preference-based HRQoL. METHODS: Data from 2967 adolescents aged 11-17 years were analysed. An interviewer-led parent/carer questionnaire was administered for demographic variables and mental disorders of adolescents during previous 12 months using the Diagnostic Interview Schedule for Children. A self-report survey was administered to derive HRQoL using the child health utility nine-dimensions instrument (CHU-9D). Weighted HRQoL was derived for several demographic groups, mental disorder diagnosis, and youth risk behaviours. RESULTS: The total population had a mean utility of 0.78 [standard deviation (SD): 0.20]. Males had a significantly higher mean utility (0.81, SD 0.18) than females (0.76, SD: 0.21) (Cohen's d = 0.23, p < 0.001), and utility decreased with age for both males and females (p < 0.001). Family type and some parent/carer variables were associated with significant lower HRQoL scores with small effect size. Youth risk behaviours were associated with reduced HRQoL with moderate effect sizes. Adolescents who self-harmed, had suicidal ideation, or had a mental disorder had significantly lower utilities scores with moderate to large effect sizes compared to those who did not have such conditions. CONCLUSIONS: This study has provided contemporary Australian population norms for HRQoL in adolescents that may be used as cross comparison between studies as well as indicators allowing estimation of population health (e.g. estimation of the burden of disease) and can be used to populate future economic models.

Biological Investigation of Amaryllidaceae Alkaloid Extracts from the Bulbs of Pancratium trianthum Collected in the Senegalese Flora.

Amaryllidaceae plants are rich in alkaloids with biological properties. Pancratium trianthum is an Amaryllidaceae species widely used in African folk medicine to treat several diseases such as central nervous system disorders, tumors, and microbial infections, and it is used to heal wounds. The current investigation explored the biological properties of alkaloid extracts from bulbs of P. trianthum collected in the Senegalese flora. Alkaloid extracts were analyzed and identified by chromatography and mass spectrometry. Alkaloid extracts from P. trianthum displayed pleiotropic biological properties. Cytotoxic activity of the extracts was determined on hepatocarcinoma Huh7 cells and on acute monocytic leukemia THP-1 cells, while agar diffusion and microdilution assays were used to evaluate antibacterial activity. Antiviral activity was measured by infection of extract-treated cells with dengue virus (DENVGFP) and human immunodeficiency virus-1 (HIV-1GFP) reporter vectors. Cytotoxicity and viral inhibition were the most striking of P. trianthum's extract activities. Importantly, non-cytotoxic concentrations were highly effective in completely preventing DENVGFP replication and in reducing pseudotyped HIV-1GFP infection levels. Our results show that P. trianthum is a rich source of molecules for the potential discovery of new treatments against various diseases. Herein, we provide scientific evidence to rationalize the traditional uses of P. trianthum for wound treatment as an anti-dermatosis and antiseptic agent.

miR-222 isoforms are differentially regulated by type-I interferon.

Endogenous microRNAs (miRNAs) often exist as multiple isoforms (known as "isomiRs") with predominant variation around their 3'-end. Increasing evidence suggests that different isomiRs of the same family can have diverse functional roles, as recently demonstrated with the example of miR-222-3p 3'-end variants. While isomiR levels from a same miRNA family can vary between tissues and cell types, change of templated isomiR stoichiometry to stimulation has not been reported to date. Relying on small RNA-sequencing analyses, we demonstrate here that miR-222-3p 3'-end variants >23 nt are specifically decreased upon interferon (IFN) ß stimulation of human fibroblasts, while shorter isoforms are spared. This length-dependent dynamic regulation of long miR-222-3p 3'-isoforms and >40 other miRNA families was confirmed in human monocyte-derived dendritic cells following infection with Salmonella Typhimurium, underlining the breadth of 3'-length regulation by infection, beyond the example of miR-222-3p. We further show that stem-loop miRNA Taqman RT-qPCR exhibits selectivity between 3'-isoforms, according to their length, and that this can lead to misinterpretation of results when these isoforms are differentially regulated. Collectively, and to our knowledge, this work constitutes the first demonstration that the stoichiometry of highly abundant templated 3'-isoforms of a same miRNA family can be dynamically regulated by a stimulus. Given that such 3'-isomiRs can have different functions, our study underlines the need to consider isomiRs when investigating miRNA-based regulation.

Implicit play or explicit cognitive behaviour therapy: The impact of intervention approaches to facilitate social skills development in adolescents.

INTRODUCTION: Early adolescence is a time of increased social interaction with peers. Social competence is related to pretend play ability in younger children, but a lack of pretend play ability in childhood may also be associated with social challenges in early adolescence. Adolescents who find social situations challenging experience alienation from peers resulting in lowered self-regard. This paper presents an exploratory study comparing an Implicit group intervention (age-appropriate play based group (PB)) to an Explicit group intervention Cognitive Behavioural Therapy (CBT) to increase social ability in adolescents. METHODS: Six adolescents, three female and three male, were in the Implicit group (PB; mean age 12.3 years, SD = 1.21). Six male adolescents were in the Explicit group (CBT; mean age 13.3 years, SD = 1.03). All participants were assessed pre- and post the 8-week intervention for social competence, cognitive flexibility and narrative ability. The Implicit group (PB) was assessed through an age appropriate play assessment. Seven participants had a formal diagnosis, including autism spectrum disorder, and all were in mainstream high schools. RESULTS: The Explicit group (CBT) showed a medium effect for social engagement, total social skills, emotional engagement and a large effect for a decrease in flexible thinking. The Implicit group (PB) showed a large impact for narrative ability with increases in ability to sequence events, initiation and creation of plot, understanding character roles and total movie score, with medium effects for generation of problems, precise vocabulary and use of symbols. The Implicit group (PB) maintained cognitive flexibility, and decreased in social self-scoring which showed medium effects for externalising and internalising. CONCLUSION: This paper contributes to evidence that the choice of social skills intervention impacts different skill sets. For neuro-diverse adolescents, the cognitive intervention impacted social and emotional engagement and the play-based intervention impacted a wider range of abilities related to narrative social interaction.

Mental health consumer involvement in occupational therapy education in Australia and Aotearoa New Zealand.

INTRODUCTION: Recovery-oriented practice policies and occupational therapy education accreditation standards require that consumers are engaged in the design, delivery and evaluation of curricula. This consumer involvement (sometimes referred to as service-user involvement or patient involvement in other contexts) should go beyond consumers simply 'telling their stories' to more meaningful collaboration in curricula. This study was designed to map the current patterns of consumer involvement in occupational therapy programs across Australia and Aotearoa New Zealand. METHOD: A survey was distributed to all occupational therapy programs across Australia and Aotearoa New Zealand. The survey included questions related to: (a) perceived enablers and barriers to consumer involvement in education; (b) organisational structures and support; (c) ways in which consumer are involved in the design, delivery and evaluation of curricula; (d) access to remuneration for consumers; (e) overall ratings of the level of consumer involvement in curricula; and (f) academic confidence in working with consumers. RESULTS: Usable responses were received for 23 programs from 19 universities (83% response rate). Every program reported some consumer involvement in the curriculum. Consumer participation tended to be mainly focussed on curriculum delivery with less frequent involvement in curriculum design or evaluation. The most common barrier to consumer involvement in curricula was 'funding/remuneration for consumers' and the most common enabler of consumer involvement was 'positive attitudes of teaching staff'. CONCLUSION: In comparison to previous reports, consumer involvement in occupational therapy curricula has increased over the past decade. However, ongoing effort is required to support true collaboration in all aspects of curriculum design, delivery and evaluation. While this will require attention and effort from academic teams, changes at a university level to establish systems to engage and effectively remunerate consumers for their involvement (especially in design and evaluation elements) are also required.

Activation of cGAS-dependent antiviral responses by DNA intercalating agents.

Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)-dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells.

Longitudinal evaluation of a knowledge translation role in occupational therapy.

BACKGROUND: In 2014, a large metropolitan mental health service in Australia developed a senior role (Lead Research Occupational Therapist) to address an identified need for greater research and knowledge translation, and associated capacity building. The aim of this study was to evaluate the impact, in the first 2.5 years, of this role across a range of variables. METHODS: Multiple methods were used to gather a comprehensive range of data. Workforce surveys were completed both online and in hard copy in early 2014 (n = 42) and late 2016 (n = 44). Research key performance indicators (academic, research production and cultural) were also identified for measurement over time. The data from these surveys were analysed using descriptive and inductive analysis, and also with social network analysis. RESULTS: This role has demonstrated positive outcomes across a range of variables. There was a medium effect on the quantity of participation in quality assurance and knowledge translation activities by the workforce. Most knowledge translation behaviours were occurring regularly, although several were absent. An improving trend in attitudes towards evidence-based practice was recorded, and perceptions of the knowledge translation role were generally positive. The Lead Research Occupational Therapist moved from the periphery to the centre of the evidence based practice social network. Improved awareness of other clinicians deploying evidence based practice was observed, and the frequency of interaction between clinicians increased. The role has met all key performance indicators, across the academic, research production and cultural domains. CONCLUSIONS: The shift in focus of this role from research to knowledge translation has produced tangible outcomes for the occupational therapy workforce. These achievements have had a positive impact on the sustainability of the role, which will be continued for at least another two years. An ongoing challenge is to directly measure the impact of this role on outcomes for people with mental illness and their carers.

Threshold concept acquisition in occupational therapy: A mixed methods study of students and clinicians.

BACKGROUND/AIM: Demand for occupational therapy graduates able to work in complex and diverse workplaces is increasing. The threshold concepts framework has emerged as one pathway to assist in the development of work-ready graduates. A previous Australian study identified 10 threshold concepts for occupational therapy; the aim of this study was to explore the acquisition of these. METHOD: A mixed-methods study using observational, cross sectional design and a triangulation design convergence model was undertaken. A survey using Likert scales and open response questions was developed by the authors. Seventy-three surveys were completed by 13 first and 20 final year Victorian occupational therapy students. Twenty recent graduates and 20 experienced clinicians from across Australia also participated. Seven first and 10 final year occupational therapy students, 10 recent graduates and 10 experienced clinicians also took part in in-depth interviews. Likert scales were used by participants to rate confidence that they had acquired the threshold concepts, they also answered open-response questions (via survey or interview) asking them to provide examples of how they would use threshold concepts in practice. RESULTS: Fourth year students were statistically significantly less confident than experienced clinicians for the threshold concepts Understanding the models and theories of occupational therapy and Applying clinical reasoning (P < 0.05). When whole group data were analysed, participants were most confident for Occupation and Client centred practice (P < 0.05). These results resonated with the qualitative findings which demonstrated a shift from surface to deep knowledge with increased experience. Fourth year students reported responses that suggested some threshold concepts were still in development, while experienced clinicians used a web of threshold concepts. CONCLUSION: This exploratory study provides provisional data to suggest that students appear to still be acquiring some threshold concepts at graduation and experienced clinicians make use of a web of threshold concepts in their clinical practice.

Measuring movement skill perceptions in preschool children: A face validity and reliability study.

BACKGROUND/AIM: The aim of this study was to determine the face validity and the reliability of a pictorial scale to assess preschool children's perceived movement skills. METHODS: The pictorial scale examines the perceptions of the 12 fundamental movement skills presented in the Test of Gross Motor Development-2 (six locomotor and six object control skills) and six active play skills (e.g. cycling). A total of 91 Australian children aged four to five years from 14 preschools completed the scale on two occasions to determine test-retest reliability. Internal consistency was determined for all 18 items and for each subscale. After the second test, participants were asked open-ended questions to gain insight into their understanding of what was happening in the pictures to determine the face validity. RESULTS: Overall, children demonstrated a better understanding of object control and play skills compared to locomotor skills. Test-retest reliability values were good for object control (intra-class correlation, ICC = 0.75), locomotor (ICC = 0.78), active play skills (ICC = 0.80) and all 18 skills combined (ICC = 0.77). Internal consistency was acceptable for locomotor (Test 1 0.64, Test 2 0.75), object control (0.71, 0.76), active play skills (0.76, 0.74) and for all 18 skills combined (0.88, 0.90). CONCLUSIONS: Overall, this instrument demonstrated an acceptable reliability in preschool children and has provided preliminary information for examining the perceptions of movement skills. This age group presents a key target area for occupational therapists, who can assist preschool children to further develop fundamental movement skills, integrate these skills in their roles and occupations and increase engagement in meaningful physical activity in the long term.

Cre-dependent DNA recombination activates a STING-dependent innate immune response.

Gene-recombinase technologies, such as Cre/loxP-mediated DNA recombination, are important tools in the study of gene function, but have potential side effects due to damaging activity on DNA. Here we show that DNA recombination by Cre instigates a robust antiviral response in mammalian cells, independent of legitimate loxP recombination. This is due to the recruitment of the cytosolic DNA sensor STING, concurrent with Cre-dependent DNA damage and the accumulation of cytoplasmic DNA. Importantly, we establish a direct interplay between this antiviral response and cell-cell interactions, indicating that low cell densities in vitro could be useful to help mitigate these effects of Cre. Taking into account the wide range of interferon stimulated genes that may be induced by the STING pathway, these results have broad implications in fields such as immunology, cancer biology, metabolism and stem cell research. Further, this study sets a precedent in the field of gene-engineering, possibly applicable to other enzymatic-based genome editing technologies.

cGAS-STING Activation in the Tumor Microenvironment and Its Role in Cancer Immunity.

Stimulator of interferon (IFN) genes (STING) is a key mediator in the immune response to cytoplasmic DNA sensed by cyclic GMP-AMP (cGAMP) synthase (cGAS). After synthesis by cGAS, cGAMP acts as a second messenger activating STING in the cell harboring cytoplasmic DNA but also in adjacent cells through gap junction transfer. While the role of the cGAS-STING pathway in pathogen detection is now well established, its importance in cancer immunity has only recently started to emerge. Nonetheless, STING appears to be an essential component in the recruitment of immune cells to the tumor microenvironment, which is paramount to immune clearance of the tumor. This review presents an overview of the growing literature around the role of the cGAS-STING pathway in the tumor microenvironment, with a specific focus on the role that cancer cells may play in the direct activation of this pathway, and its amplification through cell-cell transfer of cGAMP.

Mental health education in occupational therapy professional preparation programs: Alignment between clinician priorities and coverage in university curricula.

BACKGROUND/AIM: Occupational therapy programs must prepare graduates for work in mental health. However, this area of practice is complex and rapidly changing. This study explored the alignment between educational priorities identified by occupational therapists practising in mental health and level of coverage of these topics in occupational therapy programs in Australia and New Zealand. METHODS: Surveys were distributed to heads of all occupational therapy programs across Australia and New Zealand. The survey included educational priorities identified by occupational therapists in mental health from a previous study. Respondents were requested to identify the level of coverage given to each of these priorities within their curriculum. These data were analysed to determine a ranking of educational topics in terms of level of coverage in university programs. RESULTS: Responses were received for 19 programs from 16 universities. Thirty-four topics were given 'High-level coverage' in university programs, and these were compared against the 29 topics classified as 'Essential priorities' by clinicians. Twenty topics were included in both the 'Essential priorities' and 'High-level coverage' categories. Topics considered to be 'Essential priorities' by clinicians which were not given 'High-level coverage' in university programs included the following: mental health fieldwork experiences; risk assessment and management; professional self-care resilience and sensory approaches. CONCLUSION: While there appears to be overall good alignment between mental health curricula and priorities identified by practising occupational therapists, there are some discrepancies. These discrepancies are described and establish a strong foundation for further discussion between clinicians, academics and university administration to support curriculum review and revision.