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Abstract While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.

[This corrects the article DOI: 10.1371/journal.pbio.3001480.].

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with inherited forms of Parkinson’s disease (PD), causing disease by a gain of kinase function. Here, we describe a series of isogenic iPSC lines with any of five pathogenic mutations (N1437H, R1441C, Y1699C, G2019S and I2020T); two hypothesis testing mutations (GTP binding null, T1348N, and kinase dead, K1906M) and two LRRK2 knockouts. This resource could be used to assess effects of mutations on the function of endogenous LRRK2 and/or to study LRRK2 interactors and substrates in iPSC-derived cellular models.

The desert locust remains a major threat to global food security. Control operations are a crucial tool to manage crisis; this research investigated the nature of control operations conducted between 2019–2021. Historical data on desert locust and control operations were obtained from the survey reports at the FAO Locust Hub and analysed with respect to survey reports, land cover types, cropland/rangeland extent and crop productivity data. We found that 16.1% of the grid cells with locust presence and 14.9% of the grid cells with control operations had a proportion of rangeland higher than 0.75; while 13.3% of the grid cells with locust presence and 13.2% of the grid cells with control operations had a proportion of croplands higher than 0.75, highlighting that locust presence and control operations were reported in both rangeland and cropland. Control operations continue to be used both to reduce overall locust numbers and to protect crops. Furthermore, through identifying which crops were most at risk, our analyses indicate that wheat production was under the highest strain during periods of increased locust infestations.

Abstract Background Early onset Parkinson’s disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. Methods A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved. Results We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. Conclusion Hexokinases are an important link between three major genetic causes of early onset Parkinson’s disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.

Objective: To objectively measure color vision dysfunction in idiopathic Parkinson's disease (iPD) using an easily administered, essentially free, modified Stroop test.Methods: Sixty-one iPD patients and 26 age-matched controls (HC) were enrolled after IRB approval and performed congruent (CST) and incongruent (IST) modified Stroop tests consisting of 40 words in 10 colors arranged in a 5 x 8 grid. The scorer was blinded to participant diagnosis. Errors on IST were defined as type 1 (written word reported rather than color) or type 2 (color reported different from the written word or its color).Results: The iPD group and the control group completed testing with similar CST performance. On the IST, 75.4% of iPD patients had type 2 errors (p = 0.001, OR 4.907, 95%CI 1.838–13.097) compared to 38.5% HC, with a positive predictive value of 82%. The mean number of type 2 errors was also higher in the iPD group, even with MoCA scores as a covariate in the analysis. Type 1 errors were not significantly different between the groups. A univariate logistic regression model with age, gender, MoCA, normalized IST completion time and the presence/absence of type 2 errors also resulted in type 2 errors as the only significant factor in the equation (p = 0.026).Conclusions: The modified Stroop test incorporated into the clinical evaluation of a patient may provide a quick and inexpensive objective measure of a non-motor feature of iPD, which could help in the clinical diagnosis of iPD in conjunction with the motor assessments currently used by neurologists.

Bangladesh is a globally important emerging economy with rapidly increasing energy demand. The Bangladeshi government's primary capacity expansion plan is to install 13.3 GW of new coal by 2021, including the 1.3 GW Rampal coal power plant to be developed in the Sundarbans. Inadequate geospatial and economic information on clean energy investment opportunities are often a significant barrier for policy makers. Our study helps fill this gap by applying a new method to assess energy investment opportunities, with focus on understanding land-use conflicts, particularly important in this context as Bangladesh is constrained on land for agriculture, human settlements, and ecological preservation. By extending a geospatial multi-criteria analysis model (MapRE) we analyze the cost of various renewable energy generation technologies based on resource availability and key siting criteria such as proximity to transmission and exclusion from steep slopes, dense settlements or ecologically sensitive areas. We find there is more utility-scale solar potential than previously estimated, which can be developed at lower costs than coal power and with minimal cropland tradeoff. We also find significant potential for decentralized roof-top solar in commercial and residential areas. Even with a conservative land use program that reserves maximum land for agriculture and human settlement, there is more renewable energy capacity than needed to support Bangladeshi growth. This study provides critical and timely information for capacity expansion planning in South Asia and demonstrates the use of geospatial models to support decision-making in data-limited contexts.

ABSTRACT Background and Objective Migrant and refugee women, families, and their children can experience significant language, cultural, and psychosocial barriers to engage with child and family services. Integrated child and family health Hubs are increasingly promoted as a potential solution to address access barriers; however, there is scant literature on how to best implement them with migrant and refugee populations. Our aim was to explore with service providers and consumers the barriers, enablers, and experiences with Hubs and the resulting building blocks required for acceptable Hub implementation for migrant and refugee families. Design, Setting and Participants This project was undertaken in Sydney, New South Wales, in communities characterised by cultural diversity. In this qualitative study, we used semi‐structured interviews guided by the consolidated framework for implementation research, with service providers from health and social services (32 participants) and migrant and refugee parents (14 parents) of children who had accessed Hubs. Research and Discussion Our initial qualitative data themes were developed into step‐by‐step building blocks, representing a way to address contextual determinants to establish and sustain a Hub that can support migrant and refugee families. These include the setting‐up phase activities of buy‐in and partnership development, which outlines mechanisms to foster collective action and collaboration between health and social services. Following this, our orientation model articulates the need to establish Hub coordination and navigation, activities that enhance a Hub's relevance for migrant and refugee families and ongoing integration mechanisms, such as engagement of same‐language general practitioners. This is the first study to explore the building blocks required for acceptable Hub implementation to meet the needs of migrant and refugee families in the first 2000 days of a child's life—a critical time to optimise child development and health. Patient or Public Contribution The research questions were developed based on qualitative research undertaken with Hub participants, community members, and service providers. The original investigator team had a consumer representative who has since relocated and consultation was undertaken with local Hub partner services. The researchers also consulted multicultural health services, including cultural support workers, to ensure research materials were culturally nuanced. Patients or participants have not directly been involved in the current study design. Clinical Trial Registration This trial was registered with the Australian New Zealand Clinical Trials (ACTRN12621001088831).

Incarcerated women's perceptions of the prison environment were explored with respect to relative level of safety from interpersonal abuse in prison as compared to before incarceration. Perceived levels of safety were analyzed based on reported past experiences of interpersonal violence. Participants were 65 women incarcerated in a medium security prison for women with mental and physical health problems. Women's perceptions of safety were evaluated using close-ended quantitative and open-ended qualitative self-report questions. The results suggest that, for some women, prison may be a relatively safe environment and that perceived level of safety may vary with the extent of previous experience of interpersonal violence in childhood and adulthood. Given that the structure of correctional institutions often incorporates abusive dynamics, the directionality of the findings is theoretically and socially important. The patterns apparent in these data are also consistent with other research and theory on the experiences of incarcerated women. (Contains 1 table.)

Abstract Background Children and families from priority populations experienced significant psychosocial and mental health issues to the COVID-19 pandemic. Yet they also faced significant barriers to service access, particularly families from culturally and linguistically diverse (CALD) backgrounds. With most child and family health nurse clinics ceasing in-person consultations due to the pandemic, many children missed out on health and developmental checks. The aim of this study was to investigate the perspectives and experiences of family members and service providers from an urban, CALD community regarding the implementation of a digital, developmental surveillance, Watch Me Grow-Electronic (WMG-E) program. Methods Semi-structured interviews were conducted with 17 family members, service navigators, and service providers in a multicultural community in South Western Sydney, Australia. This qualitative study is an implementation evaluation which formed as part of a larger, two-site, randomised controlled trial of the WMG-E program. A reflexive thematic analysis approach, using inductive coding, was adopted to analyse the data. Results Participants highlighted the comprehensive and personalised support offered by existing child and family health services. The WMG-E was deemed beneficial because the weblink was easy and quick to use and it enabled access to a service navigator who support family access to relevant services. However, the WMG-E was problematic because of technology or language barriers, and it did not facilitate immediate clinician involvement when families completed the weblink. Conclusions Families and service providers in this qualitative study found that using WMG-E empowered parents and caregivers to access developmental screening and learn more about their child’s development and engage with relevant services. This beds down a new and innovative solution to the current service delivery gap and create mechanisms that can engage families currently not accessing services, and increases knowledge around navigating the health and social care services. Notwithstanding the issues that were raised by families and service providers, which include accessibility challenges for CALD communities, absence of clinical oversight during screening, and narrow scope of engagement with available services being offered, it is worth noting that improvements regarding these implementation factors must be considered and addressed in order to have longevity and sustainability of the program. Trial registration. The study is part of a large randomised controlled trial (Protocol No. 1.0, Version 3.1) was registered with ANZCTR (registration number: ACTRN12621000766819) on July 21st, 2021 and reporting of the trial results will be according to recommendations in the CONSORT Statement.

A study to ascertain the relationship betweenchildhood abuseand the risk of developing stress disorder symptoms in adults was conducted. Results did not find any significant relation but suggested a potential gene-childhood environment that could cause adult posttraumatic stress disorder.