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The benefits of the fourth industrial revolution are realised through accurate capture and processing of data relating to product, process, asset and supply chain activities. Although services such as Global Positioning Services (GPS) can be relied on outdoors, indoor positioning remains a challenge due to the characteristics of indoor environments (including metal structures, changing environments and personnel). An accurate Indoor Positioning System (IPS) is required to provide end-to-end asset tracking within a manufacturing supply chain to improve security and process monitoring. Inertial measurement units (IMU) are commonly used for indoor positioning and routing services due to their low cost and ease of implementation. However, IMU accuracy (including heading and orientation detection) is reduced by the effects of indoor environmental conditions (such as motors and metallic structures) and require low-cost reliable solutions to improve accuracy. The current state of the art utilises algorithms to adjust the IMU data and improve accuracy, resulting in error propagation. The research outlined in this paper explores the use of passive RFID tags as a low cost, non-invasive method to reorient an IMU step and heading algorithm. This is achieved by confirming reference location to correct drift in scenarios where magnetometer and zero velocity updates are not available. The RFID tag correction method is demonstrated to map the route taken by an asset carried by personnel in an indoor environment. The test scenario task is representative of warehousing and delivery tasks where asset and personnel tracking are required.

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden.

In response to the rapid spread of SARS-CoV-2, hospitals in Canada enacted temporary visitor restrictions to limit the spread of COVID-19 and preserve personal protective equipment supplies. This study describes the extent, variation, and fluctuation of Canadian adult intensive care unit (ICU) visitation policies before and during the first wave of the COVID-19 pandemic. We conducted an environmental scan of Canadian hospital visitation policies throughout the first wave of the pandemic. We conducted a two-phased study analyzing both quantitative and qualitative data. We collected 257 documents with reference to visitation policies (preCOVID, 101 [39%]; midCOVID, 71 [28%]; and lateCOVID, 85 [33%]). Of these 257 documents, 38 (15%) were ICU-specific and 70 (27%) referenced the ICU. Most policies during the midCOVID/lateCOVID pandemic period allowed no visitors with specific exceptions (e.g., end-of-life). Framework analysis revealed five overarching themes: 1) reasons for restricted visitation policies; 2) visitation policies and expectations; 3) exceptions to visitation policy; 4) patient and family-centred care; and 5) communication and transparency. During the first wave of the COVID-19 pandemic, most Canadian hospitals had public-facing visitor restriction policies with specific exception categories, most commonly for patients at end-of-life, patients requiring assistance, or COVID-19 positive patients (varying from not allowed to case-by-case). Further studies are needed to understand the consistency with which visitation policies were operationalized and how they may have impacted patient- and family-centred care.

The development hardware and software aspects of a novel system for monitoring performance in the strength and conditioning domain are summarized in this paper. A development framework is presented to enable the capture of development processes and support detailed comparison of performance monitoring systems. The framework couples the established Computer Integrated Manufacture Open Systems Architecture (CIMOSA) with Unified Modelling Language (UML) to document both the software development and implementation. Corrective algorithms are proposed that have increased the accuracy of the IMU outputs in monitoring the performance of a countermovement jump. Lastly, a wireless Inertial Measurement Unit (IMU) has been validated for use within the strength and conditioning domain by comparison with an optical motion capture reference measure.

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.

α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF). The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synuclein-targeted therapeutics.

Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure–function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD.

Strength asymmetry can be detrimental to athlete performance and may lead to injury. The countermovement jump (CMJ) can be used to measure strength asymmetry via shear force production. The reliability of parameters and effects of asymmetry and shear force production on vertical CMJ performance were evaluated in a study with 15 university-level sprint and high jump athletes ( m = 11, f = 4). The athletes performed three CMJs on two occasions, separated by 1 week. Tri-axial ground reaction force (GRF) was recorded using two force platforms embedded within a bespoke weight training area. Key performance metrics were calculated in real-time describing total CMJ performance, asymmetry and shear force production. Changes in the means and coefficients of variation (CV) were used to express reliability. Twenty-six parameters from the Total analysis and 21 Asymmetry analysis parameters showed a CV lower than 10%. Temporal and kinetic variables describing Asymmetry analysis highlight a lower CV compared with equivalent parameters derived from Total analysis. Shear parameters show high levels of CV compared with Total analysis and Asymmetry analysis. The measures of asymmetry calculated using methods described in this work were shown to be reliable for monitoring CMJ performance. No significant negative relationships were found between measures of asymmetry or shear force and traditional performance metrics in the CMJ (e.g. jump height, specific peak power and peak force). Further work is required to identify the potential of reducing asymmetry on CMJ performance.

Purpose Customer experience is more critical than ever to firms’ successes and future growth opportunities. Typically measured through aggregate satisfaction scores, businesses have been criticized for oversimplifying what experience means. The purpose of this study is to provide a new perspective on experience management and offers a novel way forward for customer-centric strategizing. Design/methodology/approach Mapping the current digital technologies being used across businesses in all sectors to engage and connect with customers more effectively, this paper outlines some of the fundamental challenges of experience management and future opportunities to enhance business practice. Findings Businesses are capturing what they know about customers, rather than what a customer thinks and feels about the firm. Many experience management initiatives create customer pains (not gains), while for businesses, decision-making can be jeopardized by fake customer data. A framework based upon the five experience dimensions is presented for optimal customer-driven decision-making. Practical implications Going beyond aggregate satisfaction scores that serve as an output rather than an input into businesses strategizing, the paper presents an actionable framework for targeted investments and enhanced experience management practices. Originality/value Businesses are seeking to grow intelligent customer experience analysis capabilities to disrupt traditional business models toward greater customer-centricity and to track the digital spread of positive and negative experiences. Examining how this is being done and where the weaknesses lie by bridging management practice and the scientific literature, this paper provides new knowledge to advance customer-centric strategies for growth and profitability.

The aim of the research outlined in this paper is to demonstrate the implementation of a Cyber-Physical System (CPS) within the Automotive Industry for the monitoring and control of Returnable Transit Items (RTIs) toward improved quality assurance and process compliance. The socio-technical issues encountered during the real-world implementation are discussed to inform future design Automotive RTI’s are utilised in the transportation of both components and subsequently assembled products at the beginning and end of life stages. The implemented system utilises passive Ultra-High Frequency (UHF) Radio Frequency IDentification (RFID) tags for the identification of metal RTIs via associated plastic separators, whilst a distributed network of RFID portals was integrated within the RTI working environment to capture and characterise their movements. The requirements, design process and resulting architecture are presented alongside the results and lessons learnt from an implementation within the automotive industry. Through the integration of business processes, analytics and tacit domain knowledge, a real-time model of the state of RTIs was developed to support decision making by a range of stakeholders. This research contributes to the knowledge of CPSs requirements identification, design, deployment and the challenges faced within real world asset monitoring and traceability within the automotive industry. Areas for future research to support the next generation of RTI traceability, monitoring and control systems are presented.

Background: Coding variation in the Leucine rich repeat kinase 2 gene linked to Parkinson’s disease (PD) promotes enhanced activity of the encoded LRRK2 kinase, particularly with respect to autophosphorylation at S1292 and/or phosphorylation of the heterologous substrate RAB10. Objective: To determine the inter-laboratory reliability of measurements of cellular LRRK2 kinase activity in the context of wildtype or mutant LRRK2 expression using published protocols. Methods: Benchmark western blot assessments of phospho-LRRK2 and phospho-RAB10 were performed in parallel with in situ immunological approaches in HEK293T, mouse embryonic fibroblasts, and lymphoblastoid cell lines. Rat brain tissue, with or without adenovirus-mediated LRRK2 expression, and human brain tissues from subjects with or without PD, were also evaluated for LRRK2 kinase activity markers. Results: Western blots were able to detect extracted LRRK2 activity in cells and tissue with pS1292-LRRK2 or pT73-RAB10 antibodies. However, while LRRK2 kinase signal could be detected at the cellular level with over-expressed mutant LRRK2 in cell lines, we were unable to demonstrate specific detection of endogenous cellular LRRK2 activity in cell culture models or tissues that we evaluated. Conclusion: Further development of reliable methods that can be deployed in multiple laboratories to measure endogenous LRRK2 activities are likely required, especially at cellular resolution.

Pathogenic leucine-rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk.Through measurements of the LRRK2 kinase substrate pT73-Rab10 in urinary extracellular vesicles, this study seeks to understand how LRRK2 kinase activity might change with iPD progression.Using an immunoblotting approach validated in LRRK2 transgenic mice, the ratio of pT73-Rab10 to total Rab10 protein was measured in extracellular vesicles from a cross-section of G2019S LRRK2 mutation carriers (N = 45 participants) as well as 485 urine samples from a novel longitudinal cohort of iPD and controls (N = 85 participants). Generalized estimating equations were used to conduct analyses with commonly used clinical scales.Although the G2019S LRRK2 mutation did not increase pT73-Rab10 levels, the ratio of pT73-Rab10 to total Rab10 nominally increased over baseline in iPD urine vesicle samples with time, but did not increase in age-matched controls (1.34-fold vs. 1.05-fold, 95% confidence interval [CI], 0.004-0.56; P = 0.046; Welch's t test). Effect estimates adjusting for sex, age, disease duration, diagnosis, and baseline clinical scores identified increasing total Movement Disorder Society-Sponsored Revision of the Unified (MDS-UPDRS) scores (β = 0.77; CI, 0.52-1.01; P = 0.0001) with each fold increase of pT73-Rab10 to total Rab10. Lower Montreal Cognitive Assessment (MoCA) score in iPD is also associated with increased pT73-Rab10.These results provide initial insights into peripheral LRRK2-dependent Rab phosphorylation, measured in biobanked urine, where higher levels of pT73-Rab10 are associated with worse disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

No treatments exist to slow or halt Parkinson’s disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced α-syn inclusions. Mice exposed to α-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD-associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition., Antisense oligonucleotides targeting LRRK2 mRNA for degradation in the brain can attenuate α-synuclein inclusion formation and neurodegeneration caused by exposure to pre-formed α-synuclein fibrils, while bypassing the adverse systemic effects in the kidney and lung that are associated with the loss of LRRK2 expression in the periphery.

Countermovement jumps (CMJs) are widely used in athlete training, performance monitoring and research as an indicator of power output. Despite extensive scientific research on CMJs, data for elite track and field athletes is limited, particularly for non-sprint events and female athletes. The purpose of this study was threefold: (i) to compare CMJ performance between elite sprinters and high jumpers; (ii) to compare CMJ performance between elite male and female athletes in these two events; and (iii) to determine which CMJ take-off parameters correlated most strongly with jump height. Twenty-seven elite athletes (sprinters: nine male and seven female; high jumpers: five male and six female) completed three maximal CMJs. Jump height and take-off phase parameters were obtained from the force–time data and compared between groups; additionally, time series comparisons were performed on the force, power and displacement data. There was no difference in jump height or any of the take-off parameters between the sprinters and high jumpers; however, the time series analysis indicated that the sprinters maintained a lower centre of mass position during the latter concentric phase. The male athletes jumped higher than the female athletes (by 10.0 cm or 24.2%; p < 0.001) with significantly greater body weight normalised peak power (17.9%, p = 0.002) and significantly shorter eccentric time (17.4%, p = 0.035). Jump height was most strongly correlated with peak power. In addition, jump height was also strongly correlated with positive impulse and both minimum and mean concentric centre of mass position. These results support the importance of accounting for event and gender when investigating CMJ performance.

Grassland birds have experienced protracted population declines, primarily due to loss and degradation of native grasslands. Restoration of native grasses may benefit grassland birds, but such restoration within the eastern United States has been limited. Production uses of native grasses (e.g., hay, pasture, biofuel feedstock) provide market-based incentives that could lead to more extensive use of these grasses than existing conservation-focused practices, potentially influencing breeding birds. Therefore, we compared breeding bird (n = 9 target species) relative abundance among 4 types of native warm-season grass (NWSG) agricultural production fields: forage (hay and pasture; n = 22 and 7, respectively), seed (n = 21), biofuel (n = 15), and a control (idle fields in conservation programs or practices; n = 37) in Kentucky and Tennessee, 2009–2010. We detected 2 145 birds, with field sparrow (Spizella pusilla, 43%) and red-winged blackbird (Agelaius phoeniceus, 27%) encountered most often. Relative abundance did not differ between production types and controls except for field sparrow (lower on seed production fields) and northern bobwhite (Colinus virginianus, lower on hay production fields). Species richness equaled or exceeded that of control fields for all production categories. We documented negative relationships between relative abundance and landscape-scale forest cover for four species (field sparrow, grasshopper sparrow [Ammodramus savannarum], eastern meadowlark [Sturnella magna], and red-winged blackbird) and positive relationships with amount of pasture and hay cover for four species (northern bobwhite, grasshopper sparrow, eastern meadowlark, and red-winged blackbird), reinforcing the importance of nonforested environments for these species. We conclude that production stands could be a viable approach for increasing NWSG available for breeding birds and, when established in the appropriate landscape context, can provide benefits similar to those provided by conservation programs.

In product-diverse, end-of-life (EoL) production lines the relevant markets, competitors and customer bases continuously change as new products are processed. The resale market itself changes with the influx of new products, as well as hardware and software discontinuations. Competitive business decision making is often performed by a human operator and may not be timely or fully informed. These are decisions such as whether to perform a high cost repair or recycle a product or whether to use a batch of parts in repair or sell them on. These decisions can be used to optimise product life-cycle management (PLM) and profit margins. A real-time decision making capability can reduce the risk of performing non-profitable processing. The novel contribution of this work is an interoperable semantic decision support toolset that enables a capability for timely EoL decisions based on complete knowledge on profitability, predicted pricing and cost-of-production. Many decision support systems have been proposed for the EoL domain, but a lack of interoperability and use of unstructured knowledge bases has led to decisions based on knowledge that is not up to date. Using formalised, semantic technologies offers sustainable decision making in this volatile and increasingly competitive domain.

Content expertise in basic science and clinical disciplines does not assure proficiency in teaching. Faculty development to improve teaching and learning is essential for the advancement of veterinary education. The Consortium of West Region Colleges of Veterinary Medicine established the Regional Teaching Academy (RTA) with the focus of “Making Teaching Matter.” The objective of the RTA’s first effort, the Faculty Development Initiative (FDI), was to develop a multi-institutional faculty development program for veterinary educators to learn about and integrate effective teaching methods. In 2016, the Veterinary Educator Teaching and Scholarship (VETS) program was piloted at Oregon State University’s College of Veterinary Medicine. This article uses a case study approach to program evaluation of the VETS program. We describe the VETS program, participants’ perceptions, participants’ teaching method integration, and lessons learned. A modified Kirkpatrick Model (MKM) was used to categorize program outcomes and impact. Quantitative data are presented as descriptive statistics, and qualitative data are presented as the themes that emerged from participant survey comments and post-program focus groups. Results indicated outcomes and impacts that included participants’ perceptions of the program, changes in participant attitude toward teaching and learning, an increase in the knowledge level of participants, self-reported changes in participant behaviors, and changes in practices and structure at the college level. Lessons learned indicate that the following are essential for program success: (1) providing institutional and financial support; (2) creating a community of practice (COP) of faculty development facilitators, and (3) developing a program that addresses the needs of faculty and member institutions.

Significance Parkinson’s disease (PD)-linked familial mutations in LRRK2 impact its enzymatic activity by commonly increasing kinase activity, either directly within the kinase domain or indirectly via the GTPase domain by impairing GTP hydrolysis. Familial LRRK2 mutations also commonly promote neuronal toxicity in cultured cells, and for the common G2019S mutation, these effects are kinase dependent. The mechanisms underlying familial LRRK2 mutations in animal models are uncertain, due to the general lack of robust phenotypes. Our study demonstrates important roles for kinase and GTPase activities in mediating the neurodegenerative effects of G2019S LRRK2 in rodents, highlighting both as promising therapeutic targets for PD., Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson’s disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system. In this Review, Tan et al. provide an overview of the clinical and preclinical evidence that immune system dysfunction is involved in Parkinson disease, and discuss how increasing knowledge of the underlying mechanisms is driving development of immune-based therapeutic approaches.

Competencies can guide outcomes assessment in veterinary medical education by providing a core set of specific abilities expected of new veterinary graduates. A competency-guided evaluation of Colorado State University’s (CSU) equine veterinary curriculum was undertaken via an alumni survey. Published competencies for equine veterinary graduates were used to develop the survey, which was distributed to large animal alumni from CSU’s Doctor of Veterinary Medicine program. The results of the survey indicated areas for improvement, specifically in equine business, surgery, dentistry, and radiology. The desire for more hands-on experiences in their training was repeatedly mentioned by alumni, with the largest discrepancies between didactic knowledge and hands-on skills in the areas of business and equine surgery. Alumni surveys allow graduates to voice their perceived levels of preparation by the veterinary program and should be used to inform curriculum revisions. It is proposed that the definition and utilization of competencies in each phase of a curricular review process (outcomes assessment, curriculum mapping, and curricular modifications), in addition to faculty experience and internal review, is warranted.

The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson’s disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generation of poly(ADP-ribose) polymer represent key steps in the formation of toxic α-synuclein aggregates and neurodegeneration. Several studies suggest that the inhibition of poly(ADP-ribose) polymerase-1 activity via the poly(ADP-ribose) polymerase-1/2 small molecule inhibitor ABT-888 (Veliparib), a drug in clinical trials for different cancers, may prevent or ameliorate α-synuclein fibril-induced aggregation, inclusion formation and dopaminergic neurodegeneration. Herein, we evaluated the effects of poly(ADP-ribose) polymer on α-synuclein fibrillization in vitro, the effects of ABT-888 on the formation of fibril-seeded α-synuclein inclusions in primary mouse cortical neurons and the effects of an in-diet ABT-888 dosage regimen with the intracranial injection of α-synuclein fibrils into the mouse dorsal striatum. We found that poly(ADP-ribose) polymer minimally but significantly increased the rate of spontaneously formed α-synuclein fibrils in vitro. Machine-learning algorithms that quantitatively assessed α-synuclein inclusion counts in neurons, both in primary cultures and in the brains of fibril-injected mice, did not reveal differences between ABT-888- and vehicle-treated groups. The in-diet administered ABT-888 molecule demonstrated outstanding brain penetration in mice; however, dopaminergic cell loss in the substantia nigra caused by α-synuclein fibril injections in the striatum was similar between ABT-888- and vehicle-treated groups. α-Synuclein fibril-induced loss of dopaminergic fibres in the dorsal striatum was also similar between ABT-888- and vehicle-treated groups. We conclude that additional pre-clinical evaluation of ABT-888 may be warranted to justify further exploration of ABT-888 for disease modification in Lewy body diseases.

Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.