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Putative gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2), resulting in increased kinase activity and cellular toxicity, are a leading genetic cause of Parkinson's disease (PD). Hence, there is strong interest in developing LRRK2 kinase inhibitors as a disease-modifying therapy. Published reports that repeat dosing with two LRRK2 kinase inhibitors (GNE-7915 and GNE-0877) induce histopathological changes in the lung of non-human primates Fuji et al. 2015 raised concerns about potential safety liability of LRRK2 kinase inhibitors. In the present study, we sought to determine whether previously observed effects in the lung: (a) represent on-target pharmacology, but with the potential for margin of safety, (b) are reversible upon drug withdrawal, and (c) are associated with pulmonary function deficits. To this end, we evaluated the histopathological effects, toxicokinetics and target inhibition of three structurally diverse LRRK2 kinase inhibitors, GNE-7915 (30 mg/kg, BID, as a positive control), MLi-2 (15 and 50 mg/kg, QD) and PFE-360 (3 and 6 mg/kg, QD) following 2 weeks of dosing in non-human primates. Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated after 2-week dose-free periods. All three LRRK2 kinase inhibitors induced mild cytoplasmic vacuolation of type II pneumocytes, as reported previously, confirming an on-target effect of these compounds. Interestingly, despite lower doses of both PFE-360 and MLi-2 producing nearly complete inhibition of LRRK2 kinase activity in the brain as assessed by levels of pS935-LRRK2, histopathological changes in lung were absent in animals treated with low-dose PFE-360 and observed only sporadically in the low-dose MLi-2 group. The lung effect was fully reversible at 2 weeks post-dosing of GNE-7915. In a second study of identical dosing with MLi-2 and GNE-7915, no deficits were observed in a battery of translational pulmonary functional tests. In aggregate, these results do not preclude the development of LRRK2 kinase inhibitors for clinical investigation in Parkinson's disease.

Standard discriminant functions tend to perform well only with large training samples. This study developed a theoretical foundation for deriving the asymptotic expansions of the probabilities of misclassification for a broad class of discriminant functions. Three of these were evaluated: the linear discriminant function (LDF), the quadratic discriminant function (QDF), and the unbiased-density discriminant function (UDF). The UDF is based on the UMVU estimator of the multivariate normal density function and is asymptotically equivalent to the QDF. A class of polynomials with multiple matrix arguments as well as concepts of discrimination potential, efficiency, and deficiency were defined. Under the assumption of equal covariances in multivariate normal populations the deficiencies of the QDF and UDF relative to the LDF indicated that both functions are inferior to the LDF and that the UDF is always inferior to the QDF. An evaluation of efficiencies with smaller sample sizes showed that when the distance between populations is small, the relative efficiencies of the QDF and UDF are quite poor compared to the LDF with the UDF always slightly worse. Under the assumption of unequal covariances, the UDF continued to perform poorly while the QDF outperformed the LDF only for large sample sizes and large differences in covariances. An application to medical diagnosis using clinical laboratory test was studied. The main conclusions from the research were that the UDF is inferior to the QDF and that optimal density estimation does not improve the discriminant function under the conditions studied. An approach that deserves further research is the optimal estimation of the partition between population. The field of discriminant analysis needs a firmer theoretical basis instead of the current empirical approaches.

Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to lasonolide A (LasA), a macrolide derived from a marine sponge that kills certain types of cancer cells at low nanomolar concentrations. Our screens converged on a single gene, LDAH , encoding a member of the metabolite serine hydrolase family that is localized on the surface of lipid droplets. Mechanistic studies revealed that LasA accumulates in lipid droplets, where it is cleaved into a toxic metabolite by LDAH. We suggest that selective partitioning of hydrophobic drugs into the oil phase of lipid droplets can influence their activation and eventual toxicity to cells. Lasonolide A is hydrolyzed into a cytotoxic metabolite by a lipid droplet-associated orphan serine hydrolase, showing that lipid droplets can promote drug toxicity by both accumulating and metabolizing drugs in cells.

Cerebral palsy (CP) is the most common physical disability of childhood, affecting movement and posture, resulting from a neurological insult during pregnancy or the neonatal period. While the brain lesion is static, the musculoskeletal sequelae in CP are often progressive and lifelong, associated with pain and can impact the lives of children with CP, their families and the healthcare system. The Australasian Cerebral Palsy Musculoskeletal Health Network (AusCP MSK) study will conduct comprehensive, population-based surveillance of children with moderate to severe functional mobility limitations (Gross Motor Function Classification System (GMFCS) levels III-V) to explore the early biomarkers of, and interactions between, musculoskeletal complications related to CP, including hip displacement, scoliosis and skeletal fragility. The AusCP MSK study involves three cohorts of children. Cohort A (n=500) is a multicentre retrospective (3 years) and prospective (4 years) cohort study in children aged 4-9 years that will be implemented at five sites across Australia and New Zealand. Retrospective data will include clinical history, information on CP diagnosis and other investigations (previous X-rays and biochemistry). Primary prospective outcomes will involve measures of hip displacement (migration percentage, acetabular index, femoral head orientation, Hilgenreiner's epiphyseal angle), scoliosis (Anteroposterior/Posteroanterior and lateral spine X-ray), skeletal fragility (Dual Energy X-ray Absorptiometry, peripheral quantitative computed tomography), motor function (GMFCS, Manual Ability Classification System (MACS) and Communication Function Classification System (CFCS)) and range of movement (lower limb and spine). Cohort B (n=4000) is a retrospective analysis of data to evaluate fractures in children up to 18 years of age with CP (GMFCS I-V) from the New South Wales (NSW)/Australian Capital Territory CP Registers linked with corresponding records from NSW administrative health data (n=3000), and a New Zealand cohort of linked data from the New Zealand Cerebral Palsy Register to the Accident Compensation Corporation data for fracture claims (n=1000). Cohort C (n=30) will cross-sectionally examine bone quality through a transiliac bone biopsy in children undergoing scheduled hip surgery. Relationships between early biomarkers, early brain structure and musculoskeletal complications will be explored using multilevel mixed-effect models. Ethical approval for this study was granted by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee, The University of Queensland Human Research Ethics Committee and the New Zealand Health and Disability Ethics Committee.Research outcomes will be disseminated via scientific conferences and publications in peer-reviewed journals; to the National Bodies and Clinicians; and to people with CP and their families. Australian New Zealand Clinical Trials Registry number: ACTRN12622000788774p.

The presence of concomitant aortic insufficiency (AI) and mitral regurgitation (MR) is common and may further accelerate cardiac dysfunction. However, there exists no US regulatory–approved transcatheter device for the treatment of AI. The effectiveness of isolated transcatheter mitral therapy in this population is not well-understood; thus, we aimed to evaluate outcomes for patients with combined AI and MR compared with isolated MR who underwent mitral transcatheter edge-to-edge repair (m-TEER). Retrospective data were obtained from the Northwell m-TEER registry. A total of 587 patients who underwent m-TEER at 4 high-volume transcatheter aortic valve replacement/transcatheter edge-to-edge repair centers within the Northwell Health system were included. All patients had severe MR and were divided into 2 groups: group 1 with ≥3+ AI (AI+) and the group 2 with <3+ AI (AI−). Echocardiographic outcomes were evaluated at 1 month. Clinical outcomes were evaluated at 1 month and 1 year. The primary end point was death or rehospitalization at 1 year. A total of 587 patients were included in the study, with 92 in the AI+ group. Baseline characteristics were similar in both groups. Approximately 2/3 of patients in the AI+ group demonstrated an improvement in AI severity after isolated mitral therapy. There was no difference in the primary outcome at 1 month or 1 year. There was also no significant difference in New York Heart Association functional class at 1 month between the groups. In conclusion, patients who underwent m-TEER with combined MR and AI (AI+ group) fared well compared with those with isolated mitral valve dysfunction (AI− group), with no discernible differences in survival, New York Heart Association class, or rehospitalization rates at 1 month or 1 year. Hence, isolated m-TEER is a reasonable treatment approach in patients with a high surgical risk with combined AI and MR.

Neuropathic pain is a debilitating secondary condition for many individuals with spinal cord injury. Spinal cord injury neuropathic pain often is poorly responsive to existing pharmacological and nonpharmacological treatments. A growing body of evidence supports the potential for brain-computer interface systems to reduce spinal cord injury neuropathic pain via electroencephalographic neurofeedback. However, further studies are needed to provide more definitive evidence regarding the effectiveness of this intervention.BACKGROUNDNeuropathic pain is a debilitating secondary condition for many individuals with spinal cord injury. Spinal cord injury neuropathic pain often is poorly responsive to existing pharmacological and nonpharmacological treatments. A growing body of evidence supports the potential for brain-computer interface systems to reduce spinal cord injury neuropathic pain via electroencephalographic neurofeedback. However, further studies are needed to provide more definitive evidence regarding the effectiveness of this intervention.The primary objective of this study is to evaluate the effectiveness of a multiday course of a brain-computer interface neuromodulative intervention in a gaming environment to provide pain relief for individuals with neuropathic pain following spinal cord injury.OBJECTIVEThe primary objective of this study is to evaluate the effectiveness of a multiday course of a brain-computer interface neuromodulative intervention in a gaming environment to provide pain relief for individuals with neuropathic pain following spinal cord injury.We have developed a novel brain-computer interface-based neuromodulative intervention for spinal cord injury neuropathic pain. Our brain-computer interface neuromodulative treatment includes an interactive gaming interface, and a neuromodulation protocol targeted to suppress theta (4-8 Hz) and high beta (20-30 Hz) frequency powers, and enhance alpha (9-12 Hz) power. We will use a single-case experimental design with multiple baselines to examine the effectiveness of our self-developed brain-computer interface neuromodulative intervention for the treatment of spinal cord injury neuropathic pain. We will recruit 3 participants with spinal cord injury neuropathic pain. Each participant will be randomly allocated to a different baseline phase (ie, 7, 10, or 14 days), which will then be followed by 20 sessions of a 30-minute brain-computer interface neuromodulative intervention over a 4-week period. The visual analog scale assessing average pain intensity will serve as the primary outcome measure. We will also assess pain interference as a secondary outcome domain. Generalization measures will assess quality of life, sleep quality, and anxiety and depressive symptoms, as well as resting-state electroencephalography and thalamic γ-aminobutyric acid concentration.METHODSWe have developed a novel brain-computer interface-based neuromodulative intervention for spinal cord injury neuropathic pain. Our brain-computer interface neuromodulative treatment includes an interactive gaming interface, and a neuromodulation protocol targeted to suppress theta (4-8 Hz) and high beta (20-30 Hz) frequency powers, and enhance alpha (9-12 Hz) power. We will use a single-case experimental design with multiple baselines to examine the effectiveness of our self-developed brain-computer interface neuromodulative intervention for the treatment of spinal cord injury neuropathic pain. We will recruit 3 participants with spinal cord injury neuropathic pain. Each participant will be randomly allocated to a different baseline phase (ie, 7, 10, or 14 days), which will then be followed by 20 sessions of a 30-minute brain-computer interface neuromodulative intervention over a 4-week period. The visual analog scale assessing average pain intensity will serve as the primary outcome measure. We will also assess pain interference as a secondary outcome domain. Generalization measures will assess quality of life, sleep quality, and anxiety and depressive symptoms, as well as resting-state electroencephalography and thalamic γ-aminobutyric acid concentration.This study was approved by the Human Research Committees of the University of New South Wales in July 2019 and the University of Technology Sydney in January 2020. We plan to begin the trial in October 2020 and expect to publish the results by the end of 2021.RESULTSThis study was approved by the Human Research Committees of the University of New South Wales in July 2019 and the University of Technology Sydney in January 2020. We plan to begin the trial in October 2020 and expect to publish the results by the end of 2021.This clinical trial using single-case experimental design methodology has been designed to evaluate the effectiveness of a novel brain-computer interface neuromodulative treatment for people with neuropathic pain after spinal cord injury. Single-case experimental designs are considered a viable alternative approach to randomized clinical trials to identify evidence-based practices in the field of technology-based health interventions when recruitment of large samples is not feasible.CONCLUSIONSThis clinical trial using single-case experimental design methodology has been designed to evaluate the effectiveness of a novel brain-computer interface neuromodulative treatment for people with neuropathic pain after spinal cord injury. Single-case experimental designs are considered a viable alternative approach to randomized clinical trials to identify evidence-based practices in the field of technology-based health interventions when recruitment of large samples is not feasible.Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000556943; https://bit.ly/2RY1jRx.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000556943; https://bit.ly/2RY1jRx.PRR1-10.2196/20979.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)PRR1-10.2196/20979.

Cell-free supernatant from Shewanella oneidensis MR-1 reduced carbon tetrachloride to chloroform, a suspension of Fe(III) and solid Fe(III) to iron (II). The putative reducing agent was tentatively identified as menaquinone-1 (MQ-1)--a water-soluble menaquinone with a single isoprenoid residue in the side chain. Synthetic MQ-1 reduced carbon tetrachloride to chloroform and amorphous iron (III) hydroxide to iron (II). To test the generality of this result among menaquinones, the reductive activities of vitamin K₂ (MQ-7)--a lipid-associated menaquinone with 7 or 8 isoprenoid residues--was evaluated. This molecule also reduced carbon tetrachloride to chloroform and iron (III) to iron (II). The results indicate that molecules within the menaquinone family may contribute to both the extracellular and cell-associated reduction of carbon tetrachloride and iron (III).

RNA splicing shapes neuronal identity and disease risk, yet current maps lack the developmental resolution and depth to resolve this complexity. Here, we integrate deep long-read RNA sequencing and proteomics in iPSC-derived cortical neurons to generate a high-resolution proteogenomic atlas of human neuron development. We identify 182,371 mRNA isoforms (over half previously unknown) and provide direct peptide evidence for the translation of hundreds of novel protein-coding sequences. Population genetics demonstrates that variants affecting novel exons and splice sites are under negative selection, underscoring the potential significance of these isoforms. During neuronal maturation, we observe that ASD risk genes undergo dynamic isoform switching, including microexon inclusion and intron retention, that remodel key protein domains and regulatory regions. Furthermore, we uncover widespread, long-range coordination between splicing and polyadenylation. Finally, our atlas enables variant reinterpretation in ASD, highlighting the value of an isoform-centric view for interpreting pathogenic variation in neurodevelopment.

In 2001, there was concern by the Military Services and the US Congress about shortages of spare parts for aviation units and about the workarounds, such as part cannibalization, that are required to keep those units near readiness goals. This paper was written to provide a theoretical framework to the U.S. Navy for understanding why weapon system cannibalizations occur, what factors influence those cannibalization rates, and how to predict cannibalization rates given the interaction of these factors. Using probabilistic operations research techniques, the paper develops a model to predict the cannibalization rates necessary to achieve a specified readiness goal for a weapon system given expected customer wait times for the delivery of spare parts.

The nesting biology of the American Kestrel and the Long-eared Owl was studied during 1975 and 1976 along the Big Lost River on the INEL Site in southeastern Idaho. In 1975 the mean clutch-size of American Kestrels was 4.5 eggs/clutch (N = 13) and in 1976 it was 4.7 eggs/clutch (N = 23). Long-eared Owls laid a mean of 3.0 eggs/nest (N = 3) in 1975 and 5.3 eggs/nest (N = 15) in 1976. The productivity of American Kestrels was 3.7 young/nest in 1975 and 4.0 young/nest in 1976. The productivity of Long-eared Owls was 1.7 young/nest in 1975 and 4.1 young/nest in 1976. Avian prey composed the majority of the diet by biomass of American Kestrels in 1975 and 1976. Changes in the percent mammalian and reptilian prey occurred during these years. Mammalian prey made up 97.2% of the total diet by biomass of Long-eared Owls in 1976. Northern pocket gophers composed the highest percent in biomass. There was an increase in American Kestrel nests found on the INEL Site from 1975 to 1976 and an increase in Long-eared Owl nests in the same year. The reasons for the increase of both species may be the same--adverse weather conditions in 1975 and/or an increase in available prey. Other reasons may also have been responsible. There were more American Kestrel nest-sites in 1976 than in 1975 since the number of nesting boxes erected on the Big Lost River was increased and local Long-eared Owl populations have been known to fluctuate.