Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

© 2020 The Author(s). The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development

Sheep research and development, 1965

Sheep research and development - 1965 / D. S. Bell -- Improvement of lamb meat production through breeding / D. S. Bell, C. F. Parker and L. E. Kunkle -- Breeding performance of Targhee ewes maintained under bluegrass pasture vs. ladino clover pasture vs. barn confinement management / D. S. Bell and C. F. Parker -- Ram effect on ewe fertility / C. F. Parker and D. S. Bell -- Creep feeding native lambs / J. K. Judy, J. H. Cline, W. J. Tyznik, C. F. Parker and D. S. Bell -- Studies of the protein and energy requirements of growing-finishing lambs / R. R. Johnson, J. H. Cline and D. S. Bell -- Visual and ultrasonic evaluation of creep fed slaughter lambs / C. F. Parker, D. L. Davis and J. K. Judy -- Forages for summer feeding of farm flocks / R. W. Van Keuren -- Characteristics of consumer-preferred lamb carcass / L. E. Kunkl

Beef cows and calves, 1979: a summary of research

Response of fall-born calves to monensin on orchardgrass / alfalfa or tall fescue / alfalfa pastures / F. M. Byers, C. F. Parker, and R. W. Van Keuren -- Effects of forage system and breed type on the performance of fall calving cows / C. F. Parker and R. W. Van Keuren -- Forage management for beef production / R. W. Van Keuren, C. F. Parker, and E. W. Klosterman -- Breeding and management systems to optimize beef breeding herd productivity / E. W. Klosterman, R. W. Van Keuren, C. F. Parker, and F. M. Byers -- Voluntary feed intake of mature cows as related to breed type, condition, and forage quality / E. W. Klosterman, F. M. Byers, and C. F. Parker -- Weight and condition changes of pregnant beef cows wintered on corn stover stacks / G. R. Wilson, J. G. Gordon, J. H. Cline, K. M. Irvin, and E. W. Klosterman -- Estrus synchronization of beef cows and heifers with prostaglandin F2a under field conditions / G. R. Wilson, T. L. Benecke, K. M. Irvin, T. M. Ludwick, C. E. Marshall, and R. A. Wallac

Fall 1967

Massachusetts Turf and Lawn Grass CouncilBetter Turf Through Research and Educatio

Multi-modality machine learning predicting Parkinson's disease

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available

Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways

Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24-months old Long Evans aged rats in two groups - memory-impaired (AI) and memory-unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post-synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCγ, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here