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Keenan, R. J.

Publications and source records attributed to Keenan, R. J..

2 recordsLinked to original sources

Microstructural integrity of the major nuclei of the thalamus in Parkinson's disease

BackgroundPrevious research has shown an association between thalamus and cognition in Parkinsons disease (PD). ObjectivesTo investigate the microstructural integrity of the nuclei of the thalamus and relationship with cognition. MethodsLevel II Movement Disorder Society Task Force Criteria characterised patients with Parkinsons disease as cognitively normal (PDN, n=51); with mild cognitive impairment (PD-MCI, n=16) or with dementia (PDD, n=15). Twenty-three healthy control subjects were included for comparison. A k-means clustering approach segmented the thalamus into regions representing nine major nuclei. Volume, fractional anisotropy and mean diffusivity of nuclei were compared between cognitive groups and the relationship with cognitive domain z-scores investigated using hierarchical Bayesian regression models. ResultsThere was an overall progressive increase in mean diffusivity as cognition deteriorated (PDN: 1.4 {micro}m2/s (95% uncertainty interval [0.2, 2.7]), PDMCI: 2.4 {micro}m2/s [0.8,4.0], PDD: 4.5 {micro}m2/s [2.8, 6.3]). The largest increase was in the lateral dorsal nucleus (PDN: 0.3 {micro}m2/s [-6.7, 7.2], PDMCI: 5.4 {micro}m2/s [-4.7, 16.1], PDD: 14.8 {micro}m2/s [5.0, 25.0]). Fractional anisotropy showed minimal change between cognitive groups (PDN: 0.001 [-0.005, 0,007], PDMCI: -0.005 [-0.013, 0.003], PDD: -0.005 [-0.014, 0.003]). Increase in mean diffusivity of the thalamus is associated with a global decline in cognition, the magnitude of the effect was greatest in lateral dorsal nucleus. Fractional anisotropy only showed evidence of a relationship with cognitive domain scores in the lateral dorsal nucleus. ConclusionsThe relationship between lateral dorsal nucleus integrity and cognitive changes is likely due to its primary connectivity with frontal and temporal regions.

neuroscience

The architecture of EMC reveals a path for membrane protein insertion

Approximately 25% of eukaryotic genes code for integral membrane proteins that are assembled at the endoplasmic reticulum. An abundant and widely conserved multi-protein complex termed EMC has been implicated in membrane protein biogenesis, but its mechanism of action is poorly understood. Here, we define the composition and architecture of human EMC using biochemical assays, crystallography of individual subunits, site-specific photocrosslinking, and cryo-EM reconstruction. Our results show that EMCs cytosolic domain contains a large, moderately hydrophobic vestibule that binds a substrates transmembrane domain (TMD). The cytosolic vestibule leads into a lumenally-sealed, lipid-exposed intramembrane groove large enough to accommodate a single substrate TMD. A gap between the cytosolic vestibule and intramembrane groove provides a path for substrate egress from EMC. These findings suggest how EMC facilitates energy-independent membrane insertion of TMDs, explain why only short lumenal domains are translocated by EMC, and constrain models of EMCs proposed chaperone function.

biochemistry