Synergic control in asymptomatic welders during multi-finger force exertion and load releasing while standing.

Motor synergies, i.e., neural mechanisms that organize multiple motor elements to ensure stability of actions, are affected by several neurological condition. Asymptomatic welders showed impaired synergy controlling the stability of multi-finger action compared to non-welders and this impairment was associated with microstructural damage in the globus pallidus. We further explored the effect of welding-related metal exposure on multi-finger synergy and extended our investigation to posture-stabilizing synergy during a standing task. Occupational, MRI, and performance-stabilizing synergies during multi-finger accurate force production and load releasing while standing were obtained from 29 welders and 19 age- and sex-matched controls. R2* and R1 relaxation rate values were used to estimate brain iron and manganese content, respectively, and diffusion tensor imaging was used to reflect brain microstructural integrity. Associations of brain MRI (caudate, putamen, globus pallidus, and red nucleus), and motor synergy were explored by group status. The results revealed that welders had higher R2* values in the caudate (p = 0.03), putamen (p = 0.01), and red nucleus (p = 0.08, trend) than controls. No group effect was revealed on multi-finger synergy index during steady-state phase of action (ΔVZss). Compared to controls, welders exhibited lower ΔVZss (-0.106 ± 0.084 vs. 0.160 ± 0.092, p = 0.04) and variance that did not affect the performance variable (VUCM, 0.022 ± 0.003 vs. 0.038 ± 0.007, p = 0.03) in the load releasing, postural task. The postural synergy index, ΔVZss, was associated negatively with higher R2* in the red nucleus in welders (r = -0.44, p = 0.03), but not in controls. These results suggest that the synergy index in the load releasing during a standing task may reflect welding-related neurotoxicity in workers with chronic metals exposure. This finding may have important clinical and occupational health implications.

Phosphatidic acid-PKA signaling regulates p38 and ERK1/2 functions in ligand-independent EGFR endocytosis.

Ligand-independent epidermal growth factor receptor (EGFR) endocytosis is inducible by a variety of stress conditions converging upon p38 kinase. A less known pathway involves phosphatidic acid (PA) signaling toward the activation of type 4 phosphodiesterases (PDE4) that decrease cAMP levels and protein kinase A (PKA) activity. This PA/PDE4/PKA pathway is triggered with propranolol used to inhibit PA hydrolysis and induces clathrin-dependent and clathrin-independent endocytosis, followed by reversible accumulation of EGFR in recycling endosomes. Here we give further evidence of this signaling pathway using biosensors of PA, cAMP, and PKA in live cells and then show that it activates p38 and ERK1/2 downstream the PKA inhibition. Clathrin-silencing and IN/SUR experiments involved the activity of p38 in the clathrin-dependent route, while ERK1/2 mediates clathrin-independent EGFR endocytosis. The PA/PDE4/PKA pathway selectively increases the EGFR endocytic rate without affecting LDLR and TfR constitute endocytosis. This selectiveness is probably because of EGFR phosphorylation, as detected in Th1046/1047 and Ser669 residues. The EGFR accumulates at perinuclear recycling endosomes colocalizing with TfR, fluorescent transferrin, and Rab11, while a small proportion distributes to Alix-endosomes. A non-selective recycling arrest includes LDLR and TfR in a reversible manner. The PA/PDE4/PKA pathway involving both p38 and ERK1/2 expands the possibilities of EGFR transmodulation and interference in cancer.

Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson disease.

OBJECTIVE: Newer magnetic resonance imaging (MRI) techniques have shown promise in capturing early Parkinson disease (PD)-related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results. METHODS: A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel-based and region-of-interest approaches in normalized space. The sensitivity and specificity of the SNc T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration ≤2 years (PDE). A second independent cohort of 73 PD patients and 49 controls was used for validation. RESULTS: Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size = 164mm3 , p < 0.0001) and left (cluster size = 213mm3 , p < 0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region-of-interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p < 0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (area under the curve [AUC] = 0.926), even for PDE patients (AUC = 0.901, sensitivity = 0.857, specificity = 0.857). These results were validated in the second cohort. INTERPRETATION: The T1w/T2w ratio can detect PD-related changes in the SNc and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly for early stage patients, with high translational value for clinical practice and research. ANN NEUROL 2019;85:96-104.