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Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS.(More)
BACKGROUND Carotid endarterectomy is more effective than medical management in the prevention of stroke in patients with severe symptomatic or asymptomatic atherosclerotic carotid-artery stenosis. Stenting with the use of an emboli-protection device is a less invasive revascularization strategy than endarterectomy in carotid-artery disease. METHODS We(More)
Synapses continually replenish their synaptic vesicle (SV) pools while suppressing spontaneous fusion events, thus maintaining a high dynamic range in response to physiological stimuli. The presynaptic protein complexin can both promote and inhibit fusion through interactions between its α-helical domain and the SNARE complex. In addition, complexin's(More)
The presynaptic protein complexin (CPX) is a critical regulator of synaptic vesicle fusion, but the mechanisms underlying its regulatory effects are not well understood. Its highly conserved central helix (CH) directly binds the ternary SNARE complex and is required for all known CPX functions. The adjacent accessory helix (AH) is not conserved despite also(More)
The protein-remodeling machine Hsp104 dissolves amorphous aggregates as well as ordered amyloid assemblies such as yeast prions. Force generation originates from a tandem AAA+ (ATPases associated with various cellular activities) cassette, but the mechanism and allostery of this action remain to be established. Our cryoelectron microscopy maps of Hsp104(More)
BACKGROUND Sirolimus-eluting stents reduce rates of restenosis and reintervention, as compared with uncoated stents. Data are limited regarding the safety and efficacy of such stents in primary percutaneous coronary intervention (PCI) for acute myocardial infarction with ST-segment elevation. METHODS We performed a single-blind, multicenter, prospectively(More)
The homologous hexameric AAA(+) proteins, Hsp104 from yeast and ClpB from bacteria, collaborate with Hsp70 to dissolve disordered protein aggregates but employ distinct mechanisms of intersubunit collaboration. How Hsp104 and ClpB coordinate polypeptide handover with Hsp70 is not understood. Here, we define conserved distal loop residues between middle(More)
Alpha-synuclein is a small neuronal protein that is closely associated with the etiology of Parkinson's disease. Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites(More)
To determine the effects of cycle and run training on rating of perceived exertion at the lactate threshold (LT), college men completed a 40-session training program in 10 weeks (n = 6 run training, n = 5 cycle training, n = 5 controls). Pre- and post-training variables were measured during graded exercise tests on both the bicycle ergometer and treadmill.(More)
Complexin functions at presynaptic nerve terminals to inhibit spontaneous SNARE-mediated synaptic vesicle (SV) exocytosis, while enhancing stimulated neurotransmitter release. The C-terminal domain (CTD) of complexin is essential for its inhibitory function and has been implicated in localizing complexin to SVs via direct membrane interactions. Here we show(More)