Background: Mutant Niemann-Pick C1 (NPC1) is degraded by the proteasome. Results: NPC1 is one of the clients of HSP/CHIP (heat shock protein/carboxyl terminus of Hsp70-interacting protein) complexes and accepts ubiquitin at multiple lysine residues. Conclusion: HSPs are critical in the quality control of NPC1. Significance: Unraveling the mechanisms of NPC1 degradation is crucial for development of a chaperone therapy.

IMPORTANCELUJV is a newly identified arenavirus associated with a VHF outbreak in southern Africa. Although cell entry for many arenaviruses has been studied, cell entry for LUJV has not been characterized. In this study, we found that LUJpv utilizes neither ␣DG nor hTfR1 as a receptor and found unique characteristics of LUJV glycoprotein in membrane fusion and cell entry. Proper exclusion of cholesterol or some kinds of lipids may play important roles in LUJpv cell entry.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N′H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.

Clinical studies have shown that β-blockers could reduce incidence of cardiovascular events, as well as the mortality of patients with chronic heart failure. 7 Carvedilol is a non-selective AR antagonist that blocks β1-and β2-ARs, as well as α1-AR. 8 Carvedilol suppresses SNS activities, and decreases heart rate (HR) and contractility. This action is beneficial to patients with heart failure whose SNS is activated. 9 Carvedilol also causes vasodilation and decreases peripheral vascular resistance without reflex tachycardia by concomitant blockade of α1-and β1-ARs. 10

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