Bibliometric Analysis of Chronic Traumatic Encephalopathy Research from 1999 to 2019.

Research on chronic traumatic encephalopathy (CTE) has increased over the past two decades. However, few studies have statistically analyzed these publications. In this work, we conducted a bibliometric analysis of studies on CTE to track research trends and highlight current research hotspots. Relevant original articles were obtained from the Web of Science Core Collection database between 1999 and 2019. CiteSpace and VOSviewer software were used to perform analysis and visualization of scientific productivity and emerging trends. Our results show that the publications related to CTE dramatically increased from four publications in 1999 to 160 publications in 2019. The United States dominated this field with 732 publications (75.934%), followed by Canada with 88 publications (9.129%). Most of related publications were published in the journals with a focus on molecular biology, immunology, neurology, sports and ophthalmology, as represented by the dual-map overlay. A total of 11 major clusters were explored based on the reference co-citation analysis. In addition, three predominant research topics were summarized by clustering high-frequency keywords: epidemiological, clinical and pathological studies. The research frontiers were the diagnosis of diseases using new neuroimaging techniques, and the investigation of the molecular mechanism of tau aggregation. This study provides researchers with valuable guidance in the selection of research topics.

Norepinephrine Inhibits Alzheimer's Amyloid-ß Peptide Aggregation and Destabilizes Amyloid-ß Protofibrils: A Molecular Dynamics Simulation Study.

The abnormal self-assembly of amyloid-ß (Aß) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of ß-sheet-rich oligomer formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit Aß aggregation and disaggregate the preformed fibrils. Moreover, exercise can markedly increase the level of NE. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations to investigate the conformational ensemble of Aß1-42 dimer with and without NE molecules. Our results show that without NE molecules, Aß1-42 dimer transiently adopts a ß-hairpin-containing structure, and the ß-strand regions of this ß-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the Aß fibril structure (residues 15QKLVFFA21 and 30AIIGLMVG37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide ß-sheet content and suppress the formation of the above-mentioned ß-hairpin, leading to a more disordered coil-rich Aß dimer. Five dominant binding sites are identified, and the central hydrophobic core 16KLVFFA21 site and C-terminal 31IIGLMV36 hydrophobic site are the two most favorable ones. Our data reveal that hydrophobic, aromatic stacking, hydrogen-bonding and cation-π interactions synergistically contribute to the binding of NE molecules to Aß peptides. MD simulations of Aß1-42 protofibril show that NE molecules destabilize Aß protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit Aß1-42 aggregation and disaggregate Aß protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.

Proline hydroxylation at different sites in hypoxia-inducible factor 1α modulates its interactions with the von Hippel-Lindau tumor suppressor protein.

Hypoxia-inducible factor 1 (HIF-1) plays an essential role in the regulation of hypoxia in humans. This regulation is mediated by the interaction of the von Hippel-Lindau tumor suppressor protein (pVHL) with the hydroxylated HIF-1α at proline564 (Pro564). Experimental studies reported that Pro567 could also be hydroxylated. However, the conformational dynamics of the complex of pVHL with hydroxylated HIF-1α at Pro564 is not well understood, and whether hydroxylated Pro567 plays the similar essential role as Pro564 in regulating HIF-1α-pVHL interaction remains elusive. Herein, we performed all-atom molecular dynamics (MD) simulations on the pVHL/HIF-1α complexes with single hydroxylation at Pro564 and Pro567, double hydroxylation at both Pro564 and Pro567, and without hydroxylation. Our multiple MD simulations and binding energy calculations show that hydroxylation at Pro567 is less favorable for the binding of HIF-1α to pVHL, whereas hydroxylation at Pro564 results in an increase of structural rigidity of the pVHL/HIF-1α complex and an enhancement of the interactions between HIF-1α and pVHL. The different roles revealed here for Pro564 and Pro567 in regulating HIF-1α-pVHL interactions, together with the previous finding that HIF-prolyl hydroxylase PHD-3 participates in a negative feedback loop controlling the HIF-1 level, suggest that hydroxylated HIF-1α at Pro567 may perturb or may not participate in this negative feedback loop. Intriguingly, our simulation data and community network analysis demonstrate that the binding of hydroxylated HIF-1α at Pro564 to the ß-domain of pVHL allosterically induces the conformational change of the α-domain via an optimal communication pathway from Pro564 of HIF-1α to S168 of the pVHL α-domain. This study reveals the different roles of Pro564 and Pro567 hydroxylation in HIF-1α in HIF-1α-pVHL interactions, which will be beneficial for developing effective strategies to treat hypoxia-related diseases and understanding the molecular basis of hypoxic training/exercise.