Molecular Insights into the Differential Effects of Acetylation on the Aggregation of Tau Microtubule-Binding Repeats.

Aggregation of tau protein into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The microtubule-binding (MTB) domain of tau, containing either three or four repeats with sequence similarities, plays an important role in determining tau's aggregation. Previous studies have reported that abnormal acetylation of lysine residues displays a distinct effect on the formation of pathological tau aggregates. However, the underlying molecular mechanism remains mostly elusive. In this study, we performed extensive replica exchange molecular dynamics (REMD) simulations of 144 µs in total to systematically investigate the dimerization of four tau MTB repeats and explore the impacts of Lys280 (K280) or Lys321 (K321) acetylation on the conformational ensembles of the R2 or R3 dimer. Our results show that R3 is the most prone to aggregation among the four repeats, followed by R2 and R4, while R1 displays the weakest aggregation propensity with a disordered structure. Acetylation of K280 could promote the aggregation of R2 peptides by increasing the formation of ß-sheet structures and strengthening the interchain interaction. However, K321 acetylation decreases the ß-sheet content of the R3 dimer, reduces the ability of R3 peptides to form long ß-strands, and promotes the stable helix structure formation. The salt bridge and Y310-Y310 π-π stacking interactions of the R3 dimer are greatly weakened by K321 acetylation, resulting in the inhibition of dimerization. This study uncovers the structural ensembles of tau MTB repeats and provides mechanistic insights into the influences of acetylation on tau aggregation, which may deepen the understanding of the pathogenesis of tauopathies.

The bibliometric and altmetric analysis of chronic traumatic encephalopathy research: how great is the impact?

Background: The study of chronic traumatic encephalopathy (CTE) has received great attention from academia and the general public. This study aims to analyze the research productivity on CTE and investigate the most discussed articles in academia and the general public by conducting bibliometric and altmetric analyses. Methods: Data of articles were obtained from the Web of Science Core Databases and Altmetric Explore. VOSviewer and CiteSpace software were used to analyze and visualize the articles. The correlation between Altmetric attention scores (AAS) and citation counts were assessed by Spearman correlation coefficient. Results: 788 publications of CTE were eventually gathered and analyzed, and 100 articles with highest citation counts (Top-cited) and 100 articles with highest AASs (Top-AAS) were then identified. The keywords density map showed both the general public and the scientists were particularly interested in the risk factors and pathology of CTE, and scientists were interested in the causes and characteristics of neurodegenerative diseases while the public became increasingly concerned about the detection and prevention of CTE. By examining the shared characteristics of the 44 articles (High-High articles) that overlapped between Top-cited and Top-AAS articles, we identified certain traits that may potentially contribute to their high citation rates and high AASs. Besides, significant positive correlations with varied strength between AAS and citation were observed in the 788 articles, Top-cited, Top-AAS and High-High datasets. Conclusion: This study is the first to link bibliometric and altmetric analyses for CTE publications, which may provide deeper understanding of the attention of the scientists and the general public pay to the study of CTE, and offer some guidance and inspiration for future CTE in the selection of research topics and directions.

Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.

The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides 275VQIINK280 and 306VQIVYK311 in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 µs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long ß-strand and large ß-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to ß-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.

Mechanistic Insights into the Binding of Different Positron Emission Tomography Tracers to Chronic Traumatic Encephalopathy Tau Protofibrils.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, and it is neuropathologically defined as the accumulation of abnormally hyperphosphorylated tau (p-tau). Early detection of p-tau in the brain is of great value in the prevention and treatment of CTE. Previous experimental studies reported that positron emission tomography (PET) technique using several tau tracers are available for imaging certain neurodegenerative diseases. However, few studies have focused on the development of CTE tau tracers. In this work, we performed conventional molecular docking and molecular dynamics simulations to address the binding properties and mechanisms of PET tracers (18F-PM-PBB3, 18F-CBD-2115, 18F-PI-2620, 18F-RO-948, 18F-MK-6240, and 18F-flortaucipir) to CTE tau protofibrils. The results show that the hydrophobic cavity and the top of the concave structure of CTE tau protofibrils are the preferred binding sites for the six tracers, and 18F-PM-PBB3 has the most competitive binding affinity to CTE tau protofibrils. Further investigation into the binding patterns of the six tracers to the CTE tau protofibrils showed that 18F-CBD-2115 and 18F-PM-PBB3 have a high number of H-bonds and hydrophobic contacts with tau protofibrils, resulting in strong hydrogen bonding and hydrophobic interactions; 18F-flortaucipir/18F-PI-2620 and 18F-PI-2620/18F-RO-948 form more intense π-π and cation-π interactions with tau protofibrils, respectively. Subsequently, we conducted a detailed analysis of the binding mechanism of 18F-PM-PBB3 to CTE tau protofibrils. The benzothiazole ring of 18F-PM-PBB3 exhibits stronger π-π stacking and cation-π interactions with tau protofibrils than the pyridine ring and forms a more concentrated T-shaped π-π stacking pattern. This study contributes to understanding the binding mechanism of PET tracers to CTE tau protofibrils and provides new insights into the design of potential novel tracers.

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6.

Abnormal aggregation of the microtubule-associated protein tau into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The hexapeptide 306VQIVYK311 (PHF6) of R3 plays an important role in the aggregation of tau. Recent experimental studies reported that phosphorylation of residue tyrosine 310 (Y310) could decrease the propensity of PHF6 to form fibrils and inhibit tau aggregation. However, the underlying inhibitory mechanism is not well understood. In this work, we systematically investigated the influences of phosphorylation on the conformational ensembles and oligomerization dynamics of PHF6 by performing extensive all-atom molecular dynamics (MD) simulations. Our replica exchange MD simulations demonstrate that Y310 phosphorylation could effectively suppress the formation of ß-structure and shift PHF6 oligomers toward coil-rich aggregates. The interaction analyses show that hydrogen bonding and hydrophobic interactions among PHF6 peptides, as well as Y310-Y310 π-π stacking and I308-Y310 CH-π interactions, are weakened by phosphorylation. Additional microsecond MD simulations show that Y310 phosphorylation could inhibit the oligomerization of PHF6 by preventing the formation of large ß-sheet oligomers and multi-layer ß-sheet aggregates. This study provides mechanistic insights into the phosphorylation-inhibited tau aggregation, which may be helpful for the in-depth understanding of the pathogenesis of tauopathies.

Mechanistic insight into the disruption of Tau R3-R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study.

The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational therapeutic strategies to combat tauopathy. Previous studies reported that curcumin (Cur, a molecule of a labile natural product) and epinephrine (EP, an important neurotransmitter) could effectively inhibit the formation of Tau fibrillar aggregates and disassociate preformed fibrils. However, the underlying molecular mechanisms remain elusive. In this study, we performed multiple molecular dynamics simulations for 17.5 µs in total to investigate the influence of Cur and EP on the C-shaped Tau protofibril associated with CTE. Our simulations show that the protofibrillar pentamer is the smallest stable Tau R3-R4 protofibril. Taking the pentamer as a protofibril model, we found that both Cur and EP molecules could affect the shape of the Tau pentamer by changing the ß2-ß3 and ß7-ß8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local ß-sheets and the formation of hydrogen bonds, and thus destabilize the global protofibril structure. The contact number analysis shows that Cur has a higher binding affinity with the Tau pentamer than EP, especially in the nucleating segment PHF6. Hydrophobic, π-π and cation-π interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and π-π interactions with Tau than EP, and EP displays a stronger cation-π interaction. Our findings provide molecular insights into the disruptive mechanisms of the Tau R3-R4 protofibrils by curcumin and epinephrine, which may be useful for the design of effective drug candidates for the treatment of CTE.

A Bibliometric Analysis of the Literature on Irisin from 2012-2021.

Irisin is a hormone-like molecule mainly released by skeletal muscles in response to exercise, which is proposed to induce the 'browning' of white adipose tissue. Since its identification, irisin was reported to be closely associated with many metabolic diseases, including type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease (CVD), and metabolic bone diseases. In recent years, irisin has attracted increasing research interest, and numerous studies have been published in this field. Thus, it is essential to identify the current research status of irisin and measure research hotspots and possible future trends. In this study, by utilizing two visualization software named CiteSpace and VOSviewer, we analyzed 1510 Web of Science publications on irisin published from 2012 to 2021. Our results show that the number of irisin-related articles published annually has increased significantly. China participates in the most studies, followed by the United States and Turkey. Firat University, Harvard University, and Shandong University are three major institutions with larger numbers of publications. The analysis of keywords co-occurrence indicates that insulin resistance, inflammation, and circulating irisin levels in serum are the research hotspots. Apoptosis, BDNF, and osteoporosis will likely become the focus of future research related to irisin. Overall, this study may provide helpful insights for researchers to understand the current research situation and identify the potential frontiers of irisin.

The effect of whole body vibration on sensorimotor deficits in people with chronic ankle instability: A systematic review and meta-analysis.

OBJECTIVE: To investigate the effects of whole body vibration on chronic ankle instability-associated sensorimotor deficits in balance, strength, joint position sense and muscle activity. DATA SOURCES: Electronic databases including Cochrane Library, PubMed, Embase, Web of Science, EBSCO, China National Knowledge Infrastructure and WanFang were searched from database inception up to 31 March 2022. METHODS: The risk of bias and methodological quality of included studies were assessed using the Cochrane tool and Physiotherapy Evidence Database (PEDro) scale respectively. Standardized mean difference (SMD) and mean differences (MD) with 95% confidence interval (CI) were calculated using the RevMan 5.3 software. Meta-regression was conducted with Stata 16. RESULTS: Eight studies, with 315 subjects were eventually included in this review with an average PEDro score of 6.1/10. Significant effects of whole body vibration on balance (SMD = 0.61, 95% CI: 0.12 to 1.09, P = 0.01), and on the posterolateral direction (MD = 5.52, 95% CI: 1.02 to 10.01, P = 0.02) and medial direction (MD = 3.90, 95% CI: 0.87 to 6.94, P = 0.01) of the star excursion balance test were found. Whole body vibration significantly improved the peak torque (SMD = 0.36, 95% CI: 0.04 to 0.69, P = 0.03), joint position sense (SMD = 0.60, 95% CI: 0.10 to 1.11, P = 0.02), and muscle activity in tibialis anterior (SMD = 0.46, 95% CI: 0.04 to 0.88, P = 0.03) and gastrocnemius (SMD = 0.68, 95% CI: 0.14 to 1.23, P = 0.01). CONCLUSIONS: The current evidence supports the use of whole body vibration to improve sensorimotor deficits involving balance, strength, joint position sense, and muscle activity in people with chronic ankle instability.

Unfixed Movement Route Model, Non-Overcrowding and Social Distancing Reduce the Spread of COVID-19 in Sporting Facilities.

Localized outbreaks of COVID-19 have been reported in sporting facilities. This study used the Agent-based Modeling (ABM) method to analyze the transmission rate of COVID-19 in different sporting models, sporting spaces per capita, and situations of gathering, which contributes to understanding how COVID-19 transmits in sports facilities. The simulation results show that the transmission rate of COVID-19 was higher under the Fixed Movement Route (FMR) than under the Unfixed Movement Route (UMR) in 10 different sporting spaces per capita (1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 m2) (p = 0.000). For both FMR and UMR, the larger the sporting space per capita, the lower the virus transmission rate. Additionally, when the sporting space per capita increases from 4 m2 to 5 m2, the virus transmission rate decreases most significantly (p = 0.000). In the FMR model with a per capita sporting space of 5 m2, minimizing gathering (no more than three people) could significantly slow down the transmission rate of the COVID-19 virus (p < 0.05). This study concluded that: (1) The UMR model is suggested in training facilities or playing grounds; (2) The sporting space should be non-overcrowding, and it is recommended that the sporting space per capita in the sporting grounds should not be less than 5 m2; (3) It is important to maintain safe social distancing and minimize gathering (no more than three people) when exercising.

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.