Ionic liquids intercalation in titanium carbide MXenes: A first-principles investigation.

Herein, we present a density functional theory with dispersion correction (DFT-D) calculations that focus on the intercalation of ionic liquids (ILs) electrolytes into the two-dimensional (2D) Ti3C2Tx MXenes. These ILs include the cation 1-ethyl-3-methylimidazolium (Emim+), accompanied by three distinct anions: bis(trifluoromethylsulfonyl)imide (TFSA-), (fluorosulfonyl)imide (FSA-) and fluorosulfonyl(trifluoromethanesulfonyl)imide (FTFSA-). By altering the surface termination elements, we explore the intricate geometries of IL intercalation in neutral, negative, and positive pore systems. Accurate estimation of charge transfer is achieved through five population analysis models, such as Hirshfeld, Hirshfeld-I, DDEC6 (density derived electrostatic and chemical), Bader, and VDD (voronoi deformation density) charges. In this work, we recommend the DDEC6 and Hirshfeld-I charge models, as they offer moderate values and exhibit reasonable trends. The investigation, aimed at visualizing non-covalent interactions, elucidates the role of cation-MXene and anion-MXene interactions in governing the intercalation phenomenon of ionic liquids within MXenes. The magnitude of this role depends on two factors: the specific arrangement of the cation, and the nature of the anionic species involved in the process.

Atomistic Insights into the Stabilization of TDP-43 Protofibrils by ATP.

The aberrant accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates in the cytoplasm of motor neurons is the main pathological hallmark of amyotrophic lateral sclerosis (ALS). Previous experiments reported that adenosine triphosphate (ATP), the universal energy currency for all living cells, could induce aggregation and enhance the folding of TDP-43 fibrillar aggregates. However, the significance of ATP on TDP-43 fibrillation and the mechanism behind it remain elusive. In this work, we conducted multiple atomistic molecular dynamics (MD) simulations totaling 20 µs to search the critical nucleus size of TDP-43282-360 and investigate the impact of ATP molecules on preformed protofibrils. The results reveal that the trimer is the critical nucleus for TDP-43282-360 fibril formation and the tetramer is the minimal stable nucleus. When ATP molecules bind to the TDP-43282-360 trimer and tetramer, they can consolidate the TDP-43282-360 protofibrils by increasing the content of the ß-sheet structure and promoting the formation of hydrogen bonds (H-bonds). Binding site analyses show that the N-terminus of TDP-43282-360 protofibrils is the main binding site of ATP, and R293 dominates the direct binding of ATP. Further analyses reveal that the π-π, cation-π, salt bridge, and H-bonding interactions together contribute to the binding of ATP to TDP-43282-360 protofibrils. This study decoded the detailed stabilization mechanism of protofibrillar TDP-43282-360 oligomers by ATP, and may provide new avenues for the development of drug design against ALS.

Molecular mechanisms involved in the destabilization of two types of R3-R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin.

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3-R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3-R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher ß-sheet structure probability. FS can destabilize both types of fibrils by decreasing the ß-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and ß7-ß8 angle of the fibrils. H-bonding, π-π stacking and cation-π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.

Prokaryotic Expression, Purification, and Biological Properties of a Novel Bioactive Protein (PFAP-1) from Pinctada fucata.

Pinctada fucata meat is the main by-product of the pearl harvesting industry. It is rich in nutrition, containing a lot of protein and peptides, and holds significant value for both medicine and food. In this study, a new active protein was discovered and expressed heterogeneously through bioinformatics analysis. It was then identified using Western blot, molecular weight, and mass spectrometry. The antibacterial activity, hemolysis activity, antioxidant activity, and Angiotensin-Converting Enzyme II (ACE2) inhibitory activity were investigated. An unknown functional protein was screened through the Uniprot protein database, and its primary structure did not resemble existing proteins. It was an α-helical cationic polypeptide we named PFAP-1. The codon-optimized full-length PFAP-1 gene was synthesized and inserted into the prokaryotic expression vector pET-30a. The induced expression conditions were determined with a final isopropyl-ß-d-thiogalactoside (IPTG) concentration of 0.2 mM, an induction temperature of 15 °C, and an induction time of 16 h. The recombinant PFAP-1 protein, with low endotoxin and sterility, was successfully prepared. The recombinant PFAP-1 protein exhibited strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in vitro, and the diameter of the inhibition zone was 15.99 ± 0.02 mm. Its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were 37.5 µg/mL and 150 µg/mL, respectively, and its hemolytic activity was low (11.21%) at the bactericidal concentration. The recombinant PFAP-1 protein significantly inhibited the formation of MRSA biofilm and eradicated MRSA biofilm. It also demonstrated potent 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) scavenging activity with a half-maximal inhibitory concentration (IC50) of 40.83 µg/mL. The IC50 of ACE2 inhibition was 5.66 µg/mL. Molecular docking results revealed that the optimal docking fraction of PFAP-1 protein and ACE2 protein was -267.78 kcal/mol, with a confidence level of 0.913. The stable binding complex was primarily formed through nine groups of hydrogen bonds, three groups of salt bridges, and numerous hydrophobic interactions. In conclusion, recombinant PFAP-1 can serve as a promising active protein in food, cosmetics, or medicine.

Destabilization mechanism of R3-R4 tau protofilament by purpurin: a molecular dynamics study.

The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed 306VQIVYK311 isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the ß6-ß7 angle and the solvent-accessible surface area (SASA) of the ß4-ß6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease ß-sheet content. Purpurin molecules could insert the ß4-ß6 region and weaken the hydrophobic packing between ß1 and ß8 through π-π stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.

Difluorovinyl Liquid Crystal Diluters Improve the Electro-Optical Properties of High-∆n Liquid Crystal Mixture for AR Displays.

A liquid crystal (LC) mixture in liquid crystal on silicon (LCoS) is the core material for augmented reality (AR) displays. However, a LC mixture with high birefringence (Δn) and large dielectric anisotropy (Δε) possesses high viscosity (γ1), which results in a slow response time of LCoS devices for AR displays. This work proposes to apply difluorovinyl-based LC diluters to fine balance the low viscosity, high ∆n, and large ∆ε of the LC mixture for a fast response time. Through studying their effects on the key electro-optical properties of a high-∆n LC mixture, it is found that doping these diluter molecules to a high-∆n LC mixture can decrease the viscoelastic coefficient (γ1/K11), increase ∆ε and the figure of merit, maintain a wide nematic phase temperature range, a high clearing point, and ∆n. It also means that these diluters could effectively regulate the relationship between ∆n, ∆ε, and γ1 in the LC mixtures to achieve a fine balance of various excellent properties and further improve the LC device's response time. The widespread applications of these liquid crystal diluters in emerging liquid crystal optical devices are foreseeable.

The destructive mechanism of Aß1-42 protofibrils by norepinephrine revealed via molecular dynamics simulations.

Amyloid-ß (Aß) fibrillary plaques represent the main hallmarks of Alzheimer's disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed Aß protofibrils is considered to be one of the primary therapeutic strategies to interfere with AD. Our previous work showed that norepinephrine (NE), an important neurotransmitter in the brain, can effectively inhibit the aggregation of the Aß1-42 peptide. However, whether and how NE molecules disassemble Aß1-42 protofibrils remains to be elucidated. Herein we investigate the influence of NE (in protonated and deprotonated states) on the recently cryo-EM solved LS-shaped Aß1-42 protofibrils and the underlying molecular mechanism by performing all-atom molecular dynamics simulations. Our simulations showed that protonated and deprotonated NE exhibited distinct disruptive mechanisms on Aß1-42 protofibrils. Protonated NE could significantly disrupt the N-terminal (residues D1-H14) structure of Aß1-42 protofibrils and destabilize the global structure of the protofibril. It preferentially bound with N-terminal residues of Aß1-42 protofibrils and formed hydrogen bonds with E3, D7, E11, Q15, E22, and D23 residues and π-π stackings with H6, H13, and F20 residues, and thus destroyed the hydrogen bonds between H6 and E11 and increased the kink angle around Y10. Compared to protonated NE, deprotonated NE displayed a higher disruptive capability on Aß1-42 protofibrils, and stronger hydrophobic and π-π stacking interactions with the protofibril structure. This study revealed the molecular mechanism of NE in the destruction of Aß1-42 protofibrils, which may be helpful in the design of potent drug candidates against AD.

HDAC2-mediated upregulation of IL-6 triggers the migration of osteosarcoma cells.

Understanding the mechanisms of advanced metastasis in osteosarcoma (OS) cell is important for the targeted treatment and drug development. Emerging evidence shows that epigenetic factors such as histone deacetylases (HDACs) are involved in the progression and chemoresistance of OS, while their roles are largely unknown. Our data showed that the expression of HDAC2, while not HDAC1, 4, or 8, was significantly increased in OS cells and tissues. OS patients with increased expression of HDAC2 showed reduced overall survival with p value of 0.0001. Targeted inhibition of HDAC2 suppressed the in vitro migration and invasion of OS cells. Our data showed that the inhibition of HDAC2 can decrease the expression and transcription of interleukin-6 (IL-6) in OS cells. Overexpression of IL-6 can reverse si-HDAC2-induced suppression of cell migration. Mechanistical studies showed that inhibition of HDAC2 decreased the phosphorylation and nuclear accumulation of p65, the key factor of NF-κB complex responsible for the transcription of IL-6. This was due to that HDAC2 can activate the transcription of IKK-ß in OS cells. Collectively, our data showed that HDAC2-activated NF-κB can increase the expression of IL-6 in OS cells, which resulted in the promotion of cell migration. It suggested that targeted inhibition of HDAC2/NF-κB/IL-6 might be a potential approach for OS therapy.

Evidence mapping and quality assessment of systematic reviews on exercise intervention for Alzheimer's disease.

BACKGROUND: A significant body of literature suggests that exercise can reverse cognitive impairment and ameliorate somatic function in patients with Alzheimer's disease (AD). Systematic reviews (SRs), a common approach of evidence-based medicine, concentrate on a specific issue of a research area. The objective of this work is to provide an overview of existing evidence on the effects of exercise intervention in AD patients and report related health outcomes by reviewing SRs. METHODS: SRs on exercise intervention in AD patients were retrieved from the PubMed, the Cochrane Library, CBMdisc, Scopus, Web of Science, Embase (via Ovid), China National Knowledge Infrastructure, and WanFang databases from the time of inception to February 2023. The quality of the SRs was evaluated utilizing the A Measurement Tool to Assess Systematic Review 2 (AMSTAR 2) checklist. The results were reported according to the population-intervention-comparison-outcome (PICO) framework and the corresponding evidence mapping was illustrated in tables and bubble plots. RESULTS: A total of 26 SRs met the eligibility criteria. In terms of methodological quality, 10 SRs were rated as "critically low", 13 SRs were rated as "low", and 3 SRs were rated as "moderate". Exercise was found to exert a beneficial effect on cognitive function, functional independence, physical function, and neuropsychiatric symptoms in patients with AD. CONCLUSION: Exercise intervention benefits AD patients mainly by improving cognitive function, physical function, functional independence, and neuropsychiatric symptoms. However, due to the low-to-moderate methodology of most SRs included in this analysis, further investigations are required to support our current findings.

Atomic insights into the inhibition of R3 domain of tau protein by epigallocatechin gallate, quercetin and gallic acid.

Inhibiting tau protein aggregation has become a prospective avenue for the therapeutic development of tauopathies. The third microtubule-binding repeat (R3) domain of tau is confirmed as the most aggregation-favorable fragment of the whole protein. As dimerization is the first step of the aggregation of tau into amyloid fibrils, impeding the dimerization of the R3 domain is critical to prevent the full-length tau aggregation. Natural polyphenol small molecules epigallocatechin gallate (EGCG), quercetin (QE) and gallic acid (GA) are proven to inhibit the aggregation of the full-length recombinant tau (For EGCG and QE) or the R3 domain (For GA) of tau in vitro. However, the underlying molecular mechanisms of the inhibitive effects on the R3 domain of tau remain largely unknown. In this study, we conducted numerous all-atom molecular dynamics simulations on R3 dimers with and without EGCG, QE or GA, respectively. The results reveal that all three molecules can effectively decrease the ß structure composition of the R3 dimer, induce the dimer to adopt loosely-packed conformations, and weaken interchain interactions, thus impeding the dimerization of the R3 peptide chains. The specific preferentially binding sites for the three molecules exhibit similarities and differences. Hydrophobic, π-π stacking and hydrogen-bonding interactions collectively drive EGCG, QE and GA respectively binding on the R3 dimer, while QE also binds with the dimer through cation-π interaction. Given the incurable nature of tauopathies hitherto, our research provides helpful knowledge for the development of drugs to treat tauopathies.

Comparison of physical activity and physical fitness in children and adolescents of Chinese Han and Tibet ethnicity.

Background: Physical activity (PA) and physical fitness (PF) are important markers of health status in children and adolescents in different ethnicities. In this study, we aimed to compare the PA and PF indicators between Tibetan and Han children and adolescents. Methods: Children and adolescents of 4-9 grades were recruited in Shigatse (n = 963) and Shanghai (n = 2,525) respectively. The information related to demographic, PA, and PF was collected via a self-reported questionnaire. PA was assessed through the participation of moderate to vigorous PA (MVPA), muscle-strengthening exercise (MSE) and organized sport participation (OSP). PF was estimated using the International Fitness Scale containing components of overall fitness, cardiorespiratory fitness, speed and agility, muscular strength and flexibility. Results: Han (mean age = 13.45 ± 3.3 years; 49.7% girls) and Tibet (mean age = 13.8 ± 2.5 years; 48.3% girls) children and adolescents from Shanghai and Shigatse completed the questionnaire survey. It was revealed that Tibetan students had higher MVPA, MSE and OSP than children and adolescents of Han ethnicity (p < 0.01, small to medium effect size). A relatively higher percentage of student in Shanghai did not participate in any form of PA. On the other hand, less Tibetan students thought their PF indicators including overall fitness, cardiorespiratory fitness, speed and agility, muscular strength and flexibility were poor or very poor than their counterparts of Han ethnicity (p < 0.01, small to medium effect size). Conclusion: Tibetan children and adolescents have higher levels of PA and PF in comparison to their Han counterparts. More children and adolescents of Han ethnicity engage in no PA and think their PF indicators were poor.

Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43370-375 fragment.

The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370-375 fragment of TDP-43 (370GNNSYS375, TDP-43370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 µs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43370-375 peptides. Hydrogen bonding and polar interactions among TDP-43370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to ß-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.

Effectiveness of resistance training on body composition, muscle strength, and biomarker in sarcopenic older adults: A meta-analysis of randomized controlled trials.

This study analyzed 22 randomized controlled trials involving 959 participants to determine the impact of resistance training (RT) on body composition, muscle strength, and biomarkers in sarcopenic older adults. Regarding body composition, RT had a small effect size on relative muscle mass (RMM, SMD = 0.25[0.06,0.45]) and absolute muscle mass (AMM, SMD = 0.28[0.06,0.50]) but no effect on reducing body fat percentage (BF%). Meta-regression analysis pinpointed key predictors (p < 0.05): training period, number of sets, contraction speed, and average age. Subgroup analysis revealed that 3 sets over an 8-12 weeks training period, with slower muscle contraction speed at a 60-70 % 1-repetition maximum (1RM) training intensity, produced the most significant effects on reducing BF% and increasing RMM, respectively. Regarding muscle strength, RT had a large effect size on handgrip strength (HS, SMD = 0.83[0.43,1.23]), knee extension strength (KES, SMD = 0.90[0.50,1.30]), but no effect on chair stand test. Meta-regression analysis pinpointed key predictors (p < 0.05): training intensity, number of sets, body mass index, and sample size. Subgroup analysis revealed that the number of sets ≥ 3 and training intensity >70 % 1RM produced the most significant effect of RT on HS. Regarding biomarkers, RT had a medium effect size on insulin-like growth factor-1 (SMD = 0.70[0.10,1.30]), interleukin-10 (SMD = 0.61[0.09,1.13]), follistatin (SMD = 0.56[0.16,0.96]), but no effect on interleukin-6, tumor necrosis factor-alpha, and myostatin. It concludes that RT is an effective way to improve muscle strength and the level of synthetic hormones and anti-inflammatory factors in sarcopenic older adults, with a slight impact on body composition and no impact on pro-inflammatory factors.

Two-Dimensional Amphibian Diversity along a 3500 m Elevational Gradient at the Eastern Edge of the Qinghai-Xizang Plateau.

Amphibians serve as reliable indicators of ecosystem health and are the most threatened group of vertebrates. Studies on their spatial distribution pattern and threats are crucial to formulate conservation strategies. Gongga Mountains, with a peak at 7509 m a.s.l. and running latitudinally, are in the center of the Hengduan Mountains Range and at the eastern steep edge of the Qinghai-Xizang Plateau, providing heterogeneous habitats and varied niches for amphibians. In this study, we combined 83 days of field work with information from 3894 museum specimens that were collected over the past 80 years, and identified twenty amphibian species belonging to seven families and twelve genera by morphology. Of these species, seven were listed in the threatened categories of the Red List of China's Biodiversity and thirteen were endemic to China. Ten species were found on the plateau side (western slope) and eleven species were found on the other side close to the Sichuan Basin (eastern slope). Only one species was found on both sides, indicating different community structures horizontally. The species richness was unimodal vertically and peaking at mid elevation on both sides, with the maximum number (ten vs. nine) of species occurring at 3300-3700 vs. 1700-1900 m a.s.l. and in different types of vegetation. The elevation span and body length of species distributed on both slopes did not show significant differences. These findings help to understand the horizontal and vertical distribution pattern of amphibian diversity, laying a foundation for future biogeographical and conservation research in this area.

Impact of Metacognition on Health-Related Behavior: A Mediation Model Study.

Objective: The study aims to explore the correlation mechanism among metacognition, attitude toward physical exercise, and health-related behavior in high school students. Methods: A total of 869 students (17 ± 1.70) from Anhui, Zhejiang, Shandong, and Fujian provinces were selected by stratified sampling to complete the Metacognition Questionnaire, Health-Related Behavior Self-Rating Scale, Attitude Toward Physical Exercise Scale, and Depression-Anxiety-Stress Scale (Simplified Chinese version, DASS-21). Results: (1) Metacognition was negatively predictive of attitude toward physical exercise and health-related behavior (ß = -0.236, P < 0.01; ß = -0.239, P < 0.01) but positively predictive of negative emotion (ß = 0.496, P < 0.01); (2) attitude toward physical exercise was positively predictive of health-related behavior (ß = 0.533, P < 0.01) but negatively predictive of negative emotion (ß = -0.336, P < 0.01); and (3) negative emotion was negatively predictive of health-related behavior (ß = -0.389, P < 0.01). Conclusions: Metacognition not only has a directly predictive effect on health-related behavior but also predicts it through attitude toward physical exercise. Negative emotion also mediates the relationship between metacognition and attitude toward physical exercise.

Investigation of concussion knowledge and attitudes of Chinese amateur adolescent soccer athletes.

Concussions are a common traumatic brain injury in soccer games but are often ignored by coaches and athletes. The purpose of our study is to assess the concussion knowledge and attitudes among amateur adolescent soccer athletes in China. Data was collected from questionnaire surveying (Rosenbaum Concussion Knowledge and Attitudes Survey (Student Version)) and semi-structured interviews completed by 69 amateur adolescent soccer athletes who participated in the U17 and U15 male groups of the 2022 China Youth Soccer League. The study followed a mixed methodology cross sectional study design. The concussion knowledge index (0-25) and concussion attitude index (15-75) scores were derived from the questionnaire and descriptive statistics were used for data analysis. The mean score of concussion knowledge is 16.8 ±â€…2.4 (range 10-22), and the mean score of concussion attitude is 61.3 ±â€…8.8 (range 45-77). Thematic analysis was used to categorize the participant's responses of the semi-structured interview and the results were compared with their survey answers of questionnaire. Interestingly, the interviews revealed the inconsistencies between the questionnaire responses and intended behaviors, and multiple factors (injury severity, the importance of the game and substitution rules) influencing concussion-reporting behaviors were identified. In addition, athletes hope to acquire concussion knowledge through formal education. Our study lay the foundation for educational interventions to potentially improve concussion-reporting behaviors among amateur adolescent soccer athletes.

Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences.

Chronic traumatic encephalopathy (CTE) is a unique progressive neurodegenerative tauopathy pathologically related to the aggregation of the tau protein to neurofibrillary tangles. Disrupting tau oligomers (protofibril) is a promising strategy to prevent CTE. Quercetin (QE) and gallic acid (GA), two polyphenol small molecules abundant in natural crops, were proved to inhibit recombinant tau and the R3 fragment of human full-length tau in vitro. However, their disruptive effect on CTE-related protofibril and the underlying molecular mechanism remain elusive. Cryo-electron microscopy resolution reveals that the R3-R4 fragment of tau forms the core of the CTE-related tau protofibril. In this study, we conducted extensive all-atom molecular dynamics simulations on CTE-related R3-R4 tau protofibril with and without QE/GA molecules. The results disclose that both QE and GA can disrupt the global structure of the protofibril, while GA shows a relatively strong effect. The binding sites, exact binding patterns, and disruptive modes for the two molecules show similarities and differences. Strikingly, both QE and GA can insert into the hydrophobic cavity of the protofibril, indicating they have the potential to compete for the space in the cavity with aggregation cofactors unique to CTE-related protofibril and thus impede the further aggregation of the tau protein. Due to relatively short time scale, our study captures the early disruptive mechanism of CTE-related R3-R4 tau protofibril by QE/GA. However, our research does provide valuable knowledge for the design of supplements or drugs to prevent or delay the development of CTE.

Inhibitive and Destructive Mechanisms of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Peptide Chains and Protofibril by Epigallocatechin Gallate: Evidence from Molecular Dynamics Simulation.

Chronic traumatic encephalopathy (CTE), a unique tauopathy, is pathologically associated with the aggregation of hyperphosphorylated tau protein into fibrillar aggregates. Inhibiting tau aggregation and disaggregating tau protofibril might be promising strategies to prevent or delay the development of CTE. Newly resolved tau fibril structures from deceased CTE patients' brains show that the R3-R4 fragment of tau forms the core of the fibrils and the structures are distinct from other tauopathies. An in vitro experiment finds that epigallocatechin gallate (EGCG) can effectively inhibit human full-length tau aggregation and disaggregate preformed fibrils. However, its inhibitive and destructive effects on the CTE-related R3-R4 tau and the underlying molecular mechanisms remain elusive. In this study, we performed extensive all-atom molecular dynamics simulations on the CTE-related R3-R4 tau dimer/protofibril with and without EGCG. The results reveal that EGCG could reduce the ß-sheet structure content of the dimer, induce the dimer to form loosely packed conformations, and impede the interchain interactions, thus inhibiting the further aggregation of the two peptide chains. Besides, EGCG could reduce the structural stability, decrease the ß-sheet structure content, reduce the structural compactness, and weaken local residue-residue contacts of the protofibril, hence making the protofibril disaggregated. We also identified the dominant binding sites and pivotal interactions. EGCG preferentially binds with hydrophobic, aromatic, and positively/negatively charged residues of the dimer, while it tends to bind with polar, hydrophobic, aromatic, and positively charged residues of the protofibril. Hydrophobic, hydrogen-bonding, π-π stacking, and cation-π interactions synergistically drive the binding of EGCG on both the dimer and the protofibril, but anion-π interaction only exists in the interaction of EGCG with the dimer. Our work unravels EGCG's inhibitive and destructive effects on the CTE-related R3-R4 tau dimer/protofibril and the underlying molecular mechanisms, which provides useful implications for the design of drugs to prevent or delay the progression of CTE.

Transposable element and host silencing activity in gigantic genomes.

Transposable elements (TEs) and the silencing machinery of their hosts are engaged in a germline arms-race dynamic that shapes TE accumulation and, therefore, genome size. In animal species with extremely large genomes (>10 Gb), TE accumulation has been pushed to the extreme, prompting the question of whether TE silencing also deviates from typical conditions. To address this question, we characterize TE silencing via two pathways-the piRNA pathway and KRAB-ZFP transcriptional repression-in the male and female gonads of Ranodon sibiricus, a salamander species with a ∼21 Gb genome. We quantify 1) genomic TE diversity, 2) TE expression, and 3) small RNA expression and find a significant relationship between the expression of piRNAs and TEs they target for silencing in both ovaries and testes. We also quantified TE silencing pathway gene expression in R. sibiricus and 14 other vertebrates with genome sizes ranging from 1 to 130 Gb and find no association between pathway expression and genome size. Taken together, our results reveal that the gigantic R. sibiricus genome includes at least 19 putatively active TE superfamilies, all of which are targeted by the piRNA pathway in proportion to their expression levels, suggesting comprehensive piRNA-mediated silencing. Testes have higher TE expression than ovaries, suggesting that they may contribute more to the species' high genomic TE load. We posit that apparently conflicting interpretations of TE silencing and genomic gigantism in the literature, as well as the absence of a correlation between TE silencing pathway gene expression and genome size, can be reconciled by considering whether the TE community or the host is currently "on the attack" in the arms race dynamic.

Research Trends and Prospects of Sport-Related Concussion: A Bibliometric Study Between 2000 and 2021.

BACKGROUND: Research around sport-related concussion (SRC) has made great advances during the twenty-first century. However, few studies have systematically analyzed the published SRC research. METHODS: A bibliometric analysis was conducted of data from articles from the Web of Science Core Collection database. Descriptive statistics were used to analyze publication trends, most productive countries, institutions, authors, journals, research fields, and references with the highest citation number. VOSviewer software was used to perform network visualization and keywords co-occurrence analysis. CiteSpace software was used to perform reference co-citation analysis. RESULTS: 1) The number of publications and number of citations of research in SRC progressively increased between 2000 and 2021; 2) the United States was the leading country in research in SRC; 3) extensive cooperation among countries, institutions, and investigators was prevalent in SRC research; 4) P. McCrory, M. McCrea, and K.M. Guskiewicz were the 3 most prolific and influential authors; 5) research in SRC involved multidisciplinary perspectives and approaches; 6) research in SRC mainly covered aspects of primary prevention, diagnosis, and management, and the latter two have gained more attention in recent years; and 7) specific questions about "education," "predictors," "youth," "exercise," "reliability," "validity," and "baseline" were the research frontiers of SRC. CONCLUSIONS: Attention to research in SRC has rapidly increased in recent years. Our work is a holistic overview that summarizes the hotspots, frontiers, and prospects of SRC, thus providing valuable information and guidance concerning research directions for those who are interested in or are dedicated to SRC research.