Reactivity-matched synthesis of monodisperse Ag(In,Ga)S2 QDs with efficient luminescence.

I-III-VI quantum dots (QDs) have gained widespread attention owing to their significant advantages of non-toxicity, large structural tolerance, and efficient photoluminescence potential. However, the disbalance of reactivity between the elements will result in undesired products and compromised optical properties. Reducing the activity of highly reactive group IB elements is the most common approach, but it will reduce the overall reactivity and lead to a wide dispersion of QD sizes. In this study, we propose a method to improve the overall reactivity of the reaction system using the highly active IIIA precursor InI3, which triggers rapid nucleation and promotes the formation of Ag(In,Ga)S2 (AIGS) QDs, resulting in monodisperse particle size distributions and a significantly improved photoluminescence quantum yield (PLQY) (from 12% to 72%). Furthermore, narrow band edge emission is realized by coating a gallium sulfide (GaSx) shell on the basis of obtaining high-quality AIGS QDs. The core/shell QDs exhibit a 90% PLQY with a full width at half maximum (FWHM) of only 31 nm at 530 nm. This study provides a viable design strategy to synthesize monodisperse AIGS QDs with a narrow peak width and efficient luminescence, promoting the application of AIGS QDs in the field of luminescent displays.

Self-reporting intracellular delivery agent for singlet oxygen.

1,4-Dimethylphenazine endoperoxide releases singlet oxygen with a half-life of 89 hours at 37 °C. The thermal cycloreversion reaction is accompanied by a strong increase in the emission intensity with a peak at 490 nm, due to the formation of the phenazine core. The endoperoxide is effective against cancer cells in culture medium and tumor spheroids, with singlet oxygen-mediated cytotoxicity.

Simulations of Anisotropic Monolayer GaSCl for p-Type Sub-10 nm High-Performance and Low-Power FETs.

Two-dimensional materials have been extensively studied in field-effect transistors (FETs). However, the performance of p-type FETs has lagged behind that of n-type, which limits the development of complementary logical circuits. Here, we investigate the electronic properties and transport performance of anisotropic monolayer GaSCl for p-type FETs through first-principles calculations. The anisotropic electronic properties of monolayer GaSCl result in excellent device performance. The p-type GaSCl FETs with 10 nm channel length have an on-state current of 2351 µA/µm for high-performance (HP) devices along the y direction and an on-state current of 992 µA/µm with an on/off ratio exceeding 107 for low-power (LP) applications along the x direction. In addition, the delay-time (τ) and power dissipation product of GaSCl FETs can fully meet the International Technology Roadmap for Semiconductors standards for HP and LP applications. Our work illustrates that monolayer GaSCl is a competitive p-type channel for next-generation devices.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone, thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of HIF-1α protein, but also inhibits the TGF-ß1 induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in conventional PDT. Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

First Report of Fruit Rot Disease on melon (Cucumis melo L.) Caused by Fusarium ipomoeae in China.

Fusarium rot on melon fruit has become an important postharvest disease for producers worldwide, typically involving multiple Fusarium pathogens (Khuna et al. 2022; Medeiros Araújo et al. 2021). In 2022, Fusarium fruit rot of muskmelon (Cucumis melo var. conomon) occurred sporadically in a field at Huainan Academy of Agricultural Sciences (32.658193º N, 117.064922º E) with an incidence of about 10%. Among these diseased muskmelons, a fruit exhibiting a white to yellowish colony athe intersection of the diseased and healthy tissues was collected and labeled TGGF22-17. The streak plate method was employed to isolate fungal spores on Bengal Red PDA (potato dextrose agar), which were then incubated at 25℃ in darkness. Following isolation and purification, a single-spore strain, TGGF22-17, was obtained and analyzed using morphological characters on PDA, synthetic nutrient agar (SNA) and carnation leaf agar (CLA) (Leslie and Summerell 2006), along with molecular identification. Colours were rated according to the color charts of Kornerup and Wanscher (1978). Based on the colony morphology on PDA, the isolate displayed a rosy buff or buff color with a white to buff margin. The colony margin was undulate, with the reverse transitioning from amber-yellow to honey-yellow. Aerial macroconidia on SNA were thin-walled, hyaline, mostly 3-5 septate, falcate, and measured 18.5-46.4 (x̄=34.2) × 2.9-4.8 (x̄ =3.9) µm in size (n =50). Sporodochial macroconidia on CLA were mostly five-septate with long apical and basal cells, exhibiting dorsiventral curvature. They were hyaline, with the apical cell hooked to tapering and the basal cell foot-shaped, measuring 46.5-89.6 (x̄ =72.3) × 3.5-5.0 (x̄ =4.3) µm in size (n = 100). Portions of three loci (TEF-1α, RPB1 and RPB2) were amplified and sequenced as described by Wang et al. (2019). Sequences were deposited in GenBank with accession number PP196583 to PP196585. The three gene sequences (TEF-1α, RPB1 and RPB2) of strain TGGF2022-17 shared 99.5% (629/632bp), 97.9% (1508/1540 bp) and 99.9% (1608/1609 bp) identity to the ex-type strain F. ipomoeae LC12165 respectively by pairwise DNA alignments on the FUSARIOID-ID database (https://www.fusarium.org). Phylogenetic analysis of the partial TEF-1α and RPB2 sequences with PhyloSuite (Zhang et al. 2020) showed the isolated fungus clustered with F. ipomoeae. Based on the morphological and phylogenetic analyses, TGGF22-17 was identified as F. ipomoeae. Pathogenicity tests were performed on healthy melons, which were surface-sterilized with 75% alcohol and wounded using a sterilized inoculation needle. A 4-mm diameter plug from a 7-day-old SNA culture of TGGF22-17 was aseptically inserted in the middle of the wound, sealed with plastic bag after absorbent cotton was included to maintain moisture. Five melons were each inoculated at three points. Noncolonized PDA agar plugs served as the negative control. The inoculated and uninoculated plugs were removed approximately 48 hours after inoculation. The melon inoculated with TGGF22-17 exhibited water-soaked black lesions 48h post-inoculation, resulting in a 100% infection rate (15/15). After 7 days, mycelium was obseved on the inoculated melons. No disease symptoms were observed on the uninoculated melons. To fulfill Koch's postulates, fungi were isolated from the inoculated fruit and confirmed as F. ipomoeae by morphological observation. Fusarium ipomoeae has been reported to cause fruit rot on winter squash (Cucurbita maxima) in Japan (Kitabayashi et al. 2023). To our knowledge, this is the first report of fruit rot on muskmelon caused by F. ipomoeae in China and this report will be valuable for monitoring and management of fruit rot disease on muskmelons.

Targeted Endoperoxides Delivering Singlet Oxygen to Cancer Cell Mitochondria: Exploration of the Therapeutic Potential.

The clinical practice of photodynamic therapy of cancer (PDT) is mostly limited to superficial types of skin cancer. The major reason behind this limited applicability is the need for light in the photogeneration of ROS, and in particular singlet oxygen. In order to circumvent this major roadblock, we designed and synthesized naphthalene-derived endoperoxides with mitochondria targeting triphenylphosphonium moieties. Here, we show that these compounds release singlet oxygen by thermal cycloreversion, and initiate cell death with IC50 < 10 µM in cancer cell cultures. The mouse 4T1 breast tumor model study, where the endoperoxide compound was introduced intraperitoneally, also showed highly promising results, with negligible systemic toxicity. Targeted delivery of singlet oxygen to cancer cell mitochondria could be the breakthrough needed to transform Photodynamic Therapy into a broadly applicable methodology for cancer treatment by keeping the central tenet and discarding problematic dependencies on oxygen or external light.

Transient paper-based electrochemical biosensor Fabricated by superadditive Cu-TCPP(Fe)/Mxene for Multipathway non-invasive, highly sensitive detection of Bodily metabolites.

Current advances in non-invasive fluid diagnostics highlight unique benefits for monitoring metabolic diseases. However, the low concentrations and complex compositions of biomarkers in fluids such as sweat, urine, and saliva impose stringent demands on the sensitivity and stability of detection technologies. Here, we developed a high-sensitivity, low-cost instantaneous electrochemical sensor based on the superadditive effect mechanism of Cu-TCPP(Fe)/Mxene (MMs Paper-ECL Sensor), which has been successfully applied for the simultaneous real-time detection of glucose and uric acid. Strong interfacial interactions between Mxene and Cu-TCPP(Fe) were revealed through precise simulation calculations and multi-dimensional characterization analysis, significantly enhancing the sensor's electrocatalytic performance and reaction kinetics. Experimentally, this exceptional electrocatalytic activity was demonstrated in its unprecedented high sensitivity and wide linear detection range for glucose and uric acid, with a non-invasive linear range from 0.001 nM to 5 mM, 0.025 nM-5 mM, detection limits as low as 1.88 aM and 5.80 pM, and stability extending up to 100 days. This represents not only a breakthrough in sensitivity and stability but also provides an effective, low-cost solution that overcomes the limitations of existing electronic devices, enabling multi-channel simultaneous detection. The universality of this sensor holds vast potential for application in the field of non-invasive fluid diagnostics.

Design of Multifunctional Electrocatalysts for ORR/OER/HER/HOR: Janus Makes Difference.

Multifunctional electrocatalysts for hydrogen evolution reaction (HER), hydrogen oxidation reaction (HOR), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) have broad application prospects; However, realization of such kinds of materials remain difficulties because it requires the materials to have not only unique electronic properties, but multiple active centers to deal with different reactions. Here, employing density functional theory (DFT) computations, it is demonstrated that by decorating the Janus-type 2D transition metal dichalcogenide (TMD) of TaSSe with the single atoms, the materials can achieve multifunctionality to catalyze the ORR/OER/HER/HOR. Out of sixteen catalytic systems, Pt-VS (i.e., Pt atom embedded in the sulfur vacancy), Pd-VSe, and Pt-VSe@TaSSe are promising multifunctional catalysts with superior stability. Among them, the Pt-VS@TaSSe catalyst exhibits the highest activity with theoretical overpotentials ηORR = 0.40 V, ηOER = 0.39 V, and ηHER/HOR = 0.07 V, respectively, better than the traditional Pt (111), IrO2 (110). The interplays between the catalyst and the reaction intermediate over the course of the reaction are then systematically investigated. Generally, this study presents a viable approach for the design and development of advanced multifunctional electrocatalysts. It enriches the application of Janus, a new 2D material, in electrochemical energy storage and conversion technology.

High-Performance Sub-10 nm Two-Dimensional SbSeBr Transistors through Transport Orientation.

Exploring two-dimensional (2D) materials with a small carrier effective mass and suitable band gap is crucial for the design of metal oxide semiconductor field effect transistors (MOSFETs). Here, the quantum transport properties of stable 2D SbSeBr are simulated on the basis of first-principles calculations. Monolayer SbSeBr proves to be a competitive channel material, offering a suitable band gap of 1.18 eV and a small electron effective mass (me*) of 0.22m0. The 2D SbSeBr field effect transistor (FET) with 8 nm channel length exhibits a high on-state current of 1869 µA/µm, low power consumption of 0.080 fJ/µm, and small delay time of 0.062 ps, which can satisfy the requirements of the International Technology Roadmap for Semiconductors for high-performance devices. Moreover, despite the monolayer SbSeBr having an isotropic me*, the asymmetrical band trends enable SbSeBr FETs to display transport orientation, which emphasizes the importance of band trends and provides valuable insights for selecting channel materials.

Targeted PLK1 suppression through RNA interference mediated by high-fidelity Cas13d mitigates osteosarcoma progression via TGF-ß/Smad3 signalling.

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Overexpression of polo-like kinase 1 (PLK1) is frequent in osteosarcoma and drives disease progression and metastasis, making it a promising therapeutic target. In this study, we explored PLK1 knockdown in osteosarcoma cells using RNA interference mediated by high-fidelity Cas13d (hfCas13d). PLK1 was found to be significantly upregulated in osteosarcoma tumour tissues compared to normal bone. sgRNA-mediated PLK1 suppression via hfCas13d transfection inhibited osteosarcoma cell proliferation, induced G2/M cell cycle arrest, promoted apoptosis, reduced cell invasion and increased expression of the epithelial marker E-cadherin. Proximity labelling by TurboID coupled with co-immunoprecipitation identified novel PLK1 interactions with Smad3, a key intracellular transducer of TGF-ß signalling. PLK1 knockdown impaired Smad2/3 phosphorylation and modulated TGF-ß/Smad3 pathway inactivation. Finally, in vivo delivery of hfCas13d vectors targeting PLK1 substantially attenuated osteosarcoma xenograft growth in nude mice. Taken together, this study highlights PLK1 as a potential therapeutic target and driver of disease progression in osteosarcoma. It also demonstrates the utility of hfCas13d-mediated gene knockdown as a strategy for targeted therapy. Further optimization of PLK1 suppression approaches may ultimately improve clinical outcomes for osteosarcoma patients.

Effects of NEAT1 levels on cardiovascular events and prognosis in diabetic nephropathy patients undergoing peritoneal dialysis.

The purpose of this study was to provide observational indicators for clinically predicting cardiovascular events in patients with diabetic nephropathy (DN) undergoing peritoneal dialysis by determining the effects of nuclear enriched abundant transcript 1 (NEAT1) levels on the cardiovascular events and prognosis in DN patients receiving continuous ambulatory peritoneal dialysis (CAPD). A retrospective analysis was conducted on the data of 80 DN patients undergoing CAPD. Patients were assigned to NEAT1 high expression group and NEAT1 low expression group. NEAT1 had a substantially increased expression in the serum of DN patients, and it could serve as a potential biomarker for predicting the development of DN. Patients with highly expressed NEAT1 had an higher level of high-sensitivity C-reactive protein (hs-CRP), larger cardiac structural parameters left ventricular end-diastolic diameter (LVED), left ventricular end-systolic diameter (LVESD), interventricular septal diameter (IVSD) and left ventricular posterior wall diameter (LVPWD), but a notably lower cardiac function evaluation indicator left ventricular ejection fraction (LVEF) than those with lowly expressed NEAT1. The coefficient (r) of correlation between NEAT1 and hs-CRP level was 0.3585 (P=0.0011). The incidence rates of acute myocardial infarction, congestive heart failure and angina in NEAT1 high expression group were higher than those in NEAT1 low expression group. Patients with NEAT1 high expression exhibited a higher mortality rate than NEAT1 low expression group. With the increase in NEAT1 levels, the level of hs-CRP rose in DN patients undergoing CAPD. A higher expression level of NEAT1 indicates poorer cardiac function, higher incidence rates of cardiovascular adverse events and a poorer prognosis in diabetics undergoing CAPD.

Co-Mutations and Possible Variation Tendency of the Spike RBD and Membrane Protein in SARS-CoV-2 by Machine Learning.

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 variants capable of breakthrough infections have attracted global attention. These variants have significant mutations in the receptor-binding domain (RBD) of the spike protein and the membrane (M) protein, which may imply an enhanced ability to evade immune responses. In this study, an examination of co-mutations within the spike RBD and their potential correlation with mutations in the M protein was conducted. The EVmutation method was utilized to analyze the distribution of the mutations to elucidate the relationship between the mutations in the spike RBD and the alterations in the M protein. Additionally, the Sequence-to-Sequence Transformer Model (S2STM) was employed to establish mapping between the amino acid sequences of the spike RBD and M proteins, offering a novel and efficient approach for streamlined sequence analysis and the exploration of their interrelationship. Certain mutations in the spike RBD, G339D-S373P-S375F and Q493R-Q498R-Y505, are associated with a heightened propensity for inducing mutations at specific sites within the M protein, especially sites 3 and 19/63. These results shed light on the concept of mutational synergy between the spike RBD and M proteins, illuminating a potential mechanism that could be driving the evolution of SARS-CoV-2.

Four Parallel Pathways in T4 Ligase-Catalyzed Repair of Nicked DNA with Diverse Bending Angles.

The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase-AMP complex and the ligase-AMP-DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase-AMP complex that persist in the ligase-AMP-DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments.

AACFlow: an end-to-end model based on attention augmented convolutional neural network and flow-attention mechanism for identification of anticancer peptides.

MOTIVATION: Anticancer peptides (ACPs) have natural cationic properties and can act on the anionic cell membrane of cancer cells to kill cancer cells. Therefore, ACPs have become a potential anticancer drug with good research value and prospect. RESULTS: In this article, we propose AACFlow, an end-to-end model for identification of ACPs based on deep learning. End-to-end models have more room to automatically adjust according to the data, making the overall fit better and reducing error propagation. The combination of attention augmented convolutional neural network (AAConv) and multi-layer convolutional neural network (CNN) forms a deep representation learning module, which is used to obtain global and local information on the sequence. Based on the concept of flow network, multi-head flow-attention mechanism is introduced to mine the deep features of the sequence to improve the efficiency of the model. On the independent test dataset, the ACC, Sn, Sp, and AUC values of AACFlow are 83.9%, 83.0%, 84.8%, and 0.892, respectively, which are 4.9%, 1.5%, 8.0%, and 0.016 higher than those of the baseline model. The MCC value is 67.85%. In addition, we visualize the features extracted by each module to enhance the interpretability of the model. Various experiments show that our model is more competitive in predicting ACPs.

EACVP: An ESM-2 LM Framework Combined CNN and CBAM Attention to Predict Anti-coronavirus Peptides.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) outbreak in late 2019 killed millions worldwide. Coronaviruses cause diseases such as severe acute respiratory syndrome (SARS-Cov) and SARS-COV-2. Many peptides in the host defense system have antiviral activity. How to establish a set of efficient models to identify anti-coronavirus peptides is a meaningful study. METHODS: Given this, a new prediction model EACVP is proposed. This model uses the evolutionary scale language model (ESM-2 LM) to characterize peptide sequence information. The ESM model is a natural language processing model trained by machine learning technology. It is trained on a highly diverse and dense dataset (UR50/D 2021_04) and uses the pre-trained language model to obtain peptide sequence features with 320 dimensions. Compared with traditional feature extraction methods, the information represented by ESM-2 LM is more comprehensive and stable. Then, the features are input into the convolutional neural network (CNN), and the convolutional block attention module (CBAM) lightweight attention module is used to perform attention operations on CNN in space dimension and channel dimension. To verify the rationality of the model structure, we performed ablation experiments on the benchmark and independent test datasets. We compared the EACVP with existing methods on the independent test dataset. RESULTS: Experimental results show that ACC, F1-score, and MCC are 3.95%, 35.65% and 0.0725 higher than the most advanced methods, respectively. At the same time, we tested EACVP on ENNAVIA-C and ENNAVIA-D data sets, and the results showed that EACVP has good migration and is a powerful tool for predicting anti-coronavirus peptides. CONCLUSION: The results prove that this model EACVP could fully characterize the peptide information and achieve high prediction accuracy. It can be generalized to different data sets. The data and code of the article have been uploaded to https://github.- com/JYY625/EACVP.git.

Identifying atomically thin isolated-band channels for intrinsic steep-slope transistors by high-throughput study.

Developing low-power FETs holds significant importance in advancing logic circuits, especially as the feature size of MOSFETs approaches sub-10 nanometers. However, this has been restricted by the thermionic limitation of SS, which is limited to 60 mV per decade at room temperature. Herein, we proposed a strategy that utilizes 2D semiconductors with an isolated-band feature as channels to realize sub-thermionic SS in MOSFETs. Through high-throughput calculations, we established a guiding principle that combines the atomic structure and orbital interaction to identify their sub-thermionic transport potential. This guides us to screen 192 candidates from the 2D material database comprising 1608 systems. Additionally, the physical relationship between the sub-thermionic transport performances and electronic structures is further revealed, which enables us to predict 15 systems with promising device performances for low-power applications with supply voltage below 0.5 V. This work opens a new way for the low-power electronics based on 2D materials and would inspire extensive interests in the experimental exploration of intrinsic steep-slope MOSFETs.

iACVP-MR: Accurate Identification of Anti-coronavirus Peptide based on Multiple Features Information and Recurrent Neural Network.

BACKGROUND: Over the years, viruses have caused human illness and threatened human health. Therefore, it is pressing to develop anti-coronavirus infection drugs with clear function, low cost, and high safety. Anti-coronavirus peptide (ACVP) is a key therapeutic agent against coronavirus. Traditional methods for finding ACVP need a great deal of money and man power. Hence, it is a significant task to establish intelligent computational tools to able rapid, efficient and accurate identification of ACVP. METHODS: In this paper, we construct an excellent model named iACVP-MR to identify ACVP based on multiple features and recurrent neural networks. Multiple features are extracted by using reduced amino acid component and dipeptide component, compositions of k-spaced amino acid pairs, BLOSUM62 encoder according to the N5C5 sequence, as well as second-order moving average approach based on 16 physicochemical properties. Then, two recurrent neural networks named long-short term memory (LSTM) and bidirectional gated recurrent unit (BiGRU) combined attention mechanism are used for feature fusion and classification, respectively. RESULTS: The accuracies of ENNAVIA-C and ENNAVIA-D datasets under the 10-fold cross-validation are 99.15% and 98.92%, respectively, and other evaluation indexes have also obtained satisfactory results. The experimental results show that our model is superior to other existing models. CONCLUSION: The iACVP-MR model can be viewed as a powerful and intelligent tool for the accurate identification of ACVP. The datasets and source codes for iACVP-MR are freely downloaded at https://github.com/yunyunliang88/iACVP-MR.

Progress of charge carrier dynamics and regulation strategies in 2D CxNy-based heterojunctions.

Two-dimensional carbon nitrides (CxNy) have gained significant attention in various fields including hydrogen energy development, environmental remediation, optoelectronic devices, and energy storage owing to their extensive surface area, abundant raw materials, high chemical stability, and distinctive physical and chemical characteristics. One effective approach to address the challenges of limited visible light utilization and elevated carrier recombination rates is to establish heterojunctions for CxNy-based single materials (e.g. C2N3, g-C3N4, C3N4, C4N3, C2N, and C3N). The carrier generation, migration, and recombination of heterojunctions with different band alignments have been analyzed starting from the application of CxNy with metal oxides, transition metal sulfides (selenides), conductive carbon, and Cx'Ny' heterojunctions. Additionally, we have explored diverse strategies to enhance heterojunction performance from the perspective of carrier dynamics. In conclusion, we present some overarching observations and insights into the challenges and opportunities associated with the development of advanced CxNy-based heterojunctions.

Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on Aß40 and Aß42 Cofibrillation.

The misfolding and aggregation of amyloid-ß (Aß) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Aß40 and Aß42, the two primary isoforms of Aß, can not only self-aggregate into homogeneous aggregates but also coaggregate to form mixed fibrils. Epigallocatechin-3-gallate (EGCG), a prominent tea polyphenol, has shown the capability to prevent the self-aggregation of Aß40 and Aß42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of Aß40 and Aß42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of Aß40 and Aß42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of Aß40 and Aß42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on Aß40 and Aß42 are the polar residues and aromatic residues, engaging in hydrogen-bond , π-π, and cation-π interactions with EGCG. Additionally, EGCG disaggregates the Aß40-Aß42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and Aß40-Aß42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of Aß isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.

The Inhibition Effect of Epigallocatechin-3-Gallate on the Co-Aggregation of Amyloid-ß and Human Islet Amyloid Polypeptide Revealed by Replica Exchange Molecular Dynamics Simulations.

Alzheimer's disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aß and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aß and hIAPP. We found that EGCG molecules substantially diminish the ß-sheet structures within the amyloid core regions of Aß and hIAPP in their co-aggregates. Through hydrogen-bond, π-π and cation-π interactions targeting polar and aromatic residues of Aß and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aß and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.