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"Wang, Guozhen"
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Propagation of aggregated p53: Cross-reaction and coaggregation vs. seeding
Destabilized mutant p53s coaggregate with WT p53, p63, and p73 in cancer cell lines. We found that stoichiometric amounts of aggregation-prone mutants induced only small amounts of WT p53 to coaggregate, and preformed aggregates did not significantly seed the aggregation of bulk protein. Similarly, p53 mutants trapped only small amounts of p63 and p73 into their p53 aggregates. Tetrameric full-length protein aggregated at similar rates and kinetics to isolated core domains, but there was some induced aggregation of WT by mutants in hetero-tetramers. p53 aggregation thus differs from the usual formation of amyloid fibril or prion aggregates where tiny amounts of preformed aggregate rapidly seed further aggregation. The proposed aggregation mechanism of p53 of rate-determining sequential unfolding and combination of two molecules accounts for the difference. A molecule of fast-unfolding mutant preferentially reacts with another molecule of mutant and only occasionally traps a slower unfolding WT molecule. The mutant population rapidly self-aggregates before much WT protein is depleted. Subsequently, WT protein self-aggregates at its normal rate. However, the continual production of mutant p53 in a cancer cell would gradually trap more and more WT and other proteins, accounting for the observations of coaggregates in vivo. The mechanism corresponds more to trapping by cross-reaction and coaggregation rather than classical seeding and growth.
Significance Aggregation of tumor suppressor p53 oncogenic mutants not only loses their activity but may also lead to gain of oncogenic function, possibly by coaggregation with other proteins. We explored how a destabilized p53 mutant may coaggregate with WT p53 and its homologs p63 and p73. The results are explained by the simple two-step initiation mechanism we proposed. Rather than the oncogenic mutant seeding coaggregation by a prion-like process, coaggregation results from the simultaneous unfolding and cross-reaction of WT and mutant molecules. Consequently, preformed p53 aggregate displays little seeding of aggregation of p53, and high concentrations of p53 mutants are required to trap WT p53 into aggregate. Coaggregation is predominantly by trapping rather than seeding and induced propagation.
Journal Article
An ecological assessment of the potential pandemic threat of Dengue Virus in Zhejiang province of China
Dengue fever, transmitted by Aedes mosquitoes, is a significant public health concern in tropical and subtropical regions. With the end of the COVID-19 pandemic and the reopening of the borders, dengue fever remains a threat to mainland China, Zhejiang province of China is facing a huge risk of importing the dengue virus. This study aims to analyze and predict the current and future potential risk regions for Aedes vectors distribution and dengue prevalence in Zhejiang province of China.
We collected occurrence records of DENV and DENV vectors globally from 2010 to 2022, along with historical and future climate data and human population density data. In order to predict the probability of DENV distribution in Zhejiang province of China under future conditions, the ecological niche of Ae. aegypti and Ae. albopictus was first performed with historical climate data based on MaxEnt. Then, predicted results along with a set of bioclimatic variables, elevation and human population density were included in MaxEnt model to analyze the risk region of DENV in Zhejiang province. Finally, the established model was utilized to predict the spatial pattern of DENV risk in the current and future scenarios in Zhejiang province of China.
Our findings indicated that approximately 89.2% (90,805.6 KM
) of Zhejiang province of China is under risk, within about 8.0% (8,144 KM
) classified as high risk area for DENV prevalence. Ae. albopictus were identified as the primary factor influencing the distribution of DENV. Future predictions suggest that sustainable and \"green\" development pathways may increase the risk of DENV prevalence in Zhejiang province of China. Conversely, Fossil-fueled development pathways may reduce the risk due to the unsuitable environment for vectors.
The implications of this research highlight the need for effective vector control measures, community engagement, health education, and environmental initiatives to mitigate the potential spread of dengue fever in high-risk regions of Zhejiang province of China.
Journal Article
Mechanism of initiation of aggregation of p53 revealed by Φ-value analysis
Significance The tumor suppressor p53 is inactivated by aggregation in a substantial number of tumors, and those oncogenic mutants coaggregate with WT protein and other tumor suppressors. Inhibition of aggregation by small molecules is a possible drug therapy. p53 aggregation appears to have much simpler kinetics than commonly encountered in fibrillation, with two rate-determining sequential, apparently first-order, steps. We showed by combining mutagenesis and kinetics that the rate determining steps involve two molecules of p53 extensively unfolding and reacting in a bimolecular process that can appear first order. The mechanism provides a basis for understanding the progress of aggregation and coaggregation and points to the most effective drug targeting sites.
Many oncogenic mutations inactivate the tumor suppressor p53 by destabilizing it, leading to its rapid aggregation. Small molecule drugs are being developed to stabilize such mutants. The kinetics of aggregation of p53 is deceptively simple. The initial steps in the micromolar concentration range follow apparent sigmoidal sequential first-order kinetics, with rate constants k ₁ and k ₂. However, the aggregation kinetics of a panel of mutants prepared for Φ-value analysis has now revealed a bimolecular reaction hidden beneath the observed first-order kinetics. Φ ᵤ measures the degree of local unfolding on a scale of 0–1. A number of sequential Φ ᵤ-values of ∼1 for k ₁ and k ₂ over the molecule implied more than one protein molecule must be reacting, which was confirmed by finding a clear concentration dependence at submicromolar protein. Numerical simulations showed that the kinetics of the more complex mechanism is difficult, if not impossible, to distinguish experimentally from simple first order under many reaction conditions. Stabilization of mutants by small molecules will be enhanced because they decrease both k ₁ and k ₂. The regions with high Φ ᵤ-values point to the areas where stabilization of mutant proteins would have the greatest effect.
Journal Article
Preparation of high-resolution micro/nano dot array by electrohydrodynamic jet printing with enhanced uniformity
The high-resolution array is the basic structure of most kinds of microelectronics. Electrohydrodynamic jet (E-Jet) printing technology is widely applied in manufacturing array structures with high resolution, high material compatibility and multi-modal printing. It is still challenging to acquire high uniformity of printed array with micro-nanometer resolution, which greatly influences the performance and lifetime of the microelectronics. In this paper, to improve the uniformity of the printed array, the influence of each parameter on the uniformity of the E-jet printed dot array is studied on the cobuilt NEJ-E/P200 experimental platform, finding the applied voltage plays the most important role in maintaining the uniformity of the printed array. By appropriately adjusting the printing parameters, the dot arrays with different resolutions from 500 pixels per inch (PPI) to 17,000 PPI are successfully printed. For arrays below and over 10,000 PPI, the deviations of the uniformity are within 5% and 10% respectively. In this work, the dot array over 15,000 PPI is first implemented using E-jet printing. The conclusions acquired by experimental analysis of dot array printing process are of great importance in high resolution array printing as it provides practical guidance for parameters adjustment.
Journal Article
First-order rate-determining aggregation mechanism of p53 and its implications
Aggregation of p53 is initiated by first-order processes that generate an aggregation-prone state with parallel pathways of major or partial unfolding. Here, we elaborate the mechanism and explore its consequences, beginning with the core domain and extending to the full-length p53 mutant Y220C. Production of large light-scattering particles was slower than formation of the Thiof lavin T-binding state and simultaneous depletion of monomer. EDTA removes Zn²⁺ to generate apo-p53, which aggregated faster than holoApo-Apo-p53 was not an obligatory intermediate in the aggregation of holo but affords a parallel pathway that may be relevant to oncogenic mutants with impaired Zn²⁺ binding. Full-length tetrameric Y220C formed the Thiof lavin T-binding state with similar rate constants to those of core domain, consistent with a unimolecular initiation that is unaffected by neighboring subunits, but very slowly formed small light-scattering particles. Apo-Y220C and aggregated holo-Y220C had little, if any, seeding effect on the initial polymerization of holo-Y220C (measured by Thiof lavin T binding), consistent with initiation being a unimolecular process. But apo-Y220C and aggregated holo-Y220C accelerated somewhat the subsequent formation of light-scattering particles from holo-protein, implying coaggregation. The implications for cancer cells containing wild-type and unstable mutant alleles are that aggregation of wild-type p53 (or homologs) might not be seeded by aggregated mutant, but it could coaggregate with p53 or other cellular proteins that have undergone the first steps of aggregation and speed up the formation of microscopically observable aggregates.
Journal Article
Treatment of organic pollutants in coke plant wastewater by micro-nanometer catalytic ozonation, A/A/O and reverse osmosis membrane
Abstract
Coking wastewater has a complex and highly concentrated chemical composition which is toxic and does not biodegrade easily. Treating the organic pollutants in this wastewater is very challenging. The toxic substances in this wastewater make traditional biotechnological treatments inefficient. Current wastewater treatment studies are based on unit processes, and no full process studies could be found. This study used the micro-nanometer catalytic ozonation process as a pretreatment unit, and reverse osmosis membrane treatment as a depth processing unit to improve the effect of the coking wastewater degradation. The micro-nanometer catalytic ozonation pretreatment greatly improves the biodegradability of the coking wastewater and promotes the coking wastewater degradation in the anoxia/anaerobic/oxic (A/A/O) system. The integrated coagulation air flotation-micro-nanometer catalytic ozonation-A/A/O–reverse osmosis membrane system can remove 98% of the chemical oxygen demand, which meets the direct emission standard of the new national standard (China). The dominant genera in the A/A/O biochemical reactor were Thioalkalimicrobium, Proteiniphilum, Azoarcu, Bacillus, Fontibacter, and Taibaiella. This work provides a novel approach for the degradation of high-concentration organic wastewater and lays a solid foundation for the restoration of environmental water bodies.
Journal Article
Kinetic mechanism of p53 oncogenic mutant aggregation and its inhibition
Aggregation of destabilized mutants of the tumor suppressor p53 is a major route for its loss of activity. In order to assay drugs that inhibit aggregation of p53, we established the basic kinetics of aggregation of its core domain, using the mutant Y220C that has a mutation-induced, druggable cavity. Aggregation monitored by light scattering followed lag kinetics. Electron microscopy revealed the formation of small aggregates that subsequently grew to larger amorphous aggregates. The kinetics of aggregation produced surprising results: progress curves followed either by the binding of Thioflavin T or the fluorescence of the protein at 340 nm fitted well to simple two-step sequential first-order lag kinetics with rate constants k ₁ and k ₂ that were independent of protein concentration, and not to classical nucleation-growth. We suggest a mechanism of first-order formation of an aggregation competent state as being rate determining followed by rapid polymerization with the higher order kinetics. By measuring the inhibition kinetics of k ₁ and k ₂, we resolved that the process with the higher rate constant followed that of the lower. Further, there was only partial inhibition of k ₁ and k ₂, which showed two parallel pathways of aggregation, one via a state that requires unfolding of the protein and the other of partial unfolding with the ligand still bound. Inhibition kinetics of ligands provides a useful tool for probing an aggregation mechanism.
Journal Article
Peptide Assembly of Al/CuO Nanothermite for Enhanced Reactivity of Nanoaluminum Particles
Biological self-assembly procedures, which are generally carried out in an aqueous solution, have been found to be the most promising method for directing the fabrication of diverse nanothermites, including Al/CuO nanothermite. However, the aqueous environment in which Al nanoparticles self-assemble has an impact on their stability. We show that using a peptide to self-assemble Al or CuO nanoparticles considerably improves their durability in phosphate buffer aqueous solution, with Al and CuO nanoparticles remaining intact in aqueous solution for over 2 weeks with minimal changes in the structure. When peptide-assembled Al/CuO nanothermite was compared with a physically mixed sample in phosphate buffer for 30 min, the energy release of the former was higher by 26%. Furthermore, the energy release of peptide-assembled Al/CuO nanocomposite in phosphate buffer showed a 6% reduction by Day 7, while that of the peptide-assembled Al/CuO nanocomposite in ultrapure water was reduced by 75%. Taken together, our study provides an easy method for keeping the thermal activity of Al/CuO nanothermite assembled in aqueous solution.
Journal Article
Hybrid Depth-Separable Residual Networks for Hyperspectral Image Classification
At present, the classification of the hyperspectral image (HSI) based on the deep convolutional network has made great progress. Due to the high dimensionality of spectral features, limited samples of ground truth, and high nonlinearity of hyperspectral data, effective classification of HSI based on deep convolutional neural networks is still difficult. This paper proposes a novel deep convolutional network structure, namely, a hybrid depth-separable residual network, for HSI classification, called HDSRN. The HDSRN model organically combines 3D CNN, 2D CNN, multiresidual network ROR, and depth-separable convolutions to extract deeper abstract features. On the one hand, due to the addition of multiresidual structures and skip connections, this model can alleviate the problem of over fitting, help the backpropagation of gradients, and extract features more fully. On the other hand, the depth-separable convolutions are used to learn the spatial feature, which reduces the computational cost and alleviates the decline in accuracy. Extensive experiments on the popular HSI benchmark datasets show that the performance of the proposed network is better than that of the existing prevalent methods.
Journal Article