The crotonylated and succinylated proteins of jujube involved in phytoplasma-stress responses.

BACKGROUND: Protein posttranslational modifications (PTMs) are fast and early responses to environmental changes, including pathogen infection. Jujube witches' broom (JWB) is a phytoplasma disease causing great economic loss in jujube production. After phytoplasma infection, the transcriptional, translational, and metabolic levels in jujube were activated, enabling it to survive during phytoplasma invasion. However, no study has yet reported on PTMs in jujube. Lysine crotonylation (Kcr) and lysine succinylation (Ksu) have been popular studies in recent years and their function in plant phytoplasma-stress responses remains unclear. RESULTS: Here, 1656 crotonylated and 282 succinylated jujube proteins were first identified under phytoplasma-stress, of which 198 were simultaneously crotonylated and succinylated. Comparative analysis revealed that 656 proteins, 137 crotonylated and 43 succinylated proteins in jujube were regulated by phytoplasma infection, suggesting that Kcr was more universal than Ksu. Kcr differentially expressed proteins (DEPs) were related to ribosomes, photosynthetic and carbon metabolism, while Ksu DEPs were mainly involved in carbon metabolism, the TCA cycle and secondary metabolite biosynthesis. The crosstalk network among proteome, crotonylome and succinylome showed that DEPs related to ribosomal, peroxidases and glutathione redox were enriched. Among them, ZjPOD51 and ZjPHGPX2 significantly increased at the protein and Kcr level under phytoplasma-stress. Notably, 7 Kcr sites were identified in ZjPHGPX2, a unique antioxidant enzyme. After inhibitor nicotinamide (NAM) treatment, GPX enzyme activity in jujube seedlings was reduced. Further, site-directed mutagenesis of key Kcr modification sites K130 and/or K135 in ZjPHGPX2 significantly reduced its activity. CONCLUSIONS: This study firstly provided large-scale datasets of Kcr and Ksu in phytoplasma-infected jujube and revealed that Kcr modification in ZjPHGPX2 positively regulates its activity.

Recent developments in the enzymatic modifications of steroid scaffolds.

Steroids are an important family of bioactive compounds. Steroid drugs are renowned for their multifaceted pharmacological activities and are the second-largest category in the global pharmaceutical market. Recent developments in biocatalysis and biosynthesis have led to the increased use of enzymes to enhance the selectivity, efficiency, and sustainability for diverse modifications of steroids. This review discusses the advancements achieved over the past five years in the enzymatic modifications of steroid scaffolds, focusing on enzymatic hydroxylation, reduction, dehydrogenation, cascade reactions, and other modifications for future research on the synthesis of novel steroid compounds and related drugs, and new therapeutic possibilities.

Glycosylase-based base editors for efficient T-to-G and C-to-G editing in mammalian cells.

Base editors show promise for treating human genetic diseases, but most current systems use deaminases, which cause off-target effects and are limited in editing type. In this study, we constructed deaminase-free base editors for cytosine (DAF-CBE) and thymine (DAF-TBE), which contain only a cytosine-DNA or a thymine-DNA glycosylase (CDG/TDG) variant, respectively, tethered to a Cas9 nickase. Multiple rounds of mutagenesis by directed evolution in Escherichia coli generated two variants with enhanced base-converting activity-CDG-nCas9 and TDG-nCas9-with efficiencies of up to 58.7% for C-to-A and 54.3% for T-to-A. DAF-BEs achieve C-to-G/T-to-G editing in mammalian cells with minimal Cas9-dependent and Cas9-independent off-target effects as well as minimal RNA off-target effects. Additional engineering resulted in DAF-CBE2/DAF-TBE2, which exhibit altered editing windows from the 5' end to the middle of the protospacer and increased C-to-G/T-to-G editing efficiency of 3.5-fold and 1.2-fold, respectively. Compared to prime editing or CGBEs, DAF-BEs expand conversion types of base editors with similar efficiencies, smaller sizes and lower off-target effects.

Generation estimation and metals recycling potentials evaluation of retired mobile phones in Korea.

The goal of this work is to evaluate generation and metals recycling potentials of retired mobile phones in Korea. The generation estimation is conducted with the sales&new method and statistic data, such as sales of mobile phones and amount of the subscribers. The result shows that there are 17.99 million of mobile phones retired in 2022, compared 13.12 million in 2001. Accordingly, the deduced lifetime has minimum and maximum values in 2003 and 2020, which are 2.02 and 4.33 years, compared with 4.16 years in 2022 and 2.21 years in 2001. The deduced lifetime trends to increase with the increased values of subscribers and the fluctuated values of sales. The crosscheck testifies to the veracity of the result in comparison with the actual condition. The amount and dynamic of critical metals are also calculated with the content and amount of retired mobile phones.

Projecting future labor losses due to heat stress in China under climate change scenarios.

Climate change is expected to increase occupational heat stress, which will lead to diminished work performance and labor losses worldwide. However, sub-regional analyses remain insufficient, especially for countries with a heterogeneous spatial distribution of working populations, industries and climates. Here, we projected heat-induced labor losses in China, by considering local climate simulations, working population characteristics and developing an exposure-response function suitable for Chinese workers. We showed that the annual heat-induced work hours lost (WHL), compared to the baseline of 21.3 billion hours, will increase by 121.1% (111.2%-131.1%), 10.8% (8.3%-15.3%), and -17.8% (-15.3%--20.3%) by the end of the century under RCP(Representative Concentration Pathways)8.5, RCP4.5, and RCP2.6, respectively. We observed an approximately linear upward trend of WHL under RCP8.5, despite the decrease in future working population. Notably, WHL will be most prominent in the southern, eastern and central regions, with Guangdong and Henan accounting for a quarter of national total losses; this is largely due to their higher temperature exposure, larger population size, and higher shares of vulnerable population in total employment. In addition, limiting global warming to 1.5 °C would yield substantial gains. Compared to RCP2.6, RCP4.5, and RCP8.5, all provinces can avoid an average of 11.8%, 33.7%, and 53.9% of annual WHL if the 1.5 °C target is achieved, which is equivalent to avoiding 0.1%, 0.6%, and 1.4% of annual GDP losses in China, respectively. This study revealed climate change will exacerbate future labor losses, and adverse impacts can be minimized by adopting stringent mitigation policies coupled with effective adaptation measures. Policymakers in each province should tailor occupation health protection measures to their circumstances.

Few-shot remote sensing scene classification based on multi subband deep feature fusion.

Recently, convolutional neural networks (CNNs) have performed well in object classification and object recognition. However, due to the particularity of geographic data, the labeled samples are seriously insufficient, which limits the practical application of CNN methods in remote sensing (RS) image processing. To address the problem of small sample RS image classification, a discrete wavelet-based multi-level deep feature fusion method is proposed. First, the deep features are extracted from the RS images using pre-trained deep CNNs and discrete wavelet transform (DWT) methods. Next, a modified discriminant correlation analysis (DCA) approach is proposed to distinguish easily confused categories effectively, which is based on the distance coefficient of between-class. The proposed approach can effectively integrate the deep feature information of various frequency bands. Thereby, the proposed method obtains the low-dimensional features with good discrimination, which is demonstrated through experiments on four benchmark datasets. Compared with several state-of-the-art methods, the proposed method achieves outstanding performance under limited training samples, especially one or two training samples per class.

Virus-Induced Gene Silencing (VIGS) in Chinese Jujube.

Virus-induced gene silencing (VIGS) is a fast and efficient method for assaying gene function in plants. At present, the VIGS system mediated by Tobacco rattle virus (TRV) has been successfully practiced in some species such as cotton and tomato. However, little research of VIGS systems has been reported in woody plants, nor in Chinese jujube. In this study, the TRV-VIGS system of jujube was firstly investigated. The jujube seedlings were grown in a greenhouse with a 16 h light/8 h dark cycle at 23 °C. After the cotyledon was fully unfolded, Agrobacterium mixture containing pTRV1 and pTRV2-ZjCLA with OD600 = 1.5 was injected into cotyledon. After 15 days, the new leaves of jujube seedlings showed obvious photo-bleaching symptoms and significantly decreased expression of ZjCLA, indicating that the TRV-VIGS system had successfully functioned on jujube. Moreover, it found that two injections on jujube cotyledon could induce higher silencing efficiency than once injection. A similar silencing effect was then also verified in another gene, ZjPDS. These results indicate that the TRV-VIGS system in Chinese jujube has been successfully established and can be applied to evaluate gene function, providing a breakthrough in gene function verification methods.

The genome of Candidatus phytoplasma ziziphi provides insights into their biological characteristics.

Phytoplasmas are obligate cell wall-less prokaryotic bacteria that primarily multiply in plant phloem tissue. Jujube witches' broom (JWB) associated with phytoplasma is a destructive disease of jujube (Ziziphus jujuba Mill.). Here we report the complete 'Candidatus Phytoplasma ziziphi' chromosome of strain Hebei-2018, which is a circular genome of 764,108-base pairs with 735 predicted CDS. Notably, extra 19,825 bp (from 621,995 to 641,819 bp) compared to the previously reported one complements the genes involved in glycolysis, such as pdhA, pdhB, pdhC, pdhD, ackA, pduL and LDH. The synonymous codon usage bias (CUB) patterns by using comparative genomics analysis among the 9 phytoplasmas were similar for most codons. The ENc-GC3s analysis among the 9 phytoplasmas showed a greater effect under the selection on the CUBs of phytoplasmas genes than mutation and other factors. The genome exhibited a strongly reduced ability in metabolic synthesis, while the genes encoding transporter systems were well developed. The genes involved in sec-dependent protein translocation system were also identified.The expressions of nine FtsHs encoding membrane associated ATP-dependent Zn proteases and Mn-SodA with redox capacity in the Ca. P. ziziphi was positively correlated with the phytoplasma concentration. Taken together, the genome will not only expand the number of phytoplasma species and provide some new information about Ca. P. ziziphi, but also contribute to exploring its pathogenic mechanism.

Genome-wide characterization of the cellulose synthase gene family in Ziziphus jujuba reveals its function in cellulose biosynthesis during fruit development.

The cellulose synthase (Ces/Csl) is a key enzyme in plant cellulose synthesis. Jujube fruits are rich in cellulose. 29 ZjCesA/Csl genes were identified in jujube genome and showed tissue-specific expression. 13 genes highly expressed in jujube fruit exhibited obviously sequential expressions during the fruit development, indicating that they might play distinct roles during the process. Meanwhile, the correlation analysis showed the expressions of ZjCesA1 and ZjCslA1 were significant positive related to the cellulose synthase activities. Furthermore, transient overexpressions of ZjCesA1 or ZjCslA1 in jujube fruits significantly increased cellulose synthase activities and contents, whereas silencing of ZjCesA1 or ZjCslA1 in jujube seedlings obviously reduced cellulose levels. Moreover, the Y2H assays verified that ZjCesA1 and ZjCslA1 may participate in cellulose synthesis by forming protein complexes. The study not only reveals the bioinformatics characteristics and functions of cellulose synthase genes in jujube, but also provides clues for studying cellulose synthesis in other fruits.

A novel NADH-dependent leucine dehydrogenase for multi-step cascade synthesis of L-phosphinothricin.

L-Phosphinothricin (L-PPT) is the effective constituent in racemic PPT (a high-efficiency and broad-spectrum herbicide), and the exploitation of green and sustainable synthesis route for L-PPT has always been the focus in pesticide industry. In recent years, "one-pot, two-step" enzyme-mediated cascade strategy is a mainstream pathway to obtain L-PPT. Herein, RgDAAO and BsLeuDH were applied to expand "one-pot, two-step" process. Notably, a NADH-dependent leucine dehydrogenase from Bacillus subtilis (BsLeuDH) was firstly characterized and attempted to generate L-PPT, achieving an excellent enantioselectivity (99.9% ee). Meanwhile, a formate dehydrogenase from Pichia pastoris (PpFDH) was utilized to implement NADH cofactor regeneration and only CO2 was by-product. Sufficient amount of the corresponding keto acid precursor PPO was obtained by oxidation of D-PPT relying on a D-amino acid oxidase from Rhodotorula gracilis (RgDAAO) with content conversion (46.1%). L-PPT was ultimately prepared from racemized PPT via oxidative deamination catalyzed by RgDAAO and reductive amination catalyzed by BsLeuDH, achieving 80.3% overall yield and > 99.9% ee value.

Underwater image enhancement based on color correction and complementary dual image multi-scale fusion.

Underwater images often suffer from color cast, poor contrast, and detail loss owing to the scattering and absorption of light in water. To solve these problems, we propose what we believe to be a novel underwater image enhancement method based on color correction and dual image multi-scale fusion. We first use the color correction method to solve the problem of color cast, and we compensate the other two-color channels with the highest mean value color channel; further, all the color channels are dynamically stretched. Next, a complementary dual image multi-scale fusion method is used to improve the contrast, pairs of complementary adaptive gamma correction with weighted distribution enhanced images are used as the two inputs of multi-scale fusion, and appropriate weight maps are selected. Then, a multi-scale detail-sharpening method is used to enhance the image details. Qualitative and quantitative evaluations prove that the proposed method can produce high-quality underwater images. Moreover, the proposed method has relatively high evaluator values compared to the state-of-the-art methods.

Projections of heatwave-attributable mortality under climate change and future population scenarios in China.

Background: In China, most previous projections of heat-related mortality have been based on modeling studies using global climate models (GCMs), which can help to elucidate the risks of extreme heat events in a changing climate. However, spatiotemporal changes in the health effects of climate change considering specific regional characteristics remain poorly understood. We aimed to use credible climate and population projections to estimate future heatwave-attributable deaths under different emission scenarios and to explore the drivers underlying these patterns of changes. Methods: We derived climate data from a regional climate model driven by three CMIP5 GCM models and calculated future heatwaves in China under Representative Concentration Pathway (RCP) 2.6, RCP4.5, and RCP8.5. The future gridded population data were based on Shared Socioeconomic Pathway 2 assumption with different fertility rates. By applying climate zone-specific exposure-response functions to mortality during heatwave events, we projected the scale of heatwave-attributable deaths under each RCP scenario. We further analyzed the factors driving changes in heatwave-related deaths and main sources of uncertainty using a decomposition method. We compared differences in death burden under the 1.5°C target, which is closely related to achieving carbon neutrality by mid-century. Findings: The number of heatwave-related deaths will increase continuously to the mid-century even under RCP2.6 and RCP4.5 scenarios, and will continue increasing throughout the century under RCP8.5. There will be 20,303 deaths caused by heatwaves in 2090 under RCP2.6, 35,025 under RCP4.5, and 72,260 under RCP8.5, with half of all heatwave-related deaths in any scenario concentrated in east and central China. Climate effects are the main driver for the increase in attributable deaths in the near future till 2060, explaining 78% of the total change. Subsequent population decline cannot offset the losses caused by higher incidence of heatwaves and an aging population under RCP8.5. Although health loss under the 1.5°C warming scenario is 1.6-fold higher than the baseline period 1986-2005, limiting the temperature rise to 1.5°C can reduce the annual mortality burden in China by 3,534 deaths in 2090 compared with RCP2.6 scenarios. Interpretation: With accelerating climate change and population aging, the effects of future heatwaves on human health in China are likely to increase continuously even under a low emission scenario. Significant health benefits are expected if the optimistic 1.5°C goal is achieved, suggesting that carbon neutrality by mid-century is a critical target for China's sustainable development. Policymakers need to tighten climate mitigation policies tailored to local conditions while enhancing climate resilience technically and infrastructurally, especially for vulnerable elderly people. Funding: National Key R&D Program of China (2018YFA0606200), Wellcome Trust (209734/Z/17/Z), Natural Science Foundation of China (41790471), and Guangdong Major Project of Basic and Applied Basic Research (2020B0301030004).

Efficient synthesis of an apremilast precursor and chiral ß-hydroxy sulfones via ketoreductase-catalyzed asymmetric reduction.

Ketoreductase (KRED)-catalyzed asymmetric reduction of prochiral ketones is an attractive method to synthesize chiral alcohols. Herein, two KREDs LfSDR1-V186A/E141I and CgKR1-F92I with complementary stereopreference were identified towards reduction of apremilast prochiral ketone intermediate 1a. LfSDR1-V186A/E141I exhibited >99% conversion and 99.2% ee yielding an apremilast chiral alcohol intermediate ((R)-2a) at 50 g L-1 substrate loading. Furthermore, we investigated the substrate scope of ß-keto sulfones by using LfSDR1-V186A/E141I and CgKR1-F92I to produce both enantiomers of the corresponding ß-hydroxy sulfones, with good-to-excellent conversion (up to >99%) and enantioselectivity (up to 99.9% ee) being obtained in most cases. Finally, the gram-scale synthesis of (R)-2a was performed by employing the crude enzyme of LfSDR1-V186A/E141I and BsGDH to afford the desired enantiomer with >99% conversion, 85.9% isolated yield and 99.2% ee. This study presents a biocatalytic strategy to synthesize chiral ß-hydroxy sulfones.

Remaining Useful Life prediction of rolling bearings based on risk assessment and degradation state coefficient.

Prediction of Remaining Useful Life (RUL) of bearings is very important for the condition-based maintenance of the rotating machinery. In order to predict the RUL more accurately, an approach of RUL prediction based on risk assessment and degradation state coefficient is proposed. The Mahalanobis Distance (MD) is calculated depending on the characteristics of vibration signals in the time domain and time-frequency domain. The features in the time-frequency domain are extracted by using Variational Mode Decomposition-Singular Value Decomposition (VMD-SVD). The monotonously increasing Health Indicator (HI) is obtained by using MD1-CUMSUM. The risk assessment is proposed to adaptively determine the thresholds of initial fault and failure, which is a trade-off between the false alarm rate and sensitivity. The RUL prediction of the testing bearing is completed based on the Genetic Algorithm-Support Vector Regression (GA-SVR) and Modified Health Indicator (MHI) with the degradation state coefficient. The proposed approach is verified by using two experimental vibration signal datasets. The results show that the proposed method has good capability to predict the RUL of rolling bearings.

A base-mediated aerobic oxidative synthesis of cyclopent-2-enol derivatives from doubly activated cyclopropanes and substituted acetonitriles.

We report here that polysubstituted cyclopent-2-enols can be constructed by the one-pot reaction of doubly activated cyclopropanes and α-EWG substituted acetonitriles under mild basic conditions via a domino-ring-opening-cyclization/deacylation/oxidation sequence. Moreover, the synthetic applications of these cyclopent-2-enols have been demonstrated in the late-stage derivatization into functionalized cyclopentapyrimidin-4-ones and 2-hydroxy cyclopentanones with good yields.

Aberrant branches of the subclavian artery and their relationship with the phrenic nerve and the brachial plexus / Ramas aberrantes de la arteria subclavia y su relación con el nervio frénico y el plexo braquial

SUMMARY: Variations in subclavian artery branches are relatively common and may impact surgical procedures and effects. During educational dissection of a male cadaver, we encountered an extremely rare variation of the right subclavian artery branches. The internal thoracic artery, the thyrocervical trunk, and the costocervical trunk arose from the third part of the right subclavian artery. In addition, the phrenic nerve displaced remarkably laterally by the thyrocervical trunk, and the course of the costocervical trunk was between the upper trunk and the middle trunk of the brachial plexus. These variations may pose a potential risk for nerve compression and increase the risk of arterial and nerve puncture. This case report would bring attention to the possibility of other similar cases, and early detection of these variations through diagnostic interventions is helpful to reduce postoperative complications.

RESUMEN: Las variaciones en las ramas de la arteria subclavia son relativamente comunes y pueden afectar los procedimientos y efectos quirúrgicos. Durante la disección educativa de un cadáver masculino, encontramos una variación extremadamente rara de las ramas de la arteria subclavia derecha. La arteria torácica interna, el tronco tirocervical y el tronco costocervical nacían de la tercera parte de la arteria subclavia derecha. Además, el nervio frénico se desplazaba lateralmente por el tronco tirocervical, y el trayecto del tronco costocervical se encontraba entre el tronco superior y el tronco medio del plexo braquial. Estas variaciones pueden suponer un riesgo potencial de compresión nerviosa y aumentar el riesgo de punción arterial y nerviosa. Este reporte de caso llamaría la atención sobre la posibilidad de otros casos similares, y la detección temprana de estas variaciones a través de diagnósticos es útil para reducir las complicaciones postoperatorias.

Selectivity mechanism of phosphodiesterase isoform inhibitor through in silico investigations.

Understanding the selectivity mechanism of inhibitors towards homology proteins helps to design selective candidates. Phosphodiesterase (PDE) family members act in the degradation of cAMP and cGMP, among which some isoforms such as PDE9A are attracting interest for Alzheimer's disease treatment, while PDE10A is used as target for treating schizophrenia. In this study, computational methods were used to investigate the major features of PDE9A/10A, with the purpose to provide deep understanding of the molecular mechanism of selective inhibition towards these two isoforms. Our result revealed that two conserved residues Gln453 and Phe456 were proven to be crucial for the binding affinity and inhibitory selectivity of PDE9A inhibitors. In addition, the high-affinity PDE9A inhibitors always interact with the conservative hydrophobic pocket as well as Tyr424 and Ala452 of PDE9A, while PDE10A selective inhibitors need to have two hydrophobic groups and two hydrogen bond donors to interact with the conservative Tyr693, Gln726, and Phe729 of PDE10A. This study provides valuable insights into the underlying mechanism of selective inhibition targeting PDE9A and PDE10A, for further search for potent and highly selective PDE9A/10A inhibitors.

Identification of four ene reductases and their preliminary exploration in the asymmetric synthesis of (R)-dihydrocarvone and (R)-profen derivatives.

The ene reductases (ERs) from the old yellow enzymes (OYEs) family have the ability to reduce activated alkenes to generate up to two stereocenters, therefore they have been received extensive attention as powerful biocatalysts. In this study, through gene mining, four ERs were identified from the genomes of Ensifer adhaerens, Pseudomonas fluorescens, and Pseudomonas veronil. The biocatalytic properties of these four ERs were identified, and their applications in the synthesis process of dihydrocarvone and profen derivatives were further evaluated. Among them, three ERs (EaER2, PvER1, and PvER2) belonging to the classic OYEs showed the best catalytic activity at 30 °C and pH 7.0 (100 mM potassium phosphate buffer) and the PfER2, which belongs to the thermophilic-like OYEs exhibited the best catalytic at 40 °C and pH 7.0 (100 mM potassium phosphate buffer). When exploring the influence of organic solvents on the catalytic efficiency, it was found that the four ERs were more sensitive to toluene and had tolerance to several other selected organic solvents. In addition, EaER2, PfER2, PvER1 and PvER2 showed excellent catalytic activity toward carvone, and the stereoselectivity of PvER2 toward carvone could reach up to 88.7 % de. EaER2 and PfER2 can catalyze the synthesis of a variety of profen derivatives with a stereoselectivity over 99 % ee. Moreover, through homology modeling and molecular docking, we preliminarily explained the mechanism of catalytic activity and stereoselectivity of the four ERs, which provided a solid base on the rational design of their stereo-preference in the future. The discovery of EaER2, PfER2, PvER1, and PvER2 provides four new enzyme sources for the study of the OYEs family and enriches the biocatalytic toolbox of ERs. Our exploration of the enzymatic properties of these four ERs will provide the sufficient data basis for future research and industrialization progress.

Jasmonic Acid and Ethylene Participate in the Gibberellin-Induced Ovule Programmed Cell Death Process in Seedless Pear '1913' (Pyrus hybrid).

Seedless fruit is a feature appreciated by consumers. The ovule abortion process is highly orchestrated and controlled by numerous environmental and endogenous signals. However, the mechanisms underlying ovule abortion in pear remain obscure. Here, we found that gibberellins (GAs) have diverse functions during ovules development between seedless pear '1913' and seeded pear, and that GA4+7 activates a potential programmed cell death process in '1913' ovules. After hormone analyses, strong correlations were determined among jasmonic acid (JA), ethylene and salicylic acid (SA) in seedless and seeded cultivars, and GA4+7 treatments altered the hormone accumulation levels in ovules, resulting in significant correlations between GA and both JA and ethylene. Additionally, SA contributed to ovule abortion in '1913'. Exogenously supplying JA, SA or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid promoted 'Bartlett' seed death. The regulatory mechanism in which ethylene controls ovule death has been demonstrated; therefore, JA's role in regulating '1913' ovule abortion was investigated. A further study identified that the JA signaling receptor MYC2 bound the SENESCENCE-ASSOCIATED 39 promoter and triggered its expression to regulate ovule abortion. Thus, we established ovule abortion-related relationships between GA and the hormones JA, ethylene and SA, and we determined their synergistic functions in regulating ovule death.

Rational design of selective HDAC2 inhibitors for liver cancer treatment: computational insights into the selectivity mechanism through molecular dynamics simulations and QM/MM calculations.

The rational design of selective histone deacetylase 2 (HDAC2) inhibitors is beneficial for the therapeutic treatment of liver cancer, though HDAC2 is highly homologous to HDAC8, which may lead to undesired side effects due to the pan-inhibition towards HDAC2 and HDAC8. To clarify the structural basis of selective inhibition towards HDAC2 over HDAC8, we utilized multiple in silico strategies, including sequence alignment, structural comparison, molecular docking, molecular dynamics simulations, free energy calculations, alanine scanning mutagenesis, pharmacophore modeling, protein contacts atlas analysis and QM/MM calculations to study the binding patterns of HDAC2/8 selective inhibitors. Through the whole process described above, it is found that although HDAC2 has conserved GLY154 and PHE210 that also exist within HDAC8, namely GLY151 and PHE208, the two isoforms exhibit diverse binding modes towards their inhibitors. Typically, HDAC2 inhibitors interact with the Zn2+ ions through the core chelate group, while HDAC8 inhibitors adopt a bent conformation within the HDAC8 pocket that inclines to be in contact with the Zn2+ ions through the terminal hydroxamic acid group. In summary, our data comprehensively elucidate the selectivity mechanism towards HDAC2 over HDAC8, which would guide the rational design of selective HDAC2 inhibitors for liver cancer treatment.