ChemMORT: an automatic ADMET optimization platform using deep learning and multi-objective particle swarm optimization.

Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.

RSS and ROS Sequentially Activated Carbon Monoxide Release for Boosting NIR Imaging-Guided On-Demand Photodynamic Therapy.

Carbon monoxide shows great therapeutic potential in anti-cancer. In particular, the construction of multifunctional CO delivery systems can promote the precise delivery of CO and achieve ideal therapeutic effects, but there are still great challenges in design. In this work, a RSS and ROS sequentially activated CO delivery system is developed for boosting NIR imaging-guided on-demand photodynamic therapy. This designed system is composed of a CO releaser (BOD-CO) and a photosensitizer (BOD-I). BOD-CO can be specifically activated by hydrogen sulfide with simultaneous release of CO donor and NIR fluorescence that can identify H2S-rich tumors and guide light therapy, also depleting H2S in the process. Moreover, BOD-I generates 1O2 under long-wavelength light irradiation, enabling both PDT and precise local release of CO via a photooxidation mechanism. Such sequential activation of CO release by RSS and ROS ensured the safety and controllability of CO delivery, and effectively avoided leakage during delivery. Importantly, cytotoxicity and in vivo studies reveal that the release of CO combined with the depletion of endogenous H2S amplified PDT, achieving ideal anticancer results. It is believed that such theranostic nanoplatform can provide a novel strategy for the precise CO delivery and combined therapy involved in gas therapy and PDT.

ABC-Net: a divide-and-conquer based deep learning architecture for SMILES recognition from molecular images.

Structural information for chemical compounds is often described by pictorial images in most scientific documents, which cannot be easily understood and manipulated by computers. This dilemma makes optical chemical structure recognition (OCSR) an essential tool for automatically mining knowledge from an enormous amount of literature. However, existing OCSR methods fall far short of our expectations for realistic requirements due to their poor recovery accuracy. In this paper, we developed a deep neural network model named ABC-Net (Atom and Bond Center Network) to predict graph structures directly. Based on the divide-and-conquer principle, we propose to model an atom or a bond as a single point in the center. In this way, we can leverage a fully convolutional neural network (CNN) to generate a series of heat-maps to identify these points and predict relevant properties, such as atom types, atom charges, bond types and other properties. Thus, the molecular structure can be recovered by assembling the detected atoms and bonds. Our approach integrates all the detection and property prediction tasks into a single fully CNN, which is scalable and capable of processing molecular images quite efficiently. Experimental results demonstrate that our method could achieve a significant improvement in recognition performance compared with publicly available tools. The proposed method could be considered as a promising solution to OCSR problems and a starting point for the acquisition of molecular information in the literature.

Isotropic Quantum Griffiths Singularity in Nd_{0.8}Sr_{0.2}NiO_{2} Infinite-Layer Superconducting Thin Films.

This work reports on the emergence of quantum Griffiths singularity (QGS) associated with the magnetic field induced superconductor-metal transition (SMT) in unconventional Nd_{0.8}Sr_{0.2}NiO_{2} infinite layer superconducting thin films. The system manifests isotropic SMT features under both in-plane and perpendicular magnetic fields. Importantly, after scaling analysis of the isothermal magnetoresistance curves, the obtained effective dynamic critical exponents demonstrate divergent behavior when approaching the zero-temperature critical point B_{c}^{*}, identifying the QGS characteristics. Moreover, the quantum fluctuation associated with the QGS can quantitatively explain the upturn of the upper critical field around zero temperature for both the in-plane and perpendicular magnetic fields in the phase boundary of SMT. These properties indicate that the QGS in the Nd_{0.8}Sr_{0.2}NiO_{2} superconducting thin film is isotropic. Moreover, a higher magnetic field gives rise to a metallic state with the resistance-temperature relation R(T) exhibiting lnT dependence among the 2-10 K range and T^{2} dependence of resistance below 1.5 K, which is significant evidence of Kondo scattering. The interplay between isotropic QGS and Kondo scattering in the unconventional Nd_{0.8}Sr_{0.2}NiO_{2} superconductor can illustrate the important role of rare region in QGS and help to uncover the exotic superconductivity mechanism in this system.

[Study on anti-inflammatory activity of phenolic acids from Leucas ciliata].

The chemical constituents from Leucas ciliata belonging to Leucas genus in Lamiaceae were systematically explored by silica gel column chromatography, ODS column chromatography, Sephadex LH-20 gel column chromatography, and preparative high performance liquid chromatography, and seventeen phenolic acids were isolated. The chemical structures of the compounds were identified by their physicochemical properties, spectroscopic data, and literature. They were 4-hydroxyphenethyl ethyl succinate(1), 4-hydroxyphenethyl methyl succinate(2), 2-(4-hydroxyphenyl) ethyl acetate(3), p-hydroxyphenylethyl anisate(4), cassia cis-trans diphenylpropanoid(5), p-coumaric acid(6), 3,4-dihydroxybenzenepropionic acid methyl ester(7), caffeic acid(8), trans-p-hydroxyl ethyl cinnamate(9), methyl p-hydroxybenzeneacetate(10), 4-hydroxyphenethyl alcohol(11), syringic acid(12), vanillin(13), protocatechuic acid(14), salicylic acid(15), p-hydroxybenzaldehyde(16), and diorcinol(17). Among them, compound 1 was new, and compounds 2-10, 12, 14, and 16-17 were isolated from the plants belonging to Leucas genus for the first time. All compounds were obtained from L. ciliata for the first time. The anti-inflammatory activity of compounds 1-17 on NO production in lipopolysaccharide(LPS)-induced mouse leukemia cells of monocyte macrophage(RAW264. 7) cells was evaluated. The results showed that compounds 5, 7, and 9 exhibited significant anti-inflammatory activity, with IC50values of(10. 14±0. 36)-(21. 17±0. 11) µmol·L~(-1).

MG-BERT: leveraging unsupervised atomic representation learning for molecular property prediction.

MOTIVATION: Accurate and efficient prediction of molecular properties is one of the fundamental issues in drug design and discovery pipelines. Traditional feature engineering-based approaches require extensive expertise in the feature design and selection process. With the development of artificial intelligence (AI) technologies, data-driven methods exhibit unparalleled advantages over the feature engineering-based methods in various domains. Nevertheless, when applied to molecular property prediction, AI models usually suffer from the scarcity of labeled data and show poor generalization ability. RESULTS: In this study, we proposed molecular graph BERT (MG-BERT), which integrates the local message passing mechanism of graph neural networks (GNNs) into the powerful BERT model to facilitate learning from molecular graphs. Furthermore, an effective self-supervised learning strategy named masked atoms prediction was proposed to pretrain the MG-BERT model on a large amount of unlabeled data to mine context information in molecules. We found the MG-BERT model can generate context-sensitive atomic representations after pretraining and transfer the learned knowledge to the prediction of a variety of molecular properties. The experimental results show that the pretrained MG-BERT model with a little extra fine-tuning can consistently outperform the state-of-the-art methods on all 11 ADMET datasets. Moreover, the MG-BERT model leverages attention mechanisms to focus on atomic features essential to the target property, providing excellent interpretability for the trained model. The MG-BERT model does not require any hand-crafted feature as input and is more reliable due to its excellent interpretability, providing a novel framework to develop state-of-the-art models for a wide range of drug discovery tasks.

Design and synthesis of chromone-nitrogen mustard derivatives and evaluation of anti-breast cancer activity.

Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC50 values of 1.83 and 1.90 µM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.

DFT Investigation of Hydrogen Atom Abstraction from NHC-Boranes by Methyl, Ethyl and Cyanomethyl Radicals-Composition and Correlation Analysis of Kinetic Barriers.

Understanding the hydrogen atom abstraction (HAA) reactions of N-heterocyclic carbene (NHC)-boranes is essential for extending the practical applications of boron chemistry. In this study, density functional theory (DFT) computations were performed for the HAA reactions of a series of NHC-boranes attacked by •CH2CN, Me• and Et• radicals. Using the computed data, we investigated the correlations of the activation and free energy barriers with their components, including the intrinsic barrier, the thermal contribution of the thermodynamic reaction energy to the kinetic barriers, the activation Gibbs free energy correction and the activation zero-point vibrational energy correction. Furthermore, to describe the dependence of the activation and free energy barriers on the thermodynamic reaction energy or reaction Gibbs free energy, we used a three-variable linear model, which was demonstrated to be more precise than the two-variable Evans-Polanyi linear free energy model and more succinct than the three-variable Marcus-theory-based nonlinear HAA model. The present work provides not only a more thorough understanding of the compositions of the barriers to the HAA reactions of NHC-boranes and the HAA reactivities of the substrates but also fresh insights into the suitability of various models for describing the relationships between the kinetic and thermodynamic physical quantities.

Does the Neophyl-like Rearrangement Play a Decisive Role in Intramolecular Cyclization of Iminyl Radicals? A Combined Quantum Chemistry and Numerical Simulation Investigation of the Cyclization Mechanism and Product Distributions of Bicyclic 2-Allyl-2-methyl-2,3-dihydro-1 H-inden-1-iminyl Radical and Several Iminyl Model Compounds.

In this study, we performed a theoretical investigation of the intramolecular cyclization of bicyclic 2-allyl-2-methyl-2,3-dihydro-1 H-inden-1-iminyl radical 1 along with several iminyl model compounds. The results were used to comparatively evaluate the reaction mechanism suggested previously, in which the neophyl-like rearrangement was deemed to play a decisive role. The present computation and numerical simulation identify the experimentally observed endo product in the high-temperature cyclization of 1. The product results from a kinetically controlled endo cyclization-reduction pathway involving an initial reversible 5- exo ring-closure/ring-opening process, not via 5- exo cyclization/neophyl-like rearrangement/ endo-radical reduction pathway as proposed previously. Considering many available theoretical and experimental results, the neophyl-like rearrangement seems to play only a minor role in the intramolecular cyclization of N- and C-centered radicals. The structural effect of cyclized radical intermediates of bicyclic 1 leads to a lower thermodynamic reaction energy of exo cyclization than of endo cyclization, which together with the temperature effect should be responsible for the formation of the dominant endo product in the high-temperature region. Additionally, this investigation provided further insight into the cyclization of 1 and compounds structurally similar to 1; that is, control of endo- or exo-regioselective products is readily available by regulating the reaction temperature.

The Synthesis and Evaluation of Arctigenin Amino Acid Ester Derivatives.

The use of arctigenin (ARG), a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of ARG have been synthesized using glycine, o-alanine, valine, leucine, and isoleucine, which have t-butyloxy carbonyl (BOC) as a protective group. In this study, we examined the effects of removing these protective groups. The results showed that the amino acid derivatives have better solubility and nitrite-clearing ability than ARG. Among the compounds tested, the amino acid derivatives without protective group were the best. Based on these results, ARG and its two amino acid derivatives without protective group (ARG8, ARG10) were selected to evaluate their anti-tumor activity in vivo at a dosage of 40 mg/kg. The results indicated that ARG8 and ARG10 both exhibit more anti-tumor activity than ARG in H22 tumor-bearing mice. The tumor inhibition rates of ARG8 and ARG10 were 69.27 and 43.58%, which was much higher than ARG. Furthermore, the mice treated with these compounds exhibited less damage to the liver, kidney and immune organs compared with the positive group. Furthermore, ARG8 and ARG10 improved the serum cytokine levels significantly compared to ARG. In brief, this study provides a method to improve the water solubility of drugs, and we also provide a reference basis for new drug development.

The clinical significance of CDK1 expression in oral squamous cell carcinoma.

OBJECTIVES: To evaluate the clinical significance of cyclin-dependent kinase 1 (CDK1) in 77 oral squamous cell carcinomas (OSCC) using immunohistochemical methods. STUDY DESIGN: Immunohistochemical expression of CDK1 was compared with various clinicopathological features in 77 OSCC and 60 controlled epithelia adjacent to the tumours. In addition, correlation of CDK1 expression and prognostic and the 5-year accumulative survival rate of OSCC were investigated. RESULTS: The CDK1 protein was expressed in 52 cases of 77 tumor tissues (67.5%), compared with 21 cases of 60 controlled (35.0%). The expression of CDK1 was significantly correlated with the histological grade of OSCC (P<0.05). The CDK1 protein was over-expressed in recurrent tumors or in those with lymph node metastasis. Statistical analysis showed a significant reduction in the 5-year accumulative survival rate in CDK1 positive cases compared with CDK1 negative cases (P<0.05). Namely, the CDK1 positive patients had poor prognosis. CONCLUSIONS: The expression of CDK1 might serve as malignant degree and prognostic markers for the survival of OSCC.

Creating one-dimensional nanoscale periodic ripples in a continuous mosaic graphene monolayer.

In previous studies, it has proved difficult to realize periodic graphene ripples with wavelengths of a few nanometers. Here we show that one-dimensional (1D) periodic graphene ripples with wavelengths from 2 nm to tens of nanometers can be implemented in the intrinsic areas of a continuous mosaic (locally N-doped) graphene monolayer by simultaneously using both the thermal strain engineering and the anisotropic surface stress of the Cu substrate. Our result indicates that the constraint imposed at the boundaries between the intrinsic and the N-doped regions play a vital role in creating these 1D ripples. We also demonstrate that the observed rippling modes are beyond the descriptions of continuum mechanics due to the decoupling of graphene's bending and tensional deformations. Scanning tunneling spectroscopy measurements indicate that the nanorippling generates a periodic electronic superlattice and opens a zero-energy gap of about 130 meV in graphene. This result may pave a facile way for tailoring the structures and electronic properties of graphene.

[Short-term follow up of treatment effect using one-time one-abutment placement in implant restoration in 35 patients with single posterior teeth loss].

PURPOSE: To evaluate the effet of one-time one-abutment placement on peri-implant tissues. METHODS: Thirty-five patients with single posterior loss were collected, who received definitive abutment at the moment of implant placement. One day and after 1 year of implant loading, radiographic assessment of marginal bone level changes and clinical status of peri-implant soft tissues were conducted. Plaque index, pocket depth as well as sulcus bleeding index were assessed. RESULTS: During 1 year follow-up period after loading, no implant failure was observed. The mean marginal bone loss of implants were (0.225±0.113) mm mesially and (0.439±0.123) mm distally. Standard periodontal probes were used to measure plaque index, probing depth, and gingival crevicular bleeding index immediately after repair and 1 year later. CONCLUSIONS: In the posterior region, one-time one-abutment placement may better protect peri-implant tissues as an ideal treatment protocol.

Analysis of the integrated role of the Yangtze River Delta based on the industrial economic resilience of cities during COVID-19.

The enhancement of regional comprehensive development ability is significantly impacted by the study on the implementation effect of regional integration strategies. The integration strategy's impact on urban development during COVID-19 in the Yangtze River Delta(YRD) is unclear. According to prior industrial transfer theory, Hefei, Anhui's capital, is difficult to transfer industries, and other YRD cities push industry integration in Anhui. This study employs the theory of economic and land resource use to examine the resilience of the industrial economy during an epidemic by using industrial land as a representation of industrial economic development. The three cities in Anhui-Wuhu, Maanshan, and Chuzhou (Wu-ma-Chu) were selected as the research area. The study employed the UNet deep learning method to detect the land use types in Wu-ma-Chu. The land transfer matrix and the standard deviation ellipse were utilised to research the alterations in industrial land use and the spatial distribution of industrial output value, respectively. The results showed that the industrial land in Machu continued to grow during the outbreak, highlighting the resilience of the region's industrial economy. During 2019-2022, the elliptical ring of industrial output value is distributed in Nanjing, revealing the radiating role of Nanjing in integrating into the integration of the YRD. This confirms China's YRD integration strategy, strengthens regional economic resilience, and encourages coordinated regional economic development.

Changes in α-Dicarbonyl Compound Contents during Storage of Various Fruits and Juices.

α-Dicarbonyl compounds (α-DCs) are commonly present in various foods. We conducted the investigation into concentration changes of α-DCs including 3-deoxyglucosone (3-DG), glyoxal (GO), and methylglyoxal (MGO) in fresh fruits and decapped commercial juices during storage at room temperature and 4 °C, as well as in homemade juices during storage at 4 °C. The studies indicate the presence of α-DCs in all samples. The initial contents of 3-DG in the commercial juices (6.74 to 65.61 µg/mL) are higher than those in the homemade ones (1.97 to 4.65 µg/mL) as well as fruits (1.58 to 3.33 µg/g). The initial concentrations of GO and MGO are normally less than 1 µg/mL in all samples. During storage, the α-DC levels in the fruits exhibit an initial increase followed by a subsequent decrease, whereas, in all juices, they tend to accumulate continuously over time. As expected, 4 °C storage reduces the increase rates of the α-DC concentrations in most samples. From the viewpoint of the α-DC contents, fruits and homemade juices should always be the first choice for daily intake of nutrients and commercial juices ought to be mostly avoided.

Formal synthesis of cephalotaxine.

A formal synthesis of cephalotaxine, the parent member of the Cephalotaxus alkaloids, was achieved. It features a practical four-step assembly of the benzazepine-bearing pentacyclic ring system through two alkylation reactions, acidic hydrolysis, and aldolization.

Screening of potential pseudo att sites of Streptomyces phage ΦC31 integrase in the human genome.

AIM: ΦC31 integrase mediates site-specific recombination between two short sequences, attP and attB, in phage and bacterial genomes, which is a promising tool in gene regulation-based therapy since the zinc finger structure is probably the DNA recognizing domain that can further be engineered. The aim of this study was to screen potential pseudo att sites of ΦC31 integrase in the human genome, and evaluate the risks of its application in human gene therapy. METHODS: TFBS (transcription factor binding sites) were found on the basis of reported pseudo att sites using multiple motif-finding tools, including AlignACE, BioProspector, Consensus, MEME, and Weeder. The human genome with the proposed motif was scanned to find the potential pseudo att sites of ΦC31 integrase. RESULTS: The possible recognition motif of ΦC31 integrase was identified, which was composed of two co-occurrence conserved elements that were reverse complement to each other flanking the core sequence TTG. In the human genome, a total of 27924 potential pseudo att sites of ΦC31 integrase were found, which were distributed in each human chromosome with high-risk specificity values in the chromosomes 16, 17, and 19. When the risks of the sites were evaluate more rigorously, 53 hits were discovered, and some of them were just the vital functional genes or regulatory regions, such as ACYP2, AKR1B1, DUSP4, etc. CONCLUSION: The results provide clues for more comprehensive evaluation of the risks of using ΦC31 integrase in human gene therapy and for drug discovery.

The interaction of banana MADS-box protein MuMADS1 and ubiquitin-activating enzyme E-MuUBA in post-harvest banana fruit.

KEY MESSAGE : The interaction of MuMADS1 and MuUBA in banana was reported, which will help us to understand the mechanism of the MADS-box gene in regulating banana fruit development and ripening. The ubiquitin-activating enzyme E1 gene fragment MuUBA was obtained from banana (Musa acuminata L.AAA) fruit by the yeast two-hybrid method using the banana MADS-box gene MuMADS1 as bait and 2-day post-harvest banana fruit cDNA library as prey. MuMADS1 interacted with MuUBA. The interaction of MuMADS1 and MuUBA in vivo was further proved by bimolecular fluorescence complementation assay. Real-time quantitative PCR evaluation of MuMADS1 and MuUBA expression patterns in banana showed that they are highly expressed in the ovule 4 stage, but present in low levels in the stem, which suggests a simultaneously differential expression action exists for both MuMADS1 and MuUBA in different tissues and developmental fruits. MuMADS1 and MuUBA expression was highly stimulated by exogenous ethylene and suppressed by 1-methylcyclopropene. These results indicated that MuMADS1 and MuUBA were co-regulated by ethylene and might play an important role in post-harvest banana fruit ripening.

[Combined use of occluder plus bare stent in the treatment of aortic dissection with tear at the area of visceral branches].

OBJECTIVE: To evaluate the novel method of combinedly use of occluder and bare stent in the treatment of aortic dissection with distal tear at visceral branches. METHODS: From April 2010 to September 2012, 6 patients (5 male and 1 female patients, aged from 29 to 62 years, mean 47.2 years) were diagnosed as Stanford type B aortic dissection that been revealed by CT angiography. The main tears were sealed with stent-grafts firstly, and then the tears at the visceral branch area were evaluated that impossible to close spontaneously. Atrium septal defect occluder and ventricular septal defect were implanted at the tears with the anterior disc in false lumen, while the posterior disc in the true lumen. After that, the bare stents were implanted in the true lumen to pull the occluders on the aortic wall. RESULTS: Among the 6 procedures, occluders were successfully implanted in 5 cases, and 1 failed anchoring at the tear, and the alternative method of coils embolization was applicated. After all the procedures, the immediate aortogrophy revealed that the false lumen disappeared in the 5 cases that occluders were used, and the visceral branches were all patent. No paraplegia, lesion of visceral organs or other complications occurred. All the cases were followed at least 5 months. There was one endoleak due to a non-sealed tear at the descending aorta, one new-occurred small tear in the descending aorta but with no communication to the false lumen. CONCLUSIONS: The combinedly use of occluder and bare stent in the treatment of aortic dissection with tears at the visceral branch area is a sum of two simple technique plus each other. It is easily to master. The lesions at the aortic that ordinary stent-grafting incapable to seal are successfully solved then. The huge trauma of open or hybrid procedures are avoided.

[Tissue culture of medicinal plant and abscisic acid].

Abscisic acid (ABA) plays a key role in many physiological processes of plants, and it was also applied to fields of medicinal plant biotechnology. The article presents a review of some recent application of ABA in enhancing the production of secondary metabolites of medicinal plants, improving the in vitro conservation in medicinal plant tissue culture system.