Guided diffusion for molecular generation with interaction prompt.

Molecular generative models have exhibited promising capabilities in designing molecules from scratch with high binding affinities in a predetermined protein pocket, offering potential synergies with traditional structural-based drug design strategy. However, the generative processes of such models are random and the atomic interaction information between ligand and protein are ignored. On the other hand, the ligand has high propensity to bind with residues called hotspots. Hotspot residues contribute to the majority of the binding free energies and have been recognized as appealing targets for designed molecules. In this work, we develop an interaction prompt guided diffusion model, InterDiff to deal with the challenges. Four kinds of atomic interactions are involved in our model and represented as learnable vector embeddings. These embeddings serve as conditions for individual residue to guide the molecular generative process. Comprehensive in silico experiments evince that our model could generate molecules with desired ligand-protein interactions in a guidable way. Furthermore, we validate InterDiff on two realistic protein-based therapeutic agents. Results show that InterDiff could generate molecules with better or similar binding mode compared to known targeted drugs.

Clinical Application and Research Progress of Remimazolam for Pediatric Patients.

Remimazolam is a novel ultrashort-acting benzodiazepine that allosterically modulates γ-aminobutyric acid type A (GABAA) receptors to exert sedative effects. Remimazolam has the properties of controllable sedation, rapid onset, and a short duration of action, along with minor depression of circulation and respiration. Remimazolam has been approved for clinical use since 2020 in Japan, and it has been applied for procedural sedation, general anesthesia induction and maintenance, and sedation in ICU patients, and has been proven to be safe and effective. Currently, no consensus has been reached on the clinical application of remimazolam in pediatric patients. This review introduces the clinical research progress and limitations of remimazolam in recent years, aiming to supply scientific guidance and a theoretical reference for the application of remimazolam in pediatric anaesthesia.

What is China's efficient power generation portfolio under carbon neutrality target? An empirical analysis considering flexibility and system cost.

Variable renewable energy (VRE) is the most promising form of primary generation under a carbon neutrality target due to its environmental benefits, incentive policy, and technological progress. However, the increasing proportion of VRE generation, such as solar and wind power, has sharply increased integration cost and reduced power grid stability. This study uses portfolio theory to investigate China's optimal power generation portfolio by 2050 considering flexibility constraint and system cost, including technical and integration costs. The results demonstrate that non-fossil-fuel power generation technologies have cost and emission reduction advantages over fossil-fuel-based technologies. VRE generation technologies must be developed in synergy with other forms of power generation when considering flexibility requirement and integration cost. A complete phase-out of fossil-fuel power generation technologies in China appears unlikely in the study period. Gas-fired and coal-fired power generation are the pillar forms of power generation to meet future flexibility needs.

Predicting Mutational Effects on Ca2+-Activated Chloride Conduction of TMEM16A Based on a Simulation Study.

The dysfunction and defects of ion channels are associated with many human diseases, especially for loss-of-function mutations in ion channels such as cystic fibrosis transmembrane conductance regulator mutations in cystic fibrosis. Understanding ion channels is of great current importance for both medical and fundamental purposes. Such an understanding should include the ability to predict mutational effects and describe functional and mechanistic effects. In this work, we introduce an approach to predict mutational effects based on kinetic information (including reaction barriers and transition state locations) obtained by studying the working mechanism of target proteins. Specifically, we take the Ca2+-activated chloride channel TMEM16A as an example and utilize the computational biology model to predict the mutational effects of key residues. Encouragingly, we verified our predictions through electrophysiological experiments, demonstrating a 94% prediction accuracy regarding mutational directions. The mutational strength assessed by Pearson's correlation coefficient is -0.80 between our calculations and the experimental results. These findings suggest that the proposed methodology is reliable and can provide valuable guidance for revealing functional mechanisms and identifying key residues of the TMEM16A channel. The proposed approach can be extended to a broad scope of biophysical systems.

Optimizing rice grain size by attenuating phosphorylation-triggered functional impairment of a chromatin modifier ternary complex.

Histone acetylation affects numerous cellular processes, such as gene transcription, in both plants and animals. However, the posttranslational modification-participated regulatory networks for crop-yield-related traits are largely unexplored. Here, we characterize a regulatory axis for controlling rice grain size and yield, centered on a potent histone acetyltransferase (chromatin modifier) known as HHC4. HHC4 interacts with and forms a ternary complex with adaptor protein ADA2 and transcription factor bZIP23, wherein bZIP23 recruits HHC4 to specific promoters, and ADA2 and HHC4 additively enhance bZIP23 transactivation on target genes. Meanwhile, HHC4 interacts with and is phosphorylated by GSK3-like kinase TGW3. The resultant phosphorylation triggers several functional impairments of the HHC4 ternary complex. In addition, we identify two major phosphorylation sites of HHC4 by TGW3-sites which play an important role in controlling rice grain size. Overall, our findings thus have critical implications for understanding epigenetic basis of grain size control and manipulating the knowledge for higher crop productivity.

Mechanistic study of the transmission pattern of the SARS-CoV-2 omicron variant.

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID-19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike-angiotensin-converting enzyme-2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse-grained model. Our study extended beyond the receptor-binding domain (RBD) of spike trimer through comprehensive modeling of the full-length spike trimer rather than just the RBD. Our free-energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full-length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

Genetic associations with longevity are on average stronger in females than in males.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

IL-22 relieves hepatic ischemia-reperfusion injury by inhibiting mitochondrial apoptosis based on the activation of STAT3.

INTRODUCTION: Interleukin-22 (IL-22) has been proven to exhibit a protective role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to explore the change of IL-22 and IL-22 receptor 1 (IL-22R1) axis in HIRI and its role in mitochondrial apoptosis associated with STAT3 activation. MATERIALS AND METHODS: I/R mice were examined for the expression of IL-22, IL-22R1 and IL-22BP. The roles of IL-22 in hepatic histopathology and oxidative stress injuries (ALT, MDA and SOD) were determined. Oxidative stress damages of AML-12 cells were induced by H2O2, and were indicated by apoptosis, Ca2+ concentration, and mitochondrial function. The effects of IL-22 on p-STAT3Try705 were analyzed. RESULTS: We found that the expression of IL-22, IL-22R1, and IL-22BP was elevated 24 h after I/R induction, while decreased 48 h after I/R induction. Furthermore, we also discovered that IL-22 rescued the morphological damages and dysfunction of hepatocytes induced by H2O2, which were antagonized by IL-22BP, an endogenous antagonist of IL-22. Additionally, increased levels of Ca2+ concentration, MDA, ROS, apoptosis and mitochondrial dysfunction were noticed in H2O2-treated hepatocytes. However, IL-22 ameliorated the effects of I/R or H2O2. The protective effects of IL-22 were reversed by AG490, a specific antagonist of STAT3. CONCLUSIONS: In conclusion, our results indicated that IL-22 inhibited I/R-induced oxidative stress injury, Ca2+ overload, and mitochondrial apoptosis via STAT3 activation.

Outcomes of Mitral Valve Repair for Degenerative Mitral Disease: A Single-Centre 10-Year Experience.

OBJECTIVE: To evaluate the long-term outcomes of degenerative mitral valve (MV) repair. METHODS: This study analysed 1,069 patients who underwent MV repair due to degenerative MV disease at Beijing Anzhen Hospital from January 2010 to December 2019. All patients were clinically followed until December 2019, with an average follow-up period of 4.7 years. Perioperative complications, 30-day mortality, long-term outcomes, and risk factors of all-cause death and recurrent mitral regurgitation (MR) were summarised. RESULTS: Ten patients died in the hospital and 33 died during the follow-up period. Recurrent MR occurred in 113 patients. Fourteen patients underwent re-operation. Rates of long-term survival, absence of recurrent MR, and no re-operation were 94.0% (91.6%-96.6%), 81.2% (77.3%-85.3%), and 98.2% (97.2%-99.3%), respectively. The risk factors for long-term all-cause death included age and an ejection fraction (EF) <60%. The risk factors for recurrent MR included age, female sex, E-wave velocity, anterior prolapse, residual 1+MR postoperatively, and lower body mass index. CONCLUSIONS: Mitral valve repair is an effective treatment for degenerative MV disease that, in an experienced heart centre, can be performed with low mortality, recurrence, and re-operation rates. Advanced age and an EF <60% were risk factors for long-term all-cause death. Age, female sex, residual 1+MR postoperatively, lower body mass index, higher peak E-wave velocity, and anterior prolapse were risk factors for recurrent MR.

Potential modulating effects of Allium mongolicum regel ethanol extract on rumen fermentation and biohydrogenation bacteria of dairy cows in vitro.

The objective of this study was to evaluate the potential modulating effects of Allium mongolicum regel ethanol extract (AME) on rumen fermentation and biohydrogenation (BH) bacteria in vitro. Four Holstein cows were used as donors for the rumen fluid used in this study. In experiment 1, five treatments (supplemented with 0 mg/g, 1 mg/g, 2 mg/g, 3 mg/g, and 4 mg/g of AME based on fermentation substrate, respectively) were conducted to evaluate the effects of different levels of AME on fermentation status in vitro. The results showed that after 24 h of fermentation, MCP was reduced with AME supplementation (p < 0.05), and the multiple combinations of different combinations index (MFAEI) value was the highest with 3 mg/g of AME. In experiment 2, six treatments were constructed which contained: control group (A1); the unsaturated fatty acid (UFA) mixture at 3% concentration (A2); the mixture of A2 and 3 mg/g of AME (A3); 3 mg/g of AME (A4); the UFA mixture at 1.5% concentration (A5); the mixture of A5 and 3 mg/g of AME (A6). The abundance of bacterial species involved in BH was measured to evaluate the potential modulating effect of AME on rumen BH in vitro. Compared with the A1 group, the A3, A4, and A6 groups both showed significant decreases in the abundance of rumen BH microbial flora including Butyrivibrio proteoclasticus, Butyrivibrio fibrisolvens, Ruminococcus albus and Clostridium aminophilum (p < 0.01). The A3 group was less inhibitory than A4 in the abundance of B. proteoclasticus, B. fibrisolvens, and R. albus, and the inhibitory effect of the A6 group was higher than that of A4. In conclusion, the supplementation with 3 mg/g of AME could modulate the rumen fermentation and affect BH key bacteria, which suggests that AME may have the potential to inhibit the rumen BH of dairy cows.

Synthesis, structure and characterization of Cd2TeO3Cl2 with unprecedented [Cd2O6Cl4] octahedral dimers.

A new mixed anionic compound Cd2TeO3Cl2 with unprecedented [Cd2O6Cl4] octahedral dimers has been synthesized, and millimeter-scale single crystals of Cd2TeO3Cl2 have been grown by the vertical Bridgman method with CdCl2 as the flux. Cd2TeO3Cl2 crystallizes in the centrosymmetric P1̄ (no. 2) space group, and shows a mixed cationic layer structure constituted by distorted [TeO3] motifs, mixed anionic [Cd2O6Cl4] chains, and [Cd2O6Cl4] octahedral dimers. Experimental and theoretical results show that Cd2TeO3Cl2 is a direct band gap compound with an experimental band gap of ∼4.25 eV. Meanwhile, the compound has good optical transmittance in the 3-5 µm atmospheric window. The results indicate that Cd2TeO3Cl2 could be used as a promising mid-IR window material, and could enrich the chemical and structural diversity of oxides.

Serum Vitamin D3 Concentration, Sleep, and Cognitive Impairment among Older Adults in China.

BACKGROUND: Cognitive decline in older adults has become one of the critical challenges to global health. This study aims to examine both cross-sectional and longitudinal associations of levels of serum 25-hydroxyvitamin D3 (25(OH)D3) (briefed as VD3) concentration and sleep quality/duration, especially their interactions, with risk of cognitive impairment among older adults in China. METHODS: We utilized a special subsample of adults aged 65-105 years (individuals = 3412, observations = 4816) from eight provinces in China derived from the 2011/2012 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey. Cognitive impairment was measured by the Mini-Mental State Examination scale. Sleep quality was classified as good versus fair/poor, and sleep duration was classified into short (<7 h), normal (≥7 but <9 h), and long (≥9 h). The VD3 concentration was divided into three levels: deficiency (VD3 < 25 nmol/L), insufficiency (25 nmol/L ≤ VD3 < 50 nmol/L), and sufficiency (VD3 ≥ 50 nmol/L). A wide set of covariates that include demographics, socioeconomic status, family support, health practice, and health conditions was adjusted for robust findings. Multilevel random intercept logit regression models were used to examine the cross-sectional associations between VD3, sleep, and cognitive impairment, whereas logit regression models were applied to investigate the longitudinal associations. RESULTS: In the cross-sectional analyses, when all covariates were adjusted, VD3 sufficiency was significantly associated with a 33% lower risk of cognitive impairment compared with VD3 deficiency; good sleep quality was associated with 34% lower odds of cognitive impairment compared with fair/poor sleep quality; sleep hours were not associated with cognitive impairment, although a long sleep duration (≥9 h) was associated with 30% higher odds of being cognitively impaired when baseline health was not controlled. Interaction analyses reveal that VD3 sufficiency could help to additionally reduce the risk of cognitive impairment for good sleep quality and normal sleep hours. In the longitudinal analyses, the association of VD3 sufficiency remains significant, whereas sleep quality and sleep duration were not significant associates. CONCLUSIONS: Good sleep quality, normal sleep hours, and VD3 sufficiency are positively associated with good cognitive function. VD3 sufficiency could enhance the associations between sleep and cognitive impairment.

Characterization of the angular memory effect of dynamic turbid media.

The optical angular memory effect (AME) is a basic feature of turbid media and defines the correlation of speckles when the incident light is tilted. AME based imaging through solid scattering media such as ground glass and biomedical tissue has been recently developed. However, in the case of liquid media such as turbid water or blood, the speckle pattern exhibits dynamic time-varying characteristics, which introduces several challenges. The AME of the thick volume dynamic media is particularly different from the layer scatterers. In practice, there are more parameters, e.g., scattering particle size, shape, density, or even the illuminating beam aperture that can influence the AME range. Experimental demonstration of AME phenomenon in liquid dynamic media and confirm the distinctions will contribution to complete the AME theory. In this paper, a dual-polarization speckle detection setup was developed to characterize the AME of dynamic turbid media, where two orthogonal polarized beams were employed for simultaneous detection by a single CCD. The AME of turbid water, milk and blood were measured. The influence of thickness, concentration, particle size and shape, and beam diameter were analyzed. The AME increasement of upon the decrease of beam diameter was tested and verified. The results demonstrate the feasibility of this method for investigating the AME phenomenon and provide guidance for AME based imaging through scattering media.

Association analysis of agronomic traits and construction of genetic networks by resequencing of 306 sugar beet (Beta vulgaris L.) lines.

Due to the relatively brief domestication history of sugar beet (Beta vulgaris ssp. vulgaris), our understanding of the genomic diversity and functional genes in its cultivars is limited, resulting in slow breeding progress. To address this issue, a total of 306 germplasm materials of major cultivars and breeding lines from China, the USA, and Europe were selected for genome resequencing. We investigated population structure and genetic diversity and performed selective scanning of genomic regions, identifying six novel genes associated with important agronomic traits: the candidate genes DFAX2 and P5CS for skin roughness; the candidate genes FRO5, GL24, and PPR91 for root yield and sugar yield, and the pleiotropic candidate gene POLX for flourishing growth vigour, plant height, crown size, flesh coarseness, and sugar yield. In addition, we constructed a protein-protein interaction network map and a phenotype-gene network map, which provide valuable information for identifying and characterizing functional genes affecting agronomic traits in sugar beet. Overall, our study sheds light on the future improvement of sugar beet agronomic traits at the molecular level.

Bibliometric and visualized analysis of myopic corneal refractive surgery research: from 1979 to 2022.

Background: Myopic corneal refractive surgery is one of the most prevalent ophthalmic procedures for correcting ametropia. This study aimed to perform a bibliometric analysis of research in the field of corneal refractive surgery over the past 40 years in order to describe the current international status and to identify most influential factors, while highlighting research hotspots. Methods: A bibliometric analysis based on the Web of Science Core Collection (WoSCC) was used to analyze the publication trends in research related to myopic corneal refractive surgery. VOSviewer v.1.6.10 was used to construct the knowledge map in order to visualize the publications, distribution of countries, international collaborations, author productivity, source journals, cited references, keywords, and research hotspots in this field. Results: A total of 4,680 publications on myopic corneal refractive surgery published between 1979 and 2022 were retrieved. The United States has published the most papers, with Emory University contributing to the most citations. The Journal of Cataract and Refractive Surgery published the greatest number of articles, and the top 10 cited references mainly focused on outcomes and wound healing in refractive surgery. Previous research emphasized "radial keratotomy (RK)" and excimer laser-associated operation methods. The keywords containing femtosecond (FS) laser associated with "small incision lenticule extraction (SMILE)" and its "safety" had higher burst strength, indicating a shift of operation methods and coinciding with the global trends in refractive surgery. The document citation network was clustered into five groups: (1) outcomes of refractive surgery: (2) preoperative examinations for refractive surgery were as follows: (3) complications of myopic corneal refractive surgery; (4) corneal wound healing and cytobiology research related to photorefractive laser keratotomy; and (5) biomechanics of myopic corneal refractive surgery. Conclusion: The bibliometric analysis in this study may provide scholars with valuable to information and help them better understand the global trends in myopic corneal refractive surgery research frontiers. Two stages of rapid development occurred around 1991 and 2013, shortly after the innovation of PRK and SMILE surgical techniques. The most cited articles mainly focused on corneal wound healing, clinical outcomes, ocular aberration, corneal ectasia, and corneal topography, representing the safety of the new techniques.

Insights into the Inhibitory Mechanisms of the Covalent Drugs for DNMT3A.

The perturbations of DNA methyltransferase 3 alpha (DNMT3A) may cause uncontrolled gene expression, resulting in cancers and tumors. The DNMT inhibitors Azacytidine (AZA) and Zebularine (ZEB) inhibit the DNMT family with no specificities, and consequently would bring side effects during the treatment. Therefore, it is vital to understand the inhibitory mechanisms in DNMT3A to inform the new inhibitor design for DNMTs. Herein, we carried out molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the inhibitory mechanisms of the AZA and ZEB. The results were compared to the methyl transfer of cytosine. We showed how the AZA might stop the methyl transfer process, whereas the ZEB might be stuck in a methyl-transferred intermediate (IM3). The IM3 state then fails the elimination due to the unique protein dynamics that result in missing the catalytic water chain. Our results brought atomic-level insights into the mechanisms of the two drugs in DNMT3A, which could benefit the new generation of drug design for the DNMTs.

Integrating ATAC-seq and RNA-seq to identify differentially expressed genes with chromatin-accessible changes during photosynthetic establishment in Populus leaves.

Leaves are the primary photosynthetic organs, providing essential substances for tree growth. It is important to obtain an anatomical understanding and regulatory network analysis of leaf development. Here, we studied leaf development in Populus Nanlin895 along a development gradient from the newly emerged leaf from the shoot apex to the sixth leaf (L1 to L6) using anatomical observations and RNA-seq analysis. It indicated that mesophyll cells possess obvious vascular, palisade, and spongy tissue with distinct intercellular spaces after L3. Additionally, vacuoles fuse while epidermal cells expand to form pavement cells. RNA-seq analysis indicated that genes highly expressed in L1 and L2 were related to cell division and differentiation, while those highly expressed in L3 were enriched in photosynthesis. Therefore, we selected L1 and L3 to integrate ATAC-seq and RNA-seq and identified 735 differentially expressed genes (DEGs) with changes in chromatin accessibility regions within their promoters, of which 87 were transcription factors (TFs), such as ABI3VP1, AP-EREBP, MYB, NAC, and GRF. Motif enrichment analysis revealed potential regulatory functions for the DEGs through upstream TFs including TCP, bZIP, HD-ZIP, Dof, BBR-BPC, and MYB. Overall, our research provides a potential molecular foundation for regulatory network exploration in leaf development during photosynthesis establishment.

Outcome of mitral repair combined with Cox-maze procedure for atrial functional mitral regurgitation with heart failure with recovered ejection fraction.

OBJECTIVES: Atrial functional mitral regurgitation (AFMR) in patients with heart failure with recovered ejection fraction has received insufficient attention. This study analysed the prognosis and outcomes of mitral valve (MV) repair combined with the Cox-maze procedure. METHODS: A prospective cohort study of patients with AFMR with left ventricular ejection fraction (LVEF) <40% was conducted. All patients received guideline-directed medical therapy. Those with recovered ejection fraction underwent MV repair combined with the Cox-maze procedure. Mortality, atrial fibrillation (AF) recurrence, mitral regurgitation (MR) and postoperative tricuspid regurgitation were assessed using the inverse probability weighting (IPW) method. RESULTS: In total, 312 patients were enrolled in this study between 2010 and 2019, 247 of whom underwent MV repair combined with the Cox-maze procedure [full recovery (LVEF > 50%): n = 132, partial recovery (LVEF of 40-50%): n = 115]. IPW-adjusted survival of patients with LVEF ≥50% and LVEF 40-50% showed no significant difference [hazard ratio (HR): 2.18, 95% confidence interval: 0.46-10.38, P = 0.33]. However, patients with LVEF ≥50% had better IPW-adjusted long-term freedom from recurrent MR [HR: 2.44 (1.28-4.63), P = 0.0065] and AF recurrence [HR: 1.85 (1.06-3.21), P = 0.030] than those with LVEF of 40-50%. CONCLUSIONS: MV repair combined with the Cox-maze procedure was effective and feasible in patients with severe AFMR with heart failure with recovered ejection fraction. Additionally, patients with LVEF ≥50% after guideline-directed medical therapy undergoing these combined procedures had better long-term freedom from recurrent AF and MR than those with LVEF of 40-50%.

Catalytic asymmetric indolization by a desymmetrizing [3 + 2] annulation strategy.

A new catalytic asymmetric indolization reaction by a desymmetrizing [3 + 2] annulation strategy is developed. The reaction proceeds via a rhodium-catalyzed enantioposition-selective addition/5-exo-trig cyclization/dehydration cascade between ortho-amino arylboronic acids and 2,2-disubstituted cyclopentene-1,3-diones to produce N-unprotected cyclopenta[b]indoles bearing an all-carbon quaternary stereocenter in high yields with good enantioselectivities. A quantitative structure-selectivity relationship (QSSR) model was established to identify the optimal chiral ligand, which effectively controlled the formation of the stereocenter away from the reaction site. Density functional theory (DFT) calculations, non-covalent interaction analysis, and Eyring analysis were performed to understand the key reaction step and the function of the ligand.

Reveal the Patterns of Prescriptions for Recurrent Respiratory Tract Infections' Treatment Based on Multiple Illustrious Senior Traditional Chinese Medicine Practitioners.

Background: Recurrent respiratory tract infections (RRTIs) are one of the most common diseases in children and adolescents. The causes of RRTIs are various. In addition to the factors related to infection, basic diseases such as respiratory system, immune system, and digestive system are also involved. The cost of patients' frequent medical treatment and hospitalization has been deemed to be a heavy burden to the society and family. In China, traditional Chinese medicine (TCM) is commonly used to treat RRTIs. TCM treatment has been appraised to be effective, for reducing the number of hospital stays. Illustrious senior TCM practitioners of pediatrics are recognized as a group of outstanding physicians with significantly better patient outcomes. However, different illustrious senior TCM practitioners can lead to differences in treatment strategies due to factors such as region, prescription theory, and individual differences of patients. This makes it difficult for the experience of illustrious senior TCM practitioners to be popularized. However, there have been no prescription mining studies for the treatment of RRTIs based on different and multiple illustrious senior TCM practitioners. We explored the core prescriptions and drug mechanisms through data mining based on the prescriptions of illustrious senior TCM practitioners treating RRTIs from different clinical settings. This is important to promote the effective treatment of RRTIs with TCM. The objective of this study is to reveal the strategies (core prescriptions) from the prescriptions of multiple illustrious senior TCM practitioners for the treatment of RRTIs. We hope that this core prescription can help all TCM pediatricians to improve RRTIs children's outcome. Meanwhile, it could provide a new way for researchers to study the treatment of RRTIs. Methods: In this study, we prospectively collected 400 children's prescriptions with RRTIs receiving TCM treatment from four illustrious senior TCM practitioners in different hospitals. We described and analyzed the characteristics of TCM prescriptions. The prescription regularity was analyzed by hierarchical clustering and association rules. Network pharmacology methods has been used to reveal the pathway mechanism of core prescriptions which have been mined and visualized with the help of SymMap, Genecards, KEGG, Metascape databases, and R. The execution of all methods was completed in May 2022. Results: According to RRTIs multiple clinical syndromes, five new prescriptions were obtained based on illustrious senior TCM practitioners. Among them, the prescription composed of Scutellariae radix (Huangqin), Armeniacae semen amarum (Kuxingren), Peucedani radix (Qianhu), and Pheretima (Dilong) is the core strategy for the treatment of RRTIs. Cold herbs and heat herbs in the core prescription are approximately equal. Scutellariae radix (Huangqin) was dominant, and other herbs exert synergistic effects. The core prescription covered 76 pathways and 226 herb-disease genes. It promotes the differentiation of Th1, Th2, and Th17 cells and the secretion of inflammatory factors through toll-like receptor signaling pathway in the immune system, T cell receptor signaling pathway, and PPAR signaling pathway in the endocrine system, thereby exerting immune regulation and anti-inflammation. Conclusion: In this study, we revealed the prescription regularity of TCM in the treatment of RRTIs and analyzed the mechanism of core prescriptions, which provided new ideas for the treatment of RRTIs.